DD239210A5 - PROCESS FOR PREPARING NEW 5-AMINO-4-HYDROXYVALERYL DERIVATIVES - Google Patents

Abstract

Described is a process for the preparation of compounds of formula I, wherein R 1 is hydrogen or acyl, A is an optionally N-alkylated a-amino acid residue which is N-terminally connected to R 1 and C-terminal to the group -NR 2 -, R 2 is hydrogen or Lower alkyl, R3 is hydrogen, lower alkyl, optionally etherified or esterified hydroxy, lower alkyl, cycloalkyl, Cycloalkylliederalkyl, Bicycloalkylniederalkyl, Tricycloalkylniederalkyl, aryl or Arylniederalkyl, R4 hydroxy, veraethertes or esterified hydroxy, R5 lower alkyl having 2 and more carbon atoms, etherified veraethertes or or esterified Hydroxyniederalykl, 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 and R6 substituted amino, and salts of such V compounds with salt-forming groups. These compounds inhibit the hypertensive effect of the enzyme renin and can be used as antihypertensives.

Description

Field of application of the invention

The invention relates to a process for the preparation of novel 5-amino-4-hydroxyvalerylderivate with valuable pharmacological properties. The compounds prepared according to the invention inhibit the action of the enzyme renin and can be used as antihypertensives and for the treatment of cardiac insufficiency.

Characteristic of known technical solutions European Patent Application 118 223 (corresponding to PCT Application 84/03044) describes tetra-, penta- and hexapeptide analogs which likewise inhibit the action of the enzyme renin. These peptide analogs contain as a central unit an analog of a dipeptide in which the peptide bond has been replaced by a 1- to 4-carbon bridge or carbon-nitrogen bridge, flanked by 1-2 aromatic, lipophilic or even basic amino acid residues ,

There is a further need for compounds that inhibit the action of the enzyme renin and can be used as antihypertensives.

Object of the invention

The object of the invention is to provide a process for the preparation of novel S-amino-hydroxyvaleryl derivatives which inhibit the action of the enzyme renin.

4 I Λ η Λ

-Ia-

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 novel 5-amino-4-hydroxyvalerylderivate de ~ formula

R _{1 is} -AN-CH-CH-CH ₂ -CH-CR ₆ (I),

wherein Ri is hydrogen or acyl except for an optionally N-substituted acyl radical of a natural amino acid, A is an optionally N-alkylated a-amino acid residue which is N-terminally attached to Rj 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, Ri, hydroxy, etherified or esterified hydroxy, R5 lower alkyl having 2 or more carbon atoms, 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 and Re substituted amino except one of of α-amino acid-derived amino groups, further prepared salts of such compounds having salt-forming groups.

_ ₂ _ 239

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 defined otherwise, include up to and including 7, and preferably up to and including 4 carbon atoms.

The C atoms substituted by R3, Ri ₊ and R5 can 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 1 have the S configuration.

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

For example, acyl Ri has up to 19 carbon atoms and is primarily the acyl group of a carboxylic acid, a carbonic half-ester, an optionally N-substituted carbamic or thiocarbamic acid, an optionally N-substituted oxalamide, a sulfonic acid or an optionally N-substituted one sulfamic acid, for example the sub-formulas R -CO-, R -0-C0-, (R ^b) (R ^b) N-CO-, (R ^b) (R ^b) N-CS- (R ^b) (R ^b ) N-CO-CO-, R ^b -SO ₂ - or (R) (R) N-SO ₂ ~, where R is an unsubstituted or substituted, saturated or unsaturated, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic hydrocarbon radical up to and including 18, preferably up to and including 10, carbon atoms or an unsubstituted or substituted aromatic, heteroaromatic, aromatic-aliphatic or heteroaromatic-aliphatic hydrocarbon radical up to and including 18, preferably up to and including 10, carbon atoms or an unsubstituted or substituted ge saturated five- or six-membered heterocycle

_ 3. 239 21O

b a

and R is hydrogen or has the meanings of R. In groups in which R occurs twice, both radicals R may be the same or different.

An acyl radical of an optionally N-substituted natural amino acid is excluded as acyl Ri.

An unsubstituted or substituted, saturated or unsaturated, aliphatic, cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical R or R is, for example, unsubstituted or substituted alkyl, e.g. Lower alkyl, lower alkenyl, lower alkynyl, mono-, bi- or tricycloalkyl, monocycloalkenyl, bicycloalkenyl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl or cycloalkenyl-lower alkyl.

Alkyl R or R preferably has 1-10 C atoms and is e.g. optionally substituted lower alkyl having 1-7 C atoms or n-octyl, n-nonyl or n-decyl.

a b Lower alkyl R or R preferably has 1-7 C atoms and is e.g. Methyl, ethyl, n -propyl, iso-propyl, η-butyl or tert -butyl which may be substituted by one or more functional groups, for example hydroxy, etherified hydroxy, e.g. Lower alkoxy, such as methoxy or ethoxy, or phenoxy, esterified hydroxy, e.g. Lower alkanoyloxy such as acetoxy, halogen, e.g. Chlorine or bromine, hydroxysulfonyloxy, carboxy, esterified carboxy, e.g. Lower alkoxycarbonyl such as methoxy or ethoxycarbonyl, amidated carboxy, e.g. Carbamoyl or mono- or di-lower alkylcarbamoyl, such as methyl or dimethylcarbamoyl, cyano, phosphono, esterified phosphono, e.g. Diniederalkoxyphosphoryl, such as dimethoxy or diethoxyphosphoryl, amino or may be substituted by oxo, wherein the substituents only

.4- 239 21 O

then in the 1-position of the lower alkyl, if this is bound in the partial formula R -CO- to the carbonyl group.

Monosubstituted lower alkyl R or R is, for example, hydroxy-lower alkyl, e.g. 2-hydroxyethyl, lower alkoxy-lower alkyl, e.g. Lower alkoxymethyl or lower alkoxyethyl, such as methoxymethyl or 2-methoxyethyl, phenoxy-lower alkyl, e.g. Phenoxymethyl, naphthoxy-lower alkyl, e.g. α- or β-naphthoxymethyl, lower alkanoyloxy-lower alkyl, e.g. Lower alkanoyloxymethyl or lower alkanoyloxyethyl, such as acetoxymethyl or 2-acetoxyethyl, halo-lower alkyl, e.g. Halomethyl or haloethyl, such as 2-chloro- or 2-bromoethyl, hydroxysulfonyloxy-lower alkyl, e.g. Hydroxysulfonyloxymethyl or 2-hydroxysulfonyloxyethyl, carboxy-lower alkyl, e.g. Carboxymethyl or 2-carboxyethyl, lower alkoxycarbonyl-lower alkyl, e.g. Lower alkoxycarbonylmethyl or lower alkoxycarbonylethyl such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, ethoxycarbonylmethyl or 2-ethoxycarbonylethyl, carbamoyl-lower alkyl, e.g. Carbamoylmethyl or 2-carbamoyl-ethyl, lower alkylcarbamoyl-lower alkyl, e.g. Methylcarbamoylmethyl, diloweralkylcarbamoylloweralkyl, e.g. Dimethylcarbamoylmethyl, cyano-lower alkyl, e.g. Cyanomethyl or 2-cyanoethyl, or oxo-lower alkyl, e.g. 2-0xopropyl or 2-oxobutyl.

a b Substituted lower alkyl R or R having two or more substituents is, for example, hydroxy-carboxy-lower alkyl, e.g. Hydroxy-carboxymethyl or 1-hydroxy-2-carboxy-aethyl, hydroxy-lower alkoxycarbonyl-lower alkyl, e.g. Hydroxy-ethoxy- or -methoxycarbonyl-ethyl, esterified hydroxy-lower alkoxycarbonyl-lower alkyl, e.g. Acetoxy-methoxycarbonyl-methyl, dihydroxy-carboxy-lower alkyl, e.g. 1,2-dihydroxy-2-carboxy-ethyl, dihydroxy-lower alkoxycarbonyl-lower alkyl, e.g. 1,2-dihydroxy-2-ethoxy- or -methoxycarbonyl-ethyl, esterified dihydroxy-lower alkoxycarbonyl-lower alkyl, e.g. 1,2-diacetoxy-2-ethoxy or -methoxycarbonyl-ethyl, a-naphthoxy-carboxy-lower alkyl, e.g. l-a-Naphthoxy-3-carboxypropyl, a-naphthoxy-lower alkoxycarbonyl-lower alkyl, e.g. a-Naphthoxy-ethoxycarbonyl-methyl, 1-a-naphthoxy-2-ethoxycarbonyl

239 21O

ethyl or 1-ci-naphthoxy-3-tert-butoxycarbonyl-propyl, a-naphthoxybenzyloxycarbonyl-lower alkyl, e.g. l-a-Naphthoxy-2-benzyloxycarbonyl-ethyl, ct -naphthoxy-carbamoyl-lower alkyl, e.g. 1-ot-naphthoxy-3-carbamoyl-propyl, a-naphthoxy-cyano-lower alkyl, e.g. ct -naphthoxy-cyano-methyl or L-ct-naphthoxy-S-cyano-propyl, o-naphthoxy-diallyl-alkylamino-lower alkyl, e.g. L-α-naphthoxy-4-dimethylamino-butyl, or α-naphthoxy-oxo-lower alkyl, e.g. 1-ct-naphthalene. thoxy-3-oxo-butyl.

a b lower alkenyl R or R contains e.g. 2-7, in particular 2-4, C atoms, wherein the double bond is only in the 1-position of the lower alkenyl when it is bound in the partial formula R -CO- to the carbonyl group, and is e.g. Vinyl, allyl or 2- or

a b 3-Butenyl. Lower alkenyl R or R may be substituted by the same substituents as lower alkyl, e.g. by hydroxy, etherified hydroxy, e.g. Methoxy, esterified hydroxy, e.g. Acetoxy, halogen, e.g. Chlorine or bromine, carboxy, esterified carboxy, e.g. Methoxycarbonyl or ethoxycarbonyl, or amidated carboxy, e.g. Carbamoyl.

a b lower alkynyl R or R contains e.g. 2-7, in particular 2-4, C atoms and is for example ethinyl, 1-propynyl or 2-propynyl.

a b cycloalkyl R or R contains e.g. 3-8, in particular 3-6, C-atoms and is e.g. Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

a b bicycloalkyl R or R contains e.g. 5-10, especially 6-9, C-atoms and is e.g. Bicyclohexyl, heptyl, octyl, nonyl or decyl, e.g. Bicyclo [3.1.0] hex-1-, -2- or -3-yl, bicyclo [4.1.0] hept-l- or -4-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, furthermore et- or decahydronaphthyl.

"" 6 "

239 21O

a b Tricycloalkyl R or R contains e.g. 8-10 C atoms and is e.g.

2 6 tricyclo [5.2.1.0 '] dec-8-yl or adamantyl, such as 1-adamantyl.

a b cycloalkenyl R or R contains e.g. 3-8, in particular 3-6, C-atoms and is for example cyclohexenyl, e.g. 1-cyclohexenyl, or cyclohexadienyl, e.g. 1,4-cyclohexadienyl.

Bicycloalkenyl R ^a or R contains, for example, 5-10, in particular 7-10, C atoms and is, for example, bicyclo [2.2.1] hept-5-en-yl, for example 5-norbornen-2-yl, bicyclo [2.2.2 ] octene-2-yl or hexahydro-4,7-methanoindlen-6-yl.

Cycloalkyl-lower alkyl R or R contains e.g. 4-10, in particular 4-7, C atoms and is for example cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

a b Cycloalkyl-lower alkenyl R or R contains e.g. 5-10, in particular 5-9, C atoms and is for example cyclohexylvinyl or cyclohexylallyl.

Cycloalkenyl-lower alkyl R or R contains e.g. 4-10, in particular 4-7, C atoms and is for example 1-Cyclohexeny! Methyl or 1,4-Cyclohexadieny! Methyl.

The stated cycloaliphatic or cycloaliphatic-aliphatic radicals may be substituted by.

Radicals can be replaced by the same substituents as lower alkyl R

An optionally substituted aromatic or aromatic-aliphatic hydrocarbon radical R or R is, for example, unsubstituted or substituted aryl, aryl-lower alkyl or aryl-lower alkenyl.

_ ₇ _ 239 21O

a b Aryl R or R contains e.g. 6 to 14 carbon atoms and is, for example, phenyl, indenyl, e.g. 2- or 4-indenyl, 1- or 2-naphthyl, anthryl, e.g. 1- or 2-anthryl, phenanthryl, e.g. 9-phenanthryl, or acenaphthenyl, e.g. 1-acenaphthenyl. Aryl R or R is exemplified by lower alkyl, e.g. Methyl, hydroxy, lower alkoxy, e.g. Methoxy, acyloxy, e.g. Lower alkanoyloxy such as acetoxy, amino, lower alkylamino, e.g. Methylamino, di-lower alkylamino, e.g. Dimethylamino, acylamino, e.g. tert-butoxycarbonylamino, or halo, e.g. Chlorine, bromine or iodine substituted, wherein the substituent in any position of the aryl radical, e.g. in the o-, m- or p-position of the phenyl radical, and the aryl radical can also be substituted several times by identical or different substituents.

a b aryl-lower alkyl R or R has e.g. 7 to 15 C atoms and contains, for example, an unsubstituted or substituted, optionally branched radical mentioned under lower alkyl R or R.

such aryl-lower alkyl is, for example, benzyl, lower alkylbenzyl such as 4-methylbenzyl, lower alkoxybenzyl such as 4-methoxybenzyl, substituted anilinobenzyl such as 2- (o, o-dichloroanilino) benzyl or 2- (o, o-dichloro-N-benzylanilino) -benzyl, 2-phenylethyl, 2- (p-hydroxyphenyl) -ethyl, diphenylmethyl, di- (4-methoxyphenyl) -methyl, trityl, α- or β- Naphthylmethyl, 2- (ct- or 0-naphthyl) -ethyl, furthermore 2-phenylethyl, 3-phenyl-2-propyl, 4-phenyl-3-butyl, 2-a-naphthylethyl, 3-a-naphthyl-2-yl propyl or 4-a-naphthyl-3-butyl, each in the 1-position by hydroxy, lower alkoxy, eg Neopentyloxy, acyloxy, e.g. Acetoxy, pivaloyloxy, ethylaminocarbonyloxy, 2-benzyloxycarbonylamino-2-methylpropionoxy, 2-amino-2-methylpropionoxy or acetoacetoxy, carboxy, esterified carboxy, e.g. Benzyloxycarbonyl, tert-butoxycarbonyl or ethoxycarbonyl, carbamoyl, substituted carbamoyl, e.g. tert -butylcarbamoyl, carboxymethylcarbamoyl, tert -butoxycarbonylmethylcarbamoyl, 2-dimethylaminoethylcarbamoyl, 3-hydroxy-2-propylcarbamoyl, 2,2-dimethoxyethylcarbarbaraoyl or S-amino-S-carboxypentylcarbamoyl, cyano, phosphono, esterified phosphono, e.g. Diethoxyphosphoryl, dimethoxyphosphoryl or hydroxymethoxy

2 3 9 21C

phosphoryl or oxo substituted, furthermore 1-phenyl or a-naphthyl-4-oxo-2-pentyl, 1-phenyl or a-naphthyl-5,5-dimethyl-4-oxo-2-hexyl, 1 Phenyl or α-naphthyl-4,4-dimethyl-3-oxo-2-pentyl, 1-phenyl-4- (2-benzofuranyl) -4-oxo-butyl, 1-phenyl or α-naphthyl-5 dimethylamino-2-pentyl, 1-phenyl or a-naphthyl-5-di-methylamino-4-oxo-2-pentyl, 1-phenyl or α-naphthyl-3-dimethylamino-2-propyl, α, ρ-diaminobenzyl or α, ρ-diacylaminobenzyl, eg α, ρ-dibenzyloxycarbonylaminobenzyl or a-pivaloylamino-p-benzyloxycarbonylaminobenzyl.

Aryl-lower alkenyl R or R has e.g. Contains from 8 to 16 carbon atoms and contains, for example, an unsubstituted or substituted radical mentioned under lower alkenyl R or R and an unsubstituted or substituted radical mentioned under aryl R or R. Such an aryl-lower alkenyl is, for example, styryl, 3-phenylallyl, 2- (ct-naphthyl ) -vinyl or 2- (β-naphthyl) -vinyl.

In a heteroaromatic or heteroaromatic-aliphatic

from the hydrocarbon radical R or R, the heterocycle is mono-, bi- or tricyclic and contains one to two nitrogen atoms and / or one oxygen or sulfur atom and is bonded to one of its ring carbon atoms with the group -CO- or -O-CO- , ^ N-CO-, ^ N-CS-, ^ N-CO-CO-, -SO2- or ^ N-SO 2 - linked. Such a heteroaryl

From R or R, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, ß-carbolinyl or a benzannelliertes, cyclopenta, cyclohexa or cycloheptaannelliertes derivative of these residues. This heterocycle may be attached to a nitrogen atom by 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. Chlorine, hydroxy, lower alkoxy, e.g. Methoxy, phenyl-lower alkoxy, e.g. Benzyloxy, or oxo substituted and partially saturated and is for example 2- or 3-pyrrolyl, phenyl-pyrrolyl, e.g. 4- or 5-phenyl

239 21Q

2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, 2-, 3- or 4-pyridyl, 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-isoquinolyl, 1-oxo -l, 2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzoxazolyl, 2-benzthiazolyl, benz [e] indol-2-yl or beta-carbolin-3-yl.

a b A heteroaromatic-aliphatic hydrocarbon radical R or R contains e.g. a unsubstituted or substituted radical mentioned under lower alkyl R or R and an unsubstituted or substituted radical mentioned under heteroaryl R or R 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.

A saturated five- or six-membered heterocycle R or R has at least one C atom, 1-3 nitrogen atoms and optionally an oxygen or sulfur atom as ring members and is connected to one of its ring C atoms with the group -CO- or -OCO -, ^ N-CO-, \ -CS-, Ni-CO-CO-, -SO ₂ - or \ -S0 ₂ - linked.

This heterocycle may be attached to one of its C atoms or to a ring nitrogen atom by lower alkyl, e.g. Methyl or ethyl, phenyl or phenyl-lower alkyl, e.g. Benzyl, or substituted on one of its carbon atoms by hydroxy or oxo and / or be Benz-fused to two adjacent carbon atoms.

Such a heterocycle is, for example, pyrrolidin-3-yl, hydroxypyrrolidin-2 or 3-yl, e.g. 4-hydroxypyrrolidin-2-yl, oxopyrrolidin-2-yl, e.g. 5-oxopyrrolidin-2-yl, piperidine-2 or 3-yl, 1-lower alkylpiperidine-2, 3, or 4-yl, e.g. 1-methylpiperidine-2-, -3- or -4-yl, morpholin-2-or 3-yl, thiomorpholine-2 or -3-yl, 1- and / or 4-lower alkylpiperazine-2 or -3 yl,

e.g. 1, 4-dimethylpiperazin-2-yl, indolinyl, e.g. 2- or 3-indolinyl, 1,2,3,4-tetrahydroquinolyl, e.g. 1 ^, S ^ -tetrahydroquinol ^ -, -3- or -4-yl or 1,2,3,4-tetrahydroisoquinolyl, e.g. 1,2,3,4-tetrahydroisoquinol-1, -3- or -4-yl or 1-oxo-l, 2,3,4-tetrahydroisoquinol-3-yl. Excluded as heterocyclic R in an acyl radical R-CO- is optionally N-substituted pyrrolidin-2-yl, i. the rest of the amino acid proline.

Preferred acyl groups Ri are, for example, alkanoyl, e.g. n-decanoyl or lower alkanoyl, e.g. Formyl, acetyl, propionyl or pivaloyl, hydroxy-lower alkanoyl, e.g. β-hydroxypropionyl, lower alkoxy-lower alkanoyl, e.g. Lower alkoxyacetyl or lower alkoxypropionyl such as methoxyacetyl or β-methoxypropionyl, phenoxy lower alkanoyl, e.g. Phenoxyacetyl, naphthoxy lower alkanoyl, e.g. α- or β-naphthoxyacetyl, lower alkanoyloxy-lower alkanoyl, e.g. Lower alkanoyloxyacetyl or lower alkanoyloxypropionyl such as acetoxyacetyl or β-acetoxypropionyl, halo-lower alkanoyl, e.g. α-haloacetyl, such as α-chloro, α-bromo, α-iodo or α, α, α-trichloroacetyl, or halopropionyl, such as β-chloro- or β-bromopropionyl, carboxy-lower alkanoyl, e.g. Carboxyacetyl or β-carboxypropionyl, lower alkoxycarbonyl-lower alkanoyl, e.g. Lower alkoxycarbonylacetyl or lower alkoxycarbonylpropionyl such as methoxycarbonylacetyl, β-methoxycarbonylpropionyl, ethoxycarbonylacetyl or β-ethoxycarbonylpropionyl, carbamoyl-loweralkanoyl, e.g. Carbamoylacetyl or β-carbamoylpropionyl, lower alkylcarbamoyl-loweralkanoyl, e.g. Methylcarbamoylacetyl, di-lower alkylcarbamoyl-loweralkanoyl, e.g. Dimethyl carboxylatoyl, oxo lower alkanoyl, e.g. Acetoacetyl or propionylacetyl, hydroxy-carboxy-lower alkanoyl, e.g. α-hydroxy-carboxy-acetyl or α-hydroxy-β-carboxy-propionyl, hydroxy-lower alkoxycarbonyl-lower alkanoyl, e.g. α-hydroxy-a-ethoxy or -methoxycarbonyl-acetyl or α-hydroxy-β-ethoxy or -methoxycarbonyl-propionyl, esterified hydroxy-lower alkoxycarbonyl-lower alkanoyl, e.g. a-acetoxy-oi-methoxycarbonyl-acetyl, dihydroxycarboxy-lower alkanoyl, e.g. α, β-dihydroxy-β-carboxy-propionyl, dihydroxy-lower alkoxycarbonyl-lower alkanoyl, e.g. α, β-dihydroxy-β-ethoxy-or -methoxycarbonyl-propionyl, esterified dihydroxy

2 10

lower alkoxycarbonyl-lower alkanoyl, for example a, ß-diacetoxy-.beta.-methoxycarbonylpropionyl, ct-naphthoxy-carboxy-lower alkanoyl, for example 2-a-naphthoxy-4-carboxy-butyryl, a-naphthoxy-lower alkoxycarbonyl 'lower alkanoyl, eg ct-naphthoxy ethoxycarbonyl-acetyl, 2-α-Na-pentoxy-3-ethoxycarbonyl-propionyl or 2-α-naphthoxy-4-tert-butoxycarbonyl-butyryl, α-naphthoxy-benzyloxycarbonyl-lower alkanoyl, eg 2-α-naphthoxy-3-benzyloxycarbonyl propionyl, a-naphthoxy-carbamoyl-lower alkanoyl, eg 2-a-naphthoxy-4-carbamoyl-butyryl, a-naphthoxy-cyano-lower alkanoyl, eg a-naphthoxycyano-acetyl or 2-a-naphthoxy-4-cyano-butyryl , a-naphthoxy-lower alkylamino-lower alkanoyl, for example 2-of-naphthoxy-5-dimethylaminopentanoyl, a-naphthoxy-oxo-lower alkanoyl, for example 2-a-naphthoxy-4-oxo-pentanoyl, lower alkenoyl, for example acryloyl, vinylacetyl, crotonoyl or 3- or 4-pentenoyl, Niederalklnoyl, for example, propiolyl or 2- or 3-butynoyl, cycloalkylcarbonyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylcarbonyl, bicyclo alkylcarbonyl, for example endo or exo-norbornyl-2-carbonyl, bicyclo [2.2.2] oct-2-ylcarbonyl or bicyclot-s-sylnone-1-ylcarbonyl, tricycloalkylcarbonyl, for example 1- or 2-adamantylcarbonyl, cycloalkenylcarbonyl, for example 1 Cyclohexenylcarbonyl or 1-cyclohexadienylcarbonyl, bicycloalkenylcarbonyl, eg 5-norbornen-2-ylcarbonyl or bicyclo [2,2,2] octen-2-ylcarbonyl, cycloalkyl-lower alkanoyl, eg cyclopropylacetyl, cyclopentylacetyl or cyclohexylacetyl, cycloalkyl-lower alkenoyl, eg cyclohexylacryloyl, cycloalkenylnederalkanoyl, eg 1- Cyclohexenylacetyl or 1,4-cyclohexadienylacetyl, benzoyl, unsubstltuiert, mono- or Mehrfachsubstituiert by lower alkyl, for example methyl, halogen, for example chlorine, hydroxy, lower alkoxy, for example methoxy, and / or nitro, for example 4-chloro, 4-methoxy or 4-nitrobenzoyl, furthermore phenyl, α-naphthyl or ß-naphthyl-lower alkanoyl, wherein phenyl is unsubstituted, mono- or multiply substituted by lower alkyl, for example methyl, halogen, for example chlorine, hydroxy, lower alkoxy, for example methoxy, and / or nitro and Lower alkanoyl can be unsubstituted or substituted, for example by hydroxy, lower alkoxy, acyloxy, carboxy, esterified carboxy, carbamoyl, substituted carbamoyl, cyano, phosphono, esterified phosphono, benzofuranyl and / or oxo and is optionally branched, for example phenylacetyl,

Οί-naphthylacetyl, fJ-naphthylacetyl, lower alkylphenylacetyl such as 4-methylphenylacetyl, lower alkoxyphenylacetyl such as 4-methoxyphenylacetyl, 3-phenylpropionyl, 3- (p-hydroxyphenyl) -propionyl, diphenylacetyl, di- (4-methoxyphenyl) -acetyl, triphenylacetyl, substituted anilinophenylacetyl, such as 2- (o, o-dichloroanilino) -phenylacetyl or 2- (o, o-dichloro-N-benzylanilino) -phenylacetyl, 3-a- or β-naphthylpropionyl, 3-phenyl- or 3-ot- Naphthyl-2-hydroxypropionyl, 3-phenyl or Sa-naphthyl-lower alkoxypropionyl such as 3-phenyl- or 3-a-naphthyl-2-neopentyloxypropionyl, 3-phenyl- or 3-a-naphthyl-2-acyloxy propionyl such as 3-phenyl-2-pivaloyloxy or 2-acetoxy-propionyl, 3-ct-naphthyl-2-pivaloyloxy or 2-acetoxy-propionyl, 3-a-naphthyl-2-acetoacetoxy-propionyl, sodium Naphthyl-ethylaminocarbonyloxy-propionyl or 3-C-naphthyl-2- (2-amino- or 2-benzyloxycarbonyl-amino-2-methylpropionyloxy) -propionyl, 3-phenyl- or 3-a-naphthyl-2-carboxymethyl-propionyl, 3 Phenyl or 3-a-naphthyl-2-n lower alkoxycarbonylpropionyl, such as 3-a-naphthyl-2-ethoxycarbonyl-propionyl, 3-phenyl- or 3-a-naphthyl-2-benzyloxycarbonylmethyl-propionyl, 3-phenyl- or sa-naphthyl -carbanioyl-propionyl, 3-phenyl- or 3-a-naphthyl-2-tert-butylcarbamoyl-propionyl, 3-phenyl or 3-ct-naphthyl-2- (2-dimethylaminoethyl) -carbamoyl-propionyl, 3-a-naphthyl-2- (carboxy or tert -butoxycarbonyl) -methylcarbamoyl-propionyl, 3-phenyl- or 3-a-naphthyl-2- (3-hydroxy-2-propyl) -carbamoyl-propionyl, 3-phenyl- or 3-ö-naphthyl-2- 2,2-dimethoxyethyl) -carbamoyl-propionyl, 3-phenyl or 3-a-naphthyl-2- (S-amino-S-carboxypentyl) -carbamoyl-propionyl, 3-phenyl or 3-a-naphthyl-2-cyano- propionyl, 3-phenyl or 3-a-naphthyl-2-cyanomethyl-propionyl, 3-phenyl-2-phosphono or phosphonomethyl-propionyl, 3-phenyl-2-dimethoxyphosphoryl or dimethoxyphosphorylmethyl-propionyl, 3-phenyl-2 diethoxyphosphoryl or diethoxyphosphorylmethyl-propionyl, 3-phenyl-2-ethoxy- or methoxy-hydroxy-phosphoryl-propionyl, 3-P henyl- or 3-a-naphthyl-2-acetonyl-propionyl, 3-phenyl- or 3-α-Na-phthhyl-2-dimethyl-ininomethyl-propionyl, 2-benzyl- or 2-a-naphthylmethyl-4-cyano-butyryl, 4 Phenyl or 4-ct-naphthyl-3-carboxy-butyryl, 4-phenyl or 4-a-naphthyl-3-benzyloxycarbonyl-butyryl, 2-benzyl-4- (2-benzofuranyl) -4-oxo-butyryl , 2-benzyl- or 2-ct-naphthylmethyl-4-oxo

pentanoyl, 2-benzyl or 2-a-naphthylmethyl-4,4-dimethyl-3-oxopentanoyl, 2-benzyl or 2-α-Na-methylmethyl-5-dinethyl-ininopentanoyl, 2-benzyl or 2-Cί-naphthylmethyl-5 -dimethylamino-4-oxopentanoyl, -2-benzyl or 2-ct-naphthhyl-5,5-di-ethyl-4-oxohexanoyl, et, p-diamino-phenylacetyl, α, p-diacylamino-phenylacetyl, such as otjp-dibenzyloxycarbonylamino phenylacetyl or ct-pivaloylaminop-benzyloxycarbonylamino-phenylacetyl, phenyl-lower alkenoyl, eg β-phenylacryloyl or β-phenylvinylacetyl, naphthylcarbonyl, e.g. et- or β-naphthylcarbonyl or 1,8-naphthalenedicarbonyl, indenylcarbonyl, e.g. 1-, 2- or 3-indenylcarbonyl, indanylcarbonyl, e.g. 1- or 2-indanylcarbonyl, phenanthrenylcarbonyl, e.g. 9-phenanthrenylcarbonyl, optionally substituted pyrrolylcarbonyl, e.g. 2- or 3-pyrrolylcarbonyl or 4- or 5-phenylpyrrolyl-2-carbonyl, furylcarbonyl, e.g. 2-furylcarbonyl, thienylcarbonyl, e.g. 2-thienylcarbonyl, pyridylcarbonyl, e.g. 2-, 3- or 4-pyridylcarbonyl, optionally substituted indolylcarbonyl, e.g. 2-, 3- or 5-indolylcarbonyl, 1-methyl, 5-methyl, 5-methoxy, 5-benzyloxy, 5-chloro- or 4,5-dimethylindolyl-2-carbonyl, 1-benzylindolyl-2 - or 3-carbonyl, 4,5,6,7-tetrahydroindolyl-2-carbonyl, CycloheptafbJ-pyrrolyl-S-carbonyl, optionally substituted quinolylcarbonyl, for example 2-, 3- or 4-quinolylcarbonyl or 4-hydroxyquinolyl-2-carbonyl, optionally substituted isoquinolylcarbonyl, e.g. 1-, 3- or 4-isoquinolylcarbonyl or 1-oxo-1,2-dihydroisoquinolyl-3-carbonyl, 2-quinoxalinylcarbonyl, 2-benzofuranylcarbonyl, benz [e] indolyl-2-carbonyl, β-carbolinyl-3-carbonyl, Pyrrolidinyl-3-carbonyl, hydroxypyrrolidinylcarbonyl, eg 3- or 4-hydroxypyrrolidinyl-2-carbonyl, oxopyrrolidinylcarbonyl, e.g. 5-oxopyrrolidinyl-2-carbonyl, piperidinylcarbonyl, e.g. 2-, 3- or 4-piperidinylcarbonyl, indolinylcarbonyl, e.g. 2- or 3-indolinylcarbonyl, 1,2,3,4-tetrahydroquinolylcarbonyl, e.g. 1,2,3,4-tetrahydroquinolyl-2-, 3- or 4-carbonyl, 1,2,3,4-tetrahydroisoquinolylcarbonyl, e.g. 1,2,3,4-tetrahydroisoquinolyl-1-, 3- or 4-carbonyl or 1-oxo-1, 2,3,4-tetrahydroisoquinolyl-3-carbonyl, lower alkoxycarbonyl, e.g. Methoxy, ethoxy or tert-lower alkoxycarbonyl, such as tert-butoxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2-chloro, 2-bromo, 2-iodo or 2,2,2-trichloroethoxy

carbonyl, aryl-lower alkoxycarbonyl, e.g. Arylmethoxycarbonyl wherein aryl is phenyl, 1- or 2-naphthyl or lower alkyl, e.g. Methyl or tert -butyl, lower alkoxy, e.g. Methoxy, ethoxy or tert-butoxy, hydroxy, halogen, e.g. Chlorine or bromine, and / or nitro mono- or poly-substituted phenyl, e.g. Benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, di (4-methoxyphenyl) methoxycarbonyl or trityloxycarbonyl, further oxamoyl or lower alkyloxamoyl, e.g. Methyl or ethyloxamoyl.

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, e.g. a substituted phenylalanine or phenylglycine wherein the substituent is lower alkyl, e.g. Methyl, halogen, e.g. Fluorine, chlorine, bromine or iodine, hydroxy, lower alkoxy, e.g. Methoxy, lower alkanoyloxy, e.g. Acetoxy, amino, lower alkylamino, e.g. Methylamino, di-lower alkylamino, e.g. Dimethylamine, lower alkanoylamino, e.g. Acetylamino or pivaloylamino, lower alkoxycarbonylamino, e.g. tert-butoxycarbonylamino, arylmethoxycarbonylamino, e.g. Benzyloxycarbonylamino, and / or nitro and may occur 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, benzannellierten α- Amino acid, eg Indoline-2-carboxylic acid or 1, ZjS-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, e.g. as lower alkyl ester group such as methoxycarbonyl or tert-butoxycarbonyl, or as carbamoyl, lower alkylcarbamoyl such as methylcarbamoyl, or as di-lower alkylcarbamoyl group such as dimethylcarbamoyl in which an amino group of the side chain is in acylated form, e.g. when

- is - 239 2 1 O

Lower alkanoylamino such as acetylamino or pivaloylamino, lower alkoxycarbonylamino such as tert-butoxycarbonylamino, or arylmethoxycarbonylamino group such as benzyloxycarbonylamino or in which a hydroxy group of the side chain is in etherified or esterified form, e.g. as the lower alkoxy group, such as methoxy, as the aryl-lower alkoxy group, such as benzyloxy, or as the lower alkanoyloxy group, such as acetoxy, or an epimer of such amino acid, i. with the unnatural D configuration.

Such amino acids are, for example, glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-VaI-OH), norvaline (ct-aminovaleric acid), leucine, (H-Leu-OH), isoleucine ( H-IIe-OH), norleucine (α-aminohexanoic acid, H-NIe-OH), serine (H-Ser-OH), homoserine (α-amino-7-hydroxybutyric acid), threonine (H-Thr-OH), methionine (H-Met-OH), cysteine (H-Cys-OH), proline (H-Pro-OH), trans-3- and trans-4-hydroxyproline, phenylalanine (H-Phe-OH), tyrosine (H- Tyr-OH), 4-nitrophenylalanine, 4-aminophenylalanine, 4-chlorophenylalanine, β-phenylserine (β-hydroxyphenylalanine), phenylglycine, ct-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 monotert-butyl ester, glutamine (H-GIn-OH), N-dimethyglutamine, histidine (H-His-OH), arginine (H-Arg-OH), lysine (H-Lys-OH) , N-tert-butoxycarbonyl-lysi n, fi-hydroxylysine, ornithine (α, θ-diaminovaleric acid), N ⁵ -pivaloyl-o: propionic acid.

N -pivaloyl-ortnithine, α, γ-diaminobutyric acid or α, β-diamino

The amino acid residue A may be N-terminal for enhancing the stability of the compound of formula I against enzymatic degradation by lower alkyl, e.g. Methyl or ethyl.

A is preferably the bivalent radical of alanine, valine, norvaline, leucine, norleucine, serine, etherified serine, proline, phenylalanine, β-phenylserine, α-naphthylalanine, cyclohexylalanine, indoline-2-carboxylic acid, 1,2,3,4- Tetrahydroisoquinoline-3-carboxylic acid, aspartic acid,

esterified aspartic acid, asparagine, aminomalonic acid, aminomalonic acid monoamide, glutamic acid, esterified glutamic acid, glutamine, di-lower alkyl glutamine, histidine, lysine, acylated lycin, ornithine or acylated ornithine, N-terminal, if desired, by lower alkyl, e.g. Methyl, substituted. Most preferred group A is the bivalent residue of histidine.

Lower alkyl R2 or R3 has the meanings mentioned above for lower alkyl R or R. Lower alkyl R2 is preferably methyl or ethyl. Lower alkyl R3 is preferably isopropyl, isobutyl or tert-butyl.

Hydroxiloweralkyl R3 or R5 is preferably hydroxymethyl or hydroxyethyl and is optionally etherified or esterified by one of the groups given below for etherified or esterified hydroxy Ri ₁ .

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

Cycloalkyl-lower alkyl R 3 and R 5 have the above for cycloalkyl lower alkyl R od <Cyclohexy! Methyl.

lower alkyl R or R meanings and is preferably

Bicycloalkyl lower alkyl R3 or R5 contains e.g. 6-14, especially 7-12, carbon atoms and is, for example, by the more forward for

a b bicycloalkyl R or R called radicals sub; Ethyl, e.g. Bicyclo [2.2.1] hept-2-ylmethyl.

a b bicycloalkyl R or R radicals mentioned substituted methyl or

Tricycloalkyl-lower alkyl R3 or R5 contains e.g. 9-14, in particular 10-12, C-atoms and is for example by the farther forward for

239 2 ir

Tricycloalkyl R or R radicals mentioned substituted methyl or ethyl, preferably 1-adamantylmethyl.

Aryl R3 or R5 has the more forward aromatic hydrocarbon ": phenyl.

a b radical R or R meanings and is preferably

Aryl-lower alkyl R3 or R5 has the above for aryl-lower alkyl

a b R or R meanings and is preferably benzyl.

An etherified hydroxy group Ri ₊ 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 i ₁ is, for example, acyloxy-lower alkoxy, in which acyl is the acyl group of an optionally branched lower alkanecarboxylic acid or carbonyl monounestarized by optionally branched lower alkyl, eg lower alkanoyloxy lower alkoxy, such as acetoxy-ethoxy, 1-acetoxyethoxy, pivaloyloxymethoxy or 1-pivaloyloxyethoxy, or lower alkoxycarbonyloxy-lower alkoxy, such as ethoxycarbonyloxymethoxy, 1- Aethoxycarbonyloxyäthoxy, tert-Butoxycarbonyloxymethoxy or 1-tert-Butoxycarbonyloxyäthoxy.

Etherified hydroxy R i ₊ is furthermore lower alkoxy, for example methoxy or ethoxy, aryloxy, for example phenoxy, or aryl-lower alkoxy, for example benzyloxy.

Esterified hydroxy Ri ₊ is, for example, aliphatic acyloxy, for example lower alkanoyloxy, such as acetoxy or pivaloyloxy, cycloaliphatic acyloxy, for example cycloalkylcarbonyloxy, such as cyclohexylcarbonyloxy, or aromatic acyloxy, for example benzoyloxy.

239 2t O

Lower alkyl R5 has 2 or more, preferably 2-7, C atoms and is e.g. Ethyl, n-propyl, isopropyl, η-butyl, isobutyl, tert-butyl or isopentyl. Particularly preferred are isopropyl, isobutyl and tert-butyl.

Bicycloalkyl R5 has the meanings mentioned above for bicycloalkyl R or R, and is preferably a-decahydronaphthyl.

a b Tricycloalkyl R 5 has the meanings mentioned above for tricycloalkyl R or R 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 or substituted by one or two lower alkyl groups or by aryl-lower alkyl, lower alkanoyl, lower alkoxycarbonyl or arylmethoxycarbonyl and is e.g. Amino, methylamino, ethylamino, n-butylamino, dimethylamino, benzylamino, acetylamino, pivaloylamino, methoxy, ethoxy or tert-butoxycarbonylamino or benzyloxycarbonylamino, preferably dimethylamino.

Optionally substituted hydroxy R 5 is unsubstituted or etherified or esterified by one of the groups mentioned further above for etherified or esterified hydroxy R i ₁ and is for example hydroxy, methoxy, ethoxy, acetoxymethoxy, phenoxy, benzyloxy, acetoxy, pivaloyloxy or benzoyloxy.

Optionally substituted mercapto R5 is unsubstituted or substituted by lower alkyl, e.g. Methyl or ethyl, aryl, e.g. Phenyl, aryl-lower alkyl, e.g. Benzyl, lower alkanoyl, e.g. Acetyl, or

Arylcarbonyl, e.g. Benzoyl, substituted and is for example mercapto, methylthio, ethylthio, phenylthio, benzylthio, acetylthio or benzoylthio.

Substituted amino R is, for example, an amino group which is substituted by one or optionally two unsubstituted or substituted, saturated or unsaturated, aliphatic hydrocarbon radicals up to and including 18, preferably up to 10, carbon 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 substituted amino Rs 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 Re is, for example, optionally substituted alkyl having up to 10 C atoms, lower alkenyl or lower alkynyl up to and including 7 C atoms, or cycloalkyl-lower alkyl having 4-10 C atoms ,

These radicals may, like lower alkyl R or R, be substituted by one or more of the functional groups mentioned above, as well as by sulfo, amino, lower alkylamino, e.g. Methylamino, ethylamino or n-butylamino, di-lower alkylamino, e.g. Dimethylamine, lower alkanoylamino, e.g. Acetylamino or pivaloylamino, lower alkoxycarbonylamino, e.g. tert-butoxycarbonylamino, arylmethoxycarbonylamino, e.g. Benzyloxycarbonylamino, guanidino or substituted amino wherein the amino group is part of a five- or six-membered heterocycle containing one to two nitrogen atoms and, if desired, an oxygen or sulfur atom, e.g. 1-pyrrolidinyl, 1-piperidinyl, 1-pyridazinyl, 4-morpholinyl or 4-thiomorpholinyl.

- 20 - 23 9 2?

As substituents, hydroxy, lower alkoxy, e.g. Methoxy, lower alkanoyloxy, e.g. Acetoxy, substituted or unsubstituted phenyloxy, e.g. Carbamoylphenyloxy or carbamoyl-hydroxy-phenyloxy, carboxy, esterified carboxy, e.g. Lower alkoxycarbonyl such as methoxycarbonyl or tert-butoxycarbonyl, or a physiologically cleavable esterified carboxy, e.g. lower alkanoyloxy-lower alkoxycarbonyl, such as acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl or 1-propionyloxyethoxycarbonyl, 1- (lower alkoxycarbonyloxy) -lower alkoxycarbonyl, such as 1- (ethoxycarbonyloxy) -ethoxycarbonyl, or alpha-amino-lower alkanoyloxymethoxycarbonyl, such as alpha-aminoacetoxymethoxycarbonyl or (S) -t- Amino-.beta.-methylbutyryloxymethoxycarbonyl, carbamoyl, substituted or unsubstituted lower alkylcarbamoyl, eg 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. tert-butoxycarbonylamino, guanidino, nitrogen-atom-bonded, saturated five- or six-membered, optionally oxo-substituted heterocyclyl, e.g. 1-piperidyl, 4-morpholinyl or 2-oxo-1-pyrrolidinyl.

An aromatic or aromatic-aliphatic hydrocarbon radical

starting with a group Rf, has the same meanings as mentioned under R or R, and is preferably phenyl or phenyl-lower alkyl.

These radicals may be present in the aromatic e.g. by lower alkyl, e.g. 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, e.g. Lower alkoxycarbonyl such as tert-butoxycarbonyl, carbamoyl, amino, lower alkylamino, e.g. Methylamino, di-lower alkylamino, e.g., dimethylamino, acylated amino, e.g. Lower alkoxycarbonylamino, such as tert-butoxycarbonylamino, and be substituted by nitro.

-21- ²³⁹

Lower alkyl in a radical phenyl-lower alkyl may be substituted by the same substituents as alkyl in a radical R6.

A heteroaromatic or heteroaromatic-aliphatic hydrocarbyl group in a group Re has the same meanings as mentioned under R and R and is preferably pyridyl lower alkyl, e.g. 2-, 3- or 4-pyridylmethyl, imidazolyl-lower alkyl, e.g. 2- (4-imidazolyl) -ethyl, or 2- (2- [4-imidazolyl] -ethylamino) -ethyl, or indolyl-lower alkyl, e.g. 3-indolylmethyl or 2- (3-indolyl) ethyl.

Substituted amino R6 is preferably alkylamino, e.g. 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. Dimethylamine or diethylamino, hydroxy-lower alkylamino, e.g. 2-hydroxyethylamino, 1-hydroxybut-2-ylamino, 5-hydroxypentylamino or tris (hydroxymethyl) methylamino, di (hydroxyloweralkyl) amino, e.g. Di- (2-hydroxyethyl) amino, lower alkoxy-lower alkylamino, e.g. 2-methoxyethylamino, lower alkanoyloxy-lower alkylamino, e.g. 2-acetoxyethylamino, phenoxy-lower alkylamino or phenoxy-hydroxy-lower-alkylamino wherein phenoxy is optionally substituted by lower alkyl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or carbamoyl, e.g. 2-phenoxyethylamino, 2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino or 3- (3-carbamoylphenoxy) -2-hydroxypropylamino, carboxyalkylamino or amino-carboxyalkylamino, wherein the carboxy radical is not in the 1-position of the alkyl radical stands, eg 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-noctylamino, furthermore dicarboxymethylamino, lower alkoxycarbonylalkylamino or acylamino-lower alkoxycarbonylalkylamino, in which the carbonyl radical is not in the 1-position of the alkyl radical, eg 4-tert-butoxycarbonyl-n-butylamino, S-tert-butoxycarbonylamino-S-methoxycarbonyl-n-pentylamino, 7-tert-butoxycarbonyl-n-heptylamino or 8-tert-butoxycarbonyl-n-octylimino, furthermore di-lower alkoxycarbonyl-methylamino , eg Di-methoxycarbonyl-methylamino, phy-

Biodegradable esterified carboxyalkylamino wherein the ester function is not in the 1-position of the alkyl group, e.g. 4-pivaloyloxymethoxycarbonyl-h-butylamino, 7- (1-ethoxycarbonyloxyethoxycarbonyD-n-heptylamino or 7-pivaloyloxymethoxycarbonyl-n-heptylamino, carbamoylalkylamino or hydroxy-lower alkylcarbamoylalkylamino, in which the carbamoyl radical is not in the 1-position of the alkyl radical, eg 4-carbamoyl-n- butylamino, 7-carbamoyl-n-heptylamino or 4- (tris [hydroxymethyl] -methyl) -carbatoylo-n-butylamino, furthermore dicarbamoyl-methylamino, di (lower alkylcarbamoyl) -methylamino, eg di (methylcarbamoyl) -methylamino, di (hydroxy-lower alkylcarbamoyl) -methylamino, for example di- (2-hydroxyethylcarbamoyl) -methylamino, or bis- (diniederalkylcarbamoyl) -methylamino, for example bis-dimethylaminocarbamoyl-1-methylamino, aminoloweralkylamino, for example 2-aminoethylamino or 3-aminopropylamino, lower-alkylaminoloweralkylamino, for example 2- Methylaminoethylamino, di-lower alkylaminoloweralkylamino, for example 2-dimethylaminoethylamino or 3-dimethylaminopropylamino, lower alkoxycarbonylaminoloweralkylamino, eg 2- (tert-butoxycarbonyla mino) -ethylamino, guanidinoloweralkylamino, e.g. 2-guanidinoethylamino, nitrogen-atom-bonded, saturated five- or six-membered heterocyclyl-lower alkylamino, e.g. 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 optionally substituted by lower alkyl, e.g. Methyl, hydroxy, lower alkoxy, e.g. Methoxy or tert-butoxy, lower alkanoyloxy, e.g. Ethoxy, halogen, e.g. Fluorine or chlorine, carboxy, lower alkoxycarbonyl, e.g. tert-butoxycarbonyl, carbamoyl, amino, lower alkylamino, e.g. Methylamino, di-lower alkylamino, e.g. Dimethylamino, acylamino, e.g. tert-butoxycarbonylamino and / or mono- or polysubstituted by nitro, e.g. Phenylamino, 2-, 3- or 4-methylphenylamino, 4-hydroxyphenylamino, 4-methoxyphenylamino, 2,3-, 2,4- or 2,5-dimethoxyphenylamino, 4-chlorophenylaraino, 2-, 3- or 4-carboxyphenylamino, 2-, 3- or 4-methoxy or tert-butoxy-carbonyl

-23- 239 21 O

phenylamino, 2-, 3- or 4-carbamoylphenylaaino, 4-aminophenylamino, 4-tert-butoxycarbonyl-aa-n-phenylaaino or 4-nitrophenylaaino, also e.g. Benzylaaino, 4-methylbenzylamino, 4-Methoxybenzylaaino, 2-, 3- or 4-Carboxybenzylaaino, 2-, 3- or 4-tert-Butoxycarbonylbenzylaaino, 2-, 3- or 4-carbamoylbenzylamino, 2-Phenyläthylaaino or 3-Phenylpropylami. no, Pyridylniederalkylaaino »eg 2-, 3- or 4-pyridylmethyl-amino, 2- (2-, 3- or 4-pyridyl) -ethylamino or 3- (2-, 3- or 4-pyridyl) -propylamino, alaidazolyl-lower alkylamine, e.g. 4-imidazolylmethylaaino, 2- (4-iaidazolyl) ethylamino or 2- (2-f4-imidazolyl-ethylamino) -äthylaaino, or Indolylniederalkylami.no, e.g. 3-indolyl-ethyl-aoine or 2- (3-indolyl) -ethyl-aoine.

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. Sodium or potassium or alkaline earth metal salts, e.g. Magnesium or calcium salts, also zinc salts or ammonium salts, also those salts which are formed with organic amines, such as optionally substituted by hydroxy mono-, di- or trialkylamines, e.g. Diethylamine, di (2-hydroxyethyldimine, triethylamine, N, N-di-ethyl-N- (2-hydroxyethyl) -caine, tri- (2-hydroxy-ethyl) -amine or N-methyl-D-glucamine Compounds of the formula I with a basic group, for example an aza group, can form acid addition salts, for example with inorganic acids, for example hydrochloric acid, sulfuric acid or phosphoric acid, or organic carboxylic, sulfonic or sulfonic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid , Hydroxyaleinic, methylmaleic, fumaric, acetic, tartaric, citric, benzoic, cinnamic, mandelic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, eabonic, nicotinic or isonicotinic, Aoanoic acids, as well as methanesulfonic acid, Aethanaulfonsäure, 2-Hydroxyäthansulfonsäure, Aethan

239 2 ] O

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 where it causes the cleavage of angiotensinogen to form the decapeptide angiotensin I, which is then cleaved in the lungs, kidneys and other organs to form 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 III formed as a cleavage product. 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-henners.

Among other things, the effect of renin-henners is demonstrated experimentally by means of in vitro tests, whereby the reduction of 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 in vitro test is used: A kidney human renin extract (Milli-gold leaf units / ml) becomes 1-molar at 37 ° C for one hour and pH-1 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-

239 2 \ O

Pro-Phe-His-Leu-Leu-Val-Tyr-Ser-OH, incubated. The amount of angiotensin I formed is determined in a radioimmunoassay. The inhibitors according to the invention are added to the incubation mixture in different concentrations in each case. IC50 is the concentration of the respective inhibitor that reduces the formation of angiotensin I by 50%. The compounds of the present invention exhibit inhibitory effects in the in vitro systems at minimal concentrations of from about 10 to about 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 marmosets of both sexes with a body weight of about 300 g, which 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, 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. effective.

The compounds of the present invention can be used as antihypertensives, and also for the treatment of heart failure.

The invention relates in particular to compounds of the formula I in which R 1 is hydrogen or acyl having the sub-formulas R-CO-, R ^a -O-CO- or (R) (R) N-CO-CO-, in which R ^{a is} an unsubstituted or substituted one , saturated or unsaturated, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic hydrocarbon radical 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 up to and including 18, preferably up to and including 10 , C atoms or an unsubstituted or substituted, saturated five- or six-membered heterocycle

b a

and R is hydrogen or has the meanings of R, with the exception of an optionally N-substituted acyl radical of a natural amino acid, A is an optionally N-alkylated a-amino acid residue which is N-terminal with Ri and C-terminal with the group -NR 2 - R2 is hydrogen or lower alkyl, R3 is hydrogen, lower alkyl, hydroxy lower alkyl, cycloalkyl, cycloalkyl lower alkyl, bicycloalkyl lower alkyl, tricycloalkyl lower alkyl, aryl or aryl lower alkyl, Ri * hydroxy, R5 lower alkyl having 2 or more C atoms, hydroxy lower alkyl, cycloalkyl, cycloalkyl lower alkyl, bicycloalkyl, bicycloalkyl lower alkyl , Tricycloalkyl, Tricycloalkylniederalkyl, carbamoyl, Niederalkylcarbamoyl, di-lower alkylamino, aryl or aryl-lower alkyl and Rö is an amino group containing one or optionally two unsubstituted or substituted, saturated or unsaturated, aliphatic hydrocarbon radicals up to and including 18, preferably up to 10, carbon atoms or e in unsubstituted or substituted aromatic, heteroaromatic, aromatic-aliphatic or heteroaromatic-aliphatic hydrocarbon radical 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 primarily to compounds of the formula I in which R 1 is hydrogen, lower alkyl-alkanoyl-1-7 carbon atoms, e.g. Formyl, acetyl, propionyl or pivaloyl, hydroxy-lower alkanoyl, e.g. β-hydroxypropionyl, lower alkoxy-lower alkanoyl, e.g. Lower alkoxyacetyl or lower alkoxypropionyl such as methoxyacetyl or β-methoxypropionyl, phenoxy lower alkanoyl, e.g. Phenoxyacetyl, naphthoxy lower alkanoyl, e.g. α- or 0-naphthoxyacetyl, lower alkanoyloxy-lower alkanoyl, e.g. Lower alkanoyloxyacetyl or lower alkanoyloxypropionyl such as acetoxyacetyl or β-acetoxypropionyl, carboxy-lower alkanoyl, e.g. Carboxyacetyl or β-carboxypropionyl, lower alkoxycarbonyl-lower alkanoyl, e.g. Lower alkoxycarbonylacetyl or lower alkoxycarbonylpropionyl such as methoxycarbonylacetyl, .beta.-methoxycarbonylpropionyl, ethoxycarbonylacetyl or .beta.-ethoxycarbonylpropionyl, carboaoyl-lower alkanoyl, e.g. Carbamoylacetyl or 8-caraoaoylpropionyl, lower alkylcarbaaoyl-loweralkanoyl, e.g. Methylcarbamoylacetyl, diloweralkylcarbaaoyl-loweralkanoyl, e.g. Diaethylcarbaaoylacetyl, ct-naphthoxy-carboxy-lower alkanoyl, e.g. 2-a-Naphthoxy-4-carboxy-butyryl, a-naphthoxy-lower alkoxycarbonyl-lower alkanoyl, e.g. a-naphthoxy-ethoxycarbonyl-acetyl, 2-e-naphthoxy-3-ethoxycarbonyl-propionyl or 2- <x-naphthoxy-4-tert-butoxycarbonyl-butyryl, ct -naphthoxy-benzyloxycarbony-lower alkanoyl, e.g. 2-α-Naphthoxy-3-benzyloxycarbonyl-propionyl, α-haphthoxycarbaaoyl-lower alkanoyl, e.g. 2-e-Naphthoxy-4-carbamoyl-butyryl, o-naphthoxy-cyano-lower alkanoyl, e.g. α-naphthoxy-cyano-acetyl or 2-α-naphthoxy-4-cyano-butyryl, α-naphthoxy-lower alkylamino lower alkanoyl, e.g. 2-a-Naphthoxy-5-dimethyl-amino-pentanoyl, o -naphthoxy-oxo-lower alkanoyl, e.g. 2-a-Naphthoxy-4-oxopentanoyl, lower alkenoyl, 3-7 C-atoaene, e.g. Acryloyl, vinylacetyl, crotonoyl or 3- or 4-pentenoyl, lower alkynyl ait 3-7 C-atoaene, e.g. Propiolyl or 2- or 3-sutinoyl, Cycloalkylcarbonyi ait 4-9 C-Atoaen, e.g. Cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or cyclohexylcarbonyl, bicycloalkylcarbonyl ait 6-11 C-atoaene, e.g. endo or exo-norbornyl-2-carbonyl, bicyclof 2.2.2 -oct-2-ylcarbonyl or bicyclic-3,3,1,1-non-9-ylcarbonyl, tricycloalkylcarbonyl-ate 9-11 carbon atoms, e.g. 1- or 2-adaaantylcarbonyl, cycloalltenylcarbonyl ait 4-9 C-atoaene, e.g. 1-cyclohexenyl

239 2 ίΟ

arbonyl or 1,4-cyclohexadienylcarbonyl, bicycloalkenylcarbonyl having 6-11 C atoms, e.g. 5-norbornen-2-ylcarbonyl or bicyclof2.2.2] octen-2-ylcarbonyl, cycloalkyl-lower alkanoyl of 5-11 C-atoms, e.g. Cyclopropylacetyl, cyclopentylacetyl or cyclohexylacetyl, cyclo, alkyl-lower alkenoyl of 6-11 C-atoms, e.g. Cyclohexylacryloyl, cycloalkenyl-lower alkanoyl having 5-11 C atoms, e.g. 1-cyclohexenylacetyl or 1,4-cyclohexadienylacetyl, benzoyl, unsubstituted, mono- or poly-substituted by lower alkyl, e.g. Methyl, halogen, e.g. Chlorine, hydroxy, lower alkoxy, e.g. Methoxy, and / or nitro, e.g. 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, phenyl, a-naphthyl or β-naphthyl-lower alkanoyl wherein phenyl is unsubstituted, mono- or poly-substituted by lower alkyl, e.g. Methyl, halogen, e.g. Chlorine, hydroxy, lower alkoxy, e.g. Methoxy, and / or nitro and lower alkanoyl unsubstituted or substituted e.g. by hydroxy, lower alkoxy, acyloxy, carboxy, esterified carboxy, carbamoyl, substituted carbamoyl, cyano, phosphono, esterified phosphono, benzofuranyl and / or oxo, and optionally branched, e.g. Phenylacetyl, α-naphthylacetyl, β-naphthylacetyl, lower alkylphenylacetyl such as 4-methylphenylacetyl, lower alkoxyphenylacetyl such as 4-methoxyphenylacetyl, 3-phenylpropionyl, 3- (p-hydroxyphenyl) -propionyl, diphenylacetyl, di- (4-methoxyphenyl) -acetyl, Triphenylacetyl, substituted anilinophenylacetyl, such as 2- (o, o-dichloroanilino) -phenylacetyl or 2- (o, o-dichloro-N-benzylanilino) -phenylacetyl, 3-ot- or β-naphthylpropionyl, 3-phenyl- or 3-phenyl- a-naphthyl-2-hydroxypropionyl, 3-phenyl or 3-a-naphthyl-2-lower alkoxypropionyl, such as 3-phenyl or 3-a-naphthyl-2-neopentyloxy-propionyl, 3-phenyl or 3-phenyl a-naphthyl-2-acyloxy-propionyl such as 3-phenyl-2-pivaloyloxy or 2-acetoxy-propionyl, 3-a-naphthyl-2-pivaloyloxy or 2-acetoxy-propionyl, 3-a-naphthyl-2 acetoacetoxy-propionyl, 3-a-naphthyl-2-ethylaminocarbonyloxy-propionyl or 3-a-naphthyl-2- (2-amino or 2-benzyloxycarbonylamino-2-methyl-propionyloxy) -propionyl, 3-phenyl or 3 -a-naphthyl-2-carboxymethyl-propionyl, 3-phenyl or 3-phenyl a-naphthyl-2-lower alkoxycarbonyl-propionyl, such as 3-a-naphthyl-2-ethoxycarbonyl-propionyl, 3-phenyl or S-ot-naphthyl ^ -benzyloxycarbonylmethyl-propionyl, 3-phenyl- or

S-ct-naphthyl - ^ - carbamoyl-propionyl, 3-phenyl or 3-a-naphthyl-2-tert-butylcarbamoyl-propionyl, 3-phenyl or 3-ct-naphthyl-2- (2-dimethylaminoethyl) - carbamoyl-propionyl, 3-a-naphthyl-2- (carboxy- or tert-butoxycarbonyl) -methylcarbamoyl-propionyl, 3-phenyl- or 3-a-naphthyl-2- (3-hydroxy-2-propyl) -carbamoyl- propionyl, 3-phenyl- or 3-ct-naphthyl-2- (2,2-dimethoxyethyl) -carbamoyl-propionyl, 3-phenyl- or 3-a-naphthyl-2- (5-amino-5-carboxypentyl) - carbamoylpropionyl, 3-phenyl or 3-a-naphthyl-2-cyano-propionyl, 3-phenyl or 3-a-naphthyl-2-cyanomethyl-propionyl, 3-phenyl-2-phosphono or phosphonomethyl-propionyl, S Phenyl-dimethoxyphosphoryl or dimethoxyphosphorylmethylpropionyl, 3-phenyl-2-diethoxyphosphoryl or diethoxyphosphorylmethylpropionyl, 3-phenyl-2-ethoxy or methoxy-hydroxyphosphoryl-propionyl, 3-phenyl or 3-a-naphthyl 2-acetonyl-propionyl, 3-phenyl- or S-ct-naphthyl-dimethylaminomethyl-propionyl, 2-benzyl- or 2-0-naphthylmethyl-4-cyano-butyryl, 4-phenyl or 4-oi-naphthyl-3-carboxy-butyryl, 4-phenyl or 4-ct-naphthyl-3-benzyloxycarbonyl-butyryl, 2-benzyl-4- (2-benzofuranyl) -4-oxo butyryl, 2-benzyl or 2-a-naphthylmethyl-4-oxopentanoyl, 2-benzyl or 2-α-Naρhthylmethyl-4,4-dimethyl-3-oxopentanoyl, 2-benzyl or 2-α-Naρhthylιnethyl-5 -dimethylalninopentanoyl, 2-benzyl- or 2-α-Na-phthhyl-5-dimethylamino-4-oxo-pentanoyl, 2-benzyl or 2-a-naphthylmethyl-5,5-dimethyl-4-oxo-hexanoyl, α, p-diamino-phenylacetyl , α, p-Diacylamino-phenylacetyl, such as ctjp-dibenzyloxycarbonylamino-phenylacetyl or a-pivaloylaminop-benzyloxycarbonylamino-phenylacetyl, phenyl-lower alkenoyl, for example β-phenylacryloyl or β-phenylvinylacetyl, naphthylcarbonyl, e.g. α- or β-naphthylcarbonyl or 1,8-naphthalenedicarbonyl, indenylcarbonyl, e.g. 1-, 2- or 3-indenylcarbonyl, indanylcarbonyl, e.g. 1- or 2-indanylcarbonyl, phenanthrenylcarbonyl, e.g. 9-phenanthrenylcarbonyl, optionally substituted pyrrolylcarbonyl, e.g. 2- or 3-pyrrolylcarbonyl or 4- or 5-phenylpyrrolyl-2-carbonyl, furylcarbonyl, e.g. 2-furylcarbonyl, thienylcarbonyl, e.g. 2-thienylcarbonyl, pyridylcarbonyl, e.g. 2-, 3- or 4-pyridylcarbonyl, optionally substituted indolylcarbonyl, e.g. 2-, 3- or 5-indolylcarbonyl, 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethylindolyl-2-carbonyl, 1-benzyl-

indolyl-2- or 3-carbonyl, 4,5,6, T-tetrahydroindolyl ^ -carbonyl, cycloheptafblpyrrolyl-5-carbonyl, optionally substituted quinolylcarbonyl, e.g. 2-, 3- or 4-quinolylcarbonyl or 4-hydroxyquinolyl-2-carbonyl, optionally substituted isoquinolylcarbonyl, e.g. 1-, 3- or 4-isoquinolylcarbonyl or 1-oxo-1,2-dihydroisoquinolyl-3-carbonyl, 2-quinoxalinylcarbonyl, 2-benzofuranylcarbonyl, benzfelindolyl-2-carbonyl, S-carbolinyl-3-carbonyl, pyrrolidinyl-3-yl carbonyl, hydroxypyrrolidinylcarbonyl, eg 3- or 4-hydroxypyrrolidinyl-2-carbonyl, oxopyrrolidinylcarbonyl, e.g. S-oxopyrrolidinyl-2-carbonyl, piperidinylcarbonyl, e.g. Piperidinyl 2-, 3- or 4-carbonyl, indolinylcarbonyl, e.g. 2- or 3-indolinylcarbonyl, 1,2,3,4-tetrahydroquinolylcarbonyl, e.g. 1, 2,3,4-tetrahydroquinolyl-2-, 3- or 4-carbonyl, 1,2,3,4-tetrahydro-aoquinolylcarbonyl, e.g. 1 ^, S ^ -Tetrahydroisoquinolyl-1-, 3- or 4-carbonyl or 1-oxo-1, 2,3,4-tetrahydroisoquinolyl-3-carbonyl, aryl-lower alkoxycarbonyl, e.g. Arylmethoxycarbonyl wherein aryl is phenyl, 1- or 2-naphthyl or lower alkyl, e.g. Methyl or tert -butyl, lower alkoxy, e.g. Methoxy, ethoxy or tert-butoxy, hydroxy, halogen, e.g. Chlorine or bromine, and / or nitro mono or disubstituted phenyl, e.g. Benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, di- (4-nethoxyphenyl) -aethoxycarbonyl or trityloxycarbonyl, further oxaaoyl or loweralkyloxamoyl, e.g. Methyl or ethyl oxaooyl,

A is a bivalent radical of an α-amino acid, for example a natural α-amino acid of the L-configuration, as normally present in proteins, a homologue of such azoic acid, e.g. wherein the aaozoic acid side chain is extended or shortened, inter alia, one or two methylene groups and / or a MechyIgruppe is replaced by hydrogen, a substituted aromatic o-Aainosäure, e.g. a substituted phenylalanine or phenylglycine wherein the substituent is lower alkyl, e.g. Methyl, halogen, e.g. Fluorine, chlorine, Broa or iodine, hydroxy, lower alkoxy, e.g. Methoxy, lower alkanoyloxy, e.g. Acetoxy, aaino, lower alkylamino, e.g. Methyl aaino, di-lower alkyl aaino, e.g. Dimethylamines, low

alkanoylamino, e.g. Acetylamino or pivaloylamino, lower alkoxycarbonylamino, e.g. tert-butoxycarbonylamino, arylmethoxycarbonylamino, e.g. Benzyloxycarbonylamino, and / or nitro can be and 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, benzannellierten α-amino acid, eg Indoline-2-carboxylic acid or 1 →, S.A.-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, e.g. as lower alkyl ester group such as methoxycarbonyl or tert-butoxycarbonyl, or as carbamoyl, lower alkylcarbamoyl such as methylcarbamoyl, or as di-lower alkylcarbamoyl group such as dimethylcarbamoyl in which an amino group of the side chain is in acylated form, e.g. lower alkanoylamino such as acetylamino or pivaloylamino, lower alkoxycarbonylamino such as tert-butoxycarbonylamino, or arylmethoxycarbonylamino group such as benzyloxycarbonylamino, or in which a side chain hydroxy group is in etherified or esterified form, e.g. as the lower alkoxy group, such as methoxy, as the aryl-lower alkoxy group, such as benzyloxy, or as the lower alkanoyloxy group, such as acetoxy, or an epimer of such amino acid, i. with the unnatural D configuration, optionally at the N atom by lower alkyl, e.g. Methyl, substituted,

Ra is hydrogen or lower alkyl, e.g. Methyl, R 3 lower alkyl, e.g. Isopropyl or isobutyl, cycloalkyl, e.g. Cyclohexyl, cycloalkyl-lower alkyl, e.g. Cyclohexylmethyl, tricycloalkyl-lower alkyl, e.g. 1-adaraantylmethyl, phenyl-lower alkyl, e.g. Benzyl, or phenyl, R 1 * hydroxy, R 5 lower alkyl having 2 or more C atoms, e.g. Isopropyl, isobutyl or tert-butyl, cycloalkyl, e.g. Cyclopentyl or cyclohexyl, cycloalkyl-lower alkyl, e.g. Cyclohexylmethyl, bicycloalkyl, e.g. a-decahydronaphthyl, tricycloalkyl, e.g. 1-adamantyl, phenyl, phenyl-lower alkyl, e.g. Benzyl, carbamoyl or lower alkylcarbamoyl, e.g. Methylcarbamoyl or di-lower alkylamino, e.g. Dimethylamine,

239

and Re alkylamino having 1 to 10 C atoms, e.g. 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. Dimethylamine) or diethylamino, hydroxy-lower alkylamino, e.g. 2-hydroxyethylamino, 1-hydroxybut-2-ylamino, 5-hydroxypentylamino, or tris- (hydroxymethyl) -methylamino, di- (hydroxy-lower alkyl) -amino, e.g. Di- (2-hydroxyethyl) amino, lower alkoxy-lower alkylamino, e.g. 2-methoxyethylamino, lower alkanoyloxy-lower alkylamino, e.g. 2-acetoxyethylamino, phenoxy-loweralkylamino or phenoxyhydroxy-loweralkylamino wherein phenoxy is optionally substituted by lower alkyl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or carbamoyl, e.g. 2-phenoxyethylamino, 2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino or 3- (3-carbamoylphenoxy) -2-hydroxypropylamino, carboxyalkylamino or amino-carboxyalkylamino, wherein the carboxy radical is not in the 1-position of the alkyl radical stands, eg 4-carboxy-n-butyl, 5-carboxy-n-pentyl, 6-carboxy-nhexyl, 7-carboxy-n-heptyl or 8-carboxy-n-octylamino or S-amino-S-carboxy n-pentylamino, furthermore dicarboxymethylamino, lower alkoxycarbonylalkylamino or acylamino-lower alkoxycarbonyl-alkylamino, in which the carbonyl radical is not in the 1-position of the alkyl radical, eg 4-tert-butoxycarbonyl-n-butyl, 7-tert-butoxycarbonyl-n-heptyl or 8-tert-butoxycarbonyl-n-octylamino or S-tert-butoxycarbonylamino-S-methoxycarbonyl-n-pentylamino, furthermore di-lower alkoxycarbonyl-methylamino , eg Di-methoxycarbonyl-methylamino, physiologically cleavable esterified carboxyalkylamino wherein the ester function is not in the 1-position of the alkyl radical, e.g. 4-Pivaloyloxymethoxycarbonyl-n-butylamino, 7- (1-ethoxycarbonyloxyethoxycarbonyl) -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, e.g. 4-carbamoyl-n-butylamino, 7-carbamoyl-n-heptylamino or 4- (tris [hydroxymethyl] -methyl) -carbamoyl-n-butylamino, furthermore dicarbamoyl-methylamino, di-lower alkylcarbamoyl-1-methylamino, e.g. Di- (methylcarbamoyl) -methylamino, di- (hydroxy-lower alkylcarbamoyl) -methylamino, e.g. Di- (2-hydroxyethylcarbamoyl) -methylamino, or bis (lower alkylcarbamoyl) -methylamino, e.g. Bis (di-

-33- 239 2 1

aethylcarbamoyld-ethylaaino, aa-lower alkylamine, e.g. 2-aminoethylaaino or 3-aminopropylaai.no, lower alkylaquinone-alkyl-amino, e.g. 2-methyl-aminoethyl-aoine, di-lower alkyl-aa-lower alkyl-amino, e.g. 2-diethylaainoethylaaino or 3-diethylaainopropylaaino, lower alkoxycarbonyl-aa-lower alkylamine, e.g. 2- (tert-butoxycarbonyl-ao) -äthylaaino, Guanidinoniederalkylaaino, e.g. 2-guanidino-ethylaaino, via a nitrogenato bonded, saturated five- or six-membered heterocyclyl-lower alkyl aaino, e.g. 2- (4-morpholinyl) ethylaaino, 3- (4-morpholinyl) -propylaaino or 3- (2-oxopyrrolidin-1-yl) -propylaaino, lower alkenylaaino, e.g. Allylaineo or 2- or 3-butenyl-aaine, lower alkanolamine, e.g. Propargyl caseino, cycloalkyl lower alkyl casein, e.g. Cyclopropyl-ethylaaino or cyclohexyl-ethyla-amino, phenyl-acyl or phenyl-lower alkyl-aco, in which phenyl is optionally substituted by lower alkyl, e.g. Methyl, hydroxy, lower alkoxy, e.g. Methoxy or tert-butoxy, lower alkanoyloxy, e.g. Acatoxy, halogen, e.g. Fluorine or chlorine, carboxy, lower alkoxycarbonyl, e.g. tert-butoxycarbonyl, carbaoyl, aaino, lower alkylamine, e.g. Methyl aaino, di-lower alkyl aaino, e.g. Dimethylamine, acylamine, e.g. tert-butoxycarbonyl-amino and / or mono- or polysubstituted by nitro, e.g. Phenyl, 2-, 3- or 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 2,3-, 2,4- or 2,5-Diaethoxyphenyl-, 4-chlorophenyl, 2-, 3 or 4-carboxyphenyl, 2-, 3- or 4-methoxy or tert-butoxycarbonylphenyl, 2-, 3- or 4-carbaoylphenyl, 4-aminophenyl, 4-tert-butoxycarbonyla-n-phenyl or 4-nitrophenyl aaino, further eg Benzylaaino, 4-Methylbenzylaaino, 4-Methoxybenzylaaino, 2-, 3- or 4-Carboxybenzylaaino, 2-, 3- or 4-tert-Butoxycarbonylbenzylaaino, 2-, 3- or 4-Carbaaoylbenzylaaino, 2-Phenyläthylaaino, or 3-Phenylpropylaaino , Pyridylniederalkylaaino, eg 2-, 3- or 4-pyridylethyl, 2- (2-, 3- or 4-pyridyl) -ethyl or 3- (2-, 3- or 4-pyridyl) -propyliao, iaidazolyl-lower alkylamine, e.g. 4-Iaidazolyl-ethyl-aaino, 2- (4-iaidazolyl) -ethylalanine or 2- (2-f4-imidazolyl-ethyl-aoineo) -ethyl-aoine, or indolyl-lower alkylamine, e.g. 3-Indolylaethylaaino or 2- (3-indolyl) -äthylaaino, and pharmaceutically Annehabare salts of these compounds old salt-forming groups.

239 21O

The invention more particularly relates to compounds of formula I wherein R 1 is lower alkanoyl, e.g. Formyl, acetyl, propionyl or pivaloyl, lower alkenoyl, e.g. Acryloyl or crotonoyl, lower alkynyl, e.g. Propiolyl, cycloalkylcarbonyl, e.g. Cyclopentyl or cyclohexylcarbonyl, benzoyl, unsubstituted, mono- or poly-substituted by lower alkyl, e.g. Methyl, halogen, e.g. Chlorine, hydroxy, lower alkoxy, e.g. Methoxy, and / or nitro, e.g. 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, phenyl-lower alkanoyl wherein phenyl is unsubstituted, mono- or poly-substituted by lower alkyl, e.g. Methyl, halogen, e.g. Chlorine, hydroxy, lower alkoxy, e.g. Methoxy, and / or nitro and lower alkanoyl unsubstituted or substituted z: B. by hydroxy, acyloxy, carboxy or esterified carboxy, e.g. Phenylacetyl, lower alkylphenylacetyl, e.g. 4-methylphenylacetyl, lower alkoxyphenylacetyl, e.g. 4-methoxyphenylacetyl, 3-phenylpropionyl, 5-phenyl-2- (phenylmethyl) pentanoyl, 3- (p-hydroxyphenyl) propionyl, 2-hydroxy-3-phenylpropionyl, 2-acyloxy-3-phenylpropionyl, eg 2-acetoxy-3-phenylpropionyl or 2-pivaloyloxy-3-phenylpropionyl, diphenylacetyl, di- (4-methoxyphenyl) acetyl, triphenylacetyl, also substituted anilinophenylacetyl, e.g. 2- (o, o-dichloroanilino) -phenylacetyl or 2- (o, o -dichloro-N-benzylanilino) -phenylacetyl, phenyl-lower alkenoyl, e.g. β-phenylacryloyl or β-phenylvinylacetyl, naphthylcarbonyl, e.g. 1- or 2-naphthylcarbonyl, naphthyl-lower alkanoyl wherein lower alkanoyl e.g. substituted by hydroxy, acyloxy, carboxy or esterified carboxy, e.g. 1- or 2-naphthylacetyl, 2- or 3-a-naphthyl-propionyl, 2- or 3-.beta.-naphthyl-propionyl, 2-hydroxy-3- (ot- or f.sub.n-naphthyl) -propionyl, 2-acyloxy -3- (α- or β-naphthyl) -propionyl, eg 2-acetoxy-3-ct-naphthyl-propionyl or 2-pivaloyloxy-3-a-naphthyl-propionyl, 3-carboxy-4-a-naphthyl-butyryl, 3-carboxy-2- (a-naphthylmethyl) -propionyl, esterified carboxy (α- or β-naphthyl) -butyryl, eg 3-Benzyloxycarbonyl-4-anaphthyl-butyryl, esterified carboxy (α- or β-naphthylmethyl) -propionyl, e.g. 3-Benzyloxycarbonyl-2- (a-naphthylmethyl) -propionyl, indenylcarbonyl, e.g. 1-, 2- or 3-indenyl-caronyl, indanylcarbonyl, e.g. 1- or 2-indanylcarbonyl, phenanthrenylcarbonyl, e.g. 9-phenanthrenylcarbonyl, optionally substituted pyrrolyl

239 21O

carbonyl, for example 2- or 3-pyrrolylcarbonyl or 4- or 5-phenylpyrrolyl-2-carbonyl, furylcarbonyl, for example 2-furylcarbonyl, thienylcarbonyl, for example 2-thienylcarbonyl, pyridylcarbonyl, for example 2-, 3- or 4-pyridylcarbonyl, optionally substituted Indolylcarbonyl, for example 2-, 3- or 5-indolylcarbonyl, 1-methyl, 5-methyl, 5-methoxy, 5-benzyloxy, 5-chloro- or 4,5-dimethylindolyl-2-carbonyl, Benzyl-indolyl-2-carbonyl, 4,5,6,7-tetrahydroindolyl-2-carbonyl, optionally substituted quinolylcarbonyl, eg 2-, 3- or 4-quinolylcarbonyl or 4-hydroxyquinolyl-2-carbonyl, optionally substituted isoquinolylcarbonyl, eg 1-, 3- or 4-isoquinolylcarbonyl or 1-oxo-1-dihydroisoquinolyl-S-carbonyl, 2-quinoxalinylcarbonyl, 2-benzofuranylcarbonyl, benz [e] indolyl-2-carbonyl, β-carbolinyl-3-carbonyl, indolinylcarbonyl For example, 2- or 3-indolinylcarbonyl, 1,2,3,4-tetrahydroquinolylcarbonyl, for example, l, 2,3,4-tetrahydroquinolyl-2-, -3- or -4-carbonyl, 1,2,3,4- Tetrahydroisoquinolylcarbonyl, eg 1,2,3,4-tetrahyd roisoquinolyl-1-, 3- or 4-carbonyl or 1-oxo-1,2,3,4-tetrahydroisoquinolyl-3-carbonyl or arylmethoxycarbonyl having one or two aryl radicals, in which aryl is optionally substituted by lower alkyl, eg methyl or tert-butyl Butyl, lower alkoxy, for example methoxy, hydroxy, halogen, for example chlorine, and / or nitro mono-, di- or trisubstituted phenyl, for example benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, oxamoyl or Niederalkyloxamoyl For example, methyl or Aethyloxamoyl, as well as pharmaceutically acceptable salts of these compounds with salt-forming groups. *

The invention equally relates to compounds of the formula I in which 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, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid, asparagine, aminomalonic, Aminomalonsauremonoamid, glutamic acid, glutamine, Diniederalkylglutamin, histidine, lysine or ornithine, wherein the carboxy group in the side chain of aspartic acid or glutamic acid with a lower alkanol, eg Methanol or tertiary

- Jb -

Butanol, esterifies the hydroxy group in serine with lower alkyl, e.g. Methyl, or benzyl, the amino group in the side chain of lysine or ornithine by lower alkanoyl, e.g. Pivaloyl, by lower alkoxycarbonyl, e.g. tert-butoxycarbonyl, or by arylmethoxycarbonyl, e.g. Benzyloxycarbonyl, acylated and / or the ct nitrogen atom of the amino acids by lower alkyl, e.g. Methyl, and pharmaceutically acceptable salts of these compounds with salt-forming groups.

Also particularly preferred are compounds of the formula I in which R2 is hydrogen or lower alkyl, for example methyl, R3 is lower alkyl, for example isopropyl or isobutyl, cycloalkyl-lower alkyl, for example cyclohexylmethyl, or tricycloalkyl-lower alkyl, for example 1-adamantylmethyl, Ri ₊ hydroxy and R5 lower alkyl having 2 or more C Atoms, for example isopropyl or tert-butyl, cycloalkyl, for example cyclopentyl or cyclohexyl, cycloalkyl-lower alkyl, for example cyclohexylmethyl, 1-adamantyl, benzyl, carbamoyl or lower alkylcarbamoyl, for example methylcarbamoyl, and pharmaceutically acceptable salts of these compounds with salt-forming groups.

Equally preferred are compounds of formula I wherein Re is amino, alkylamino, e.g. Methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-octyl or n-decylamino, di-lower alkylamino , eg Dimethylamines, hydroxy-lower alkylamino, e.g. 2-hydroxyethylamino, 1-hydroxybut-2-ylamino or tris (hydroxymethyl) -methylamino, carboxyalkylamino, wherein the carboxy radical is not in the 1-position of the alkyl radical, e.g. 4-carboxy-n-butyl, 5-carboxy-n-pentyl, 6-carboxy-n-hexyl, 7-carboxy-n-heptyl or 8-carboxy-n-octylamino, furthermore dicarboxymethylamino, lower alkoxycarbonylalkylamino wherein the carbonyl radical is not in the 1-position of the alkyl radical, for example 4-tert-butoxycarbonyl-n-butyl, 7-tert-butoxycarbonyl-n-heptyl or 8-tert-butoxycarbonyl-n-octylamino, furthermore di-lower alkoxycarbonyl-methylamino, e.g. Di-methoxycarbonyl-methylamino, physiologically cleavable esterified carboxyalkylamino wherein the ester function is not in the 1-position of the alkyl radical, e.g. 4-pivaloyloxymethoxycarbonyl

n-butylamino, 7- (1-ethoxycarbonyloxyethoxycarbonyl) -n-heptylatnino or 7-pivaloyloxymethoxycarbonyl-n-heptylamino, carbamoyl or hydroxy-lower alkylcarbamoylalkylamiho, wherein the carbamoyl radical is not in the 1-position of the alkyl radical, e.g. 4-carbamoyl-n-butylamino, 7-carbamoyl-n-heptylamino or 4- <tris [hydroxymethyl] -methyl) -carbamoyl-n-butylamino, furthermore dicarbamoyl-methylamino, di (lower alkylcarbamoyl) -methylamino, e.g. Di- (methylcarbamoyl) -methylamino, di (hydroxy-lower alkylcarbamoyl) -methylamino, e.g. Di- (2-hydroxyethylcarbamoyl) -methylamino, or bis (lower alkylcarbamoyl) -methylamino, e.g. Bis (dimethylcarbamoyl) methylamino, amino-lower alkylamino, e.g. 2-aminoethylamino or 3-aminopropylamino, lower alkylaminoloweralkylamino, e.g. 2-methylaminoethylamino, di-lower alkylaminoloweralkylamino, e.g. 2-dimethylaminoethylamino, lower alkoxycarbonylaminoloweralkylamino, e.g. 2- (tert-butoxycarbonylamino) ethylamino, guanidinoloweralkylamino, e.g. 2-guanidinoethylamino, cycloalkyl-lower alkylamino, e.g. Cyclopropylmethylamino, benzylamino, pyridylloweralkylamino, e.g. 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 or 2- (4-imidazolyl) ethylamino, or indolyl-lower alkylamino, e.g. 3-indolylmethylamino or 2- (3-indolyl) ethylamino, as well as pharmaceutically acceptable salts of these compounds with salt-forming groups.

Preferred are compounds of formula I wherein R 1 is lower alkanoyl, e.g. Formyl, acetyl, propionyl or pivaloyl, 2- (o, o-dichloroanilino) -phenylacetyl, 2- (o, o-dichloro-N-benzylanilino) -phenylacetyl, optionally substituted pyrrolylcarbonyl, e.g. 2- or 3-pyrrolylcarbonyl or 4- or 5-phenylpyrrolyl-2-carbonyl, furylcarbonyl, e.g. 2-furylcarbonyl, thienylcarbonyl, e.g. 2-thienylcarbonyl, pyridylcarbonyl, e.g. 2-, 3- or 4-pyridylcarbonyl, optionally substituted indolylcarbonyl, e.g. 2-, 3- or 5-indolylcarbonyl, 1-methyl, 5-methyl, 5-methoxy, 5-benzyloxy, 5-chloro- or 4,5-dimethylindolyl-2-carbonyl, 4,5,6 , 7-tetrahydroindolyl-2-carbonyl, optionally substituted quinolylcarbonyl, eg 2-, 3- or 4-quinolylcarbonyl or 4-hydroxymethyl

xychinolyl-2-carbonyl, optionally substituted isoquinolylcarbonyl, e.g. 1-, 3- or 4-isoquinolylcarbonyl or 1-oxo-1,2-dihydroisoquinolyl-3-carbonyl, 2-quinoxalinylcarbonyl, 2-benzofuranylcarbonyl, benz [e] indolyl-2-carbonyl, beta-carbolinyl-3-carbonyl, indolinylcarbonyl, e.g. 2- or 3-indolinylcarbonyl, 1,2,3,4-tetrahydroquinolylcarbonyl, e.g. 1,2,3,4-tetrahydroquinolyl-2-, 3- or 4-carbonyl, 1,2,3,4-tetrahydroisoquinolylcarbonyl, e.g. 1,2,3,4-tetrahydroisoquinolyl-1-, -3- or -4-carbonyl or 1-oxo-l, 2,3,4-tetrahydroisoquinolyl-3-carbonyl,

A is the bivalent radical of the amino acids norleucine, phenylalanine, cyclohexylalanine, glutamic acid, glutamine, N-dimethyl-glutamine, ornithine or N-pivaloyl-ornithine, R ^{2 is} hydrogen, R ³ isobutyl, cyclohexylmethyl or 1-adamantylmethyl, Ri * hydroxy, R 5 isopropyl , Cyclohexyl, cyclohexylmethyl or methylcarbamoyl and

Re lower alkylamino, e.g. Methyl, ethyl, n-propyl, isopropyl, η-butyl or isopentylamino, di-lower alkylamino, e.g. Dimethylamines, hydroxy-lower alkylamino, e.g. 2-hydroxyethylamino or 1-hydroxybut-2-ylamino, carboxyalkylamino, wherein the carboxy radical is not in the 1-position of the alkyl radical, e.g. 4-carboxy-n-butylamino, 7-carboxy-n-heptylamino or 8-carboxy-n-octylamino, lower alkoxycarbonylalkylamino wherein the carbonyl radical is not in the 1-position of the alkyl radical, e.g. 4-tert-butoxycarbonyl-n-butylamino or 7-tert-butoxycarbonyl-n-hexylamino, amino-lower alkylamino, e.g. 2-Aethylaminoethylamino, guanidinoloweralkylamino, e.g. 2-guanidinoethylamino, benzylamino or pyridyl-lower alkylamino, e.g. 2-Pyridylmethylamino, as well as pharmaceutically acceptable salts of these compounds with salt-forming groups.

The invention relates primarily to compounds of formula I wherein R 1 is lower alkanoyl of 1-7 C atoms, e.g. Formyl, acetyl, propionyl or pivaloyl, phenoxy lower alkanoyl, e.g. Phenoxyacetyl, naphthoxy lower alkanoyl, e.g. α- or β-naphthoxyacetyl, α-naphthoxy-carboxy-lower alkanoyl, e.g. 2- <x-Naphthoxy-4-carboxybutyryl, α-naphthoxy-lower alkoxycarbonyl-lower alkanoyl, e.g.

a-naphthoxy-ethoxycarbonyl-acetyl, 2-a-naphthoxy-3-ethoxycarbonyl-propionyl or 2-a-naphthoxy-4-tert-butoxycarbonyl-butyryl, ct -naphthoxy-benzyloxycarbonyl-lower alkanoyl, e.g. 2-a-Naphthoxy-3-benzyloxycarbonyl-propionyl, ot -naphthoxy-carbamoyl-lower alkanoyl, e.g. 2-a-Naphthoxy-4-carbamoyl-butyryl, α-naphthoxy-cyano-lower alkanoyl, e.g. α-naphthoxy-cyano-acetyl or 2-α-naphthoxy-4-cyanobutyryl, ot -naphthoxy-lower alkylamino-lower alkanoyl, e.g. 2-a-Naphthoxy-5-dimethylamino-pentanoyl, a-naphthoxy-oxo-lower alkanoyl, e.g. 2-O-naphthoxy-4-oxo-pentanoyl, phenyl, α-naphthyl or β-naphthyl-lower alkanoyl wherein lower alkanoyl is unsubstituted or substituted e.g. by hydroxy, lower alkoxy, acyloxy, carboxy, esterified carboxy, carbamoyl, substituted carbamoyl, cyano, phosphono, esterified phosphono, benzofuranyl and / or oxo, and optionally branched, e.g. Phenylacetyl, ct-naphthylacetyl, β-naphthylacetyl, 3-phenylpropionyl, 3-a- or β-naphthylpropionyl, 3-phenyl- or 3-a-naphthyl-2-hydroxypropionyl, 3-phenyl- or 3-o-naphthyl-2 lower alkoxy-propionyl, such as 3-phenyl- or 3-α-naphthyl-2-neo-pentyloxy-propionyl, 3-phenyl- or 3-α-naphthyl-2-acyloxy-propionyl, such as 3-phenyl-2-pivaloyloxy or 2-acetoxy-propionyl, 3-a-naphthyl-2-pivaloyloxy or 2-acetoxy-propionyl, 3-a-naphthyl-2-acetoacetoxy-propionyl, 3-a-naphthyl-2-ethylaminocarbonyloxy-propionyl or 3- a-Naphthyl-2- (2-amino- or 2-benzyloxycarbonylamino-2-methyl-propionyloxy) -propionyl, 3-phenyl or 3-a-naphthyl-2-carboxyethyl-propionyl, 3-phenyl or 3-a -Naphthyl-2-lower alkoxycarbonyl-propionyl, such as 3-a-naphthyl-2-ethoxycarbonyl-propionyl, 3-phenyl or 3-a-naphthyl-2-benzyloxycarbonylmethyl-propionyl, 3-phenyl- or S-ci-naphthyl ^ -carbamoyl-propionyl, 3-phenyl or 3-a-naphthyl-2-tert-butylcarbamoyl-propionyl, 3-phenyl or 3-a-naphthyl-2- (2-dimethylaminoethyl) - carbamoyl-propionyl, 3-a-naphthyl-2- (carboxy- or tert-butoxycarbonyD-methylcarbamoyl-propionyl, 3-phenyl- or 3-a-naphthyl-2- (3-hydroxy-2-propyl) -carbamoyl-propionyl , 3-phenyl- or 3-a-naphthyl-2- (2,2-dimethoxyethyl) -carbamoyl-propionyl, 3-phenyl- or 3-ci-naphthyl-2- (5-amino-5-carboxypentyl) -carbamoyl-propionyl , 3-phenyl or 3-a-naphthyl-2-cyano-propionyl, 3-phenyl or 3-a-naphthyl-2-cyanomethyl-propionyl, 3-phenyl-2-phosphono

or phosphonomethylpropionyl, S-phenyl - ^ - dimethoxyphosphoryl or dimethoxyphosphorylmethylpropionyl, 3-phenyl-2-diathoxyphosphoryl or diethoxyphosphorylmethylpropionyl, 3-phenyl-2-ethoxy- or methoxy-hydroxyphosphoryl-propionyl, 3-phenyl or 3-a-naphthyl-2-acetonyl-propionyl, 3-phenyl or 3-a-naphthyl-2-dimethylaminomethyl-propionyl, 2-benzyl- or 2-a-naphthylmethyl-4-cyano-butyryl, 4-phenyl - or 4-a-naphthyl-3-carboxy-butyryl, 4-phenyl or 4-a-naphthyl-3-benzyloxycarbonyl-butyryl, 2-benzyl-4- (2-benzofuranyl) -4-oxo-butyryl, 2 -Benzyl- or 2-a-naphthylmethyl-4-oxopentanoyl, 2-benzyl or 2-ct-naphthylline of 1-4,4-dimethyl-3-oxopentanoyl, 2-benzyl- or 2-α-naphthylmethyl- 5-dimethylaminopentanoyl, 2-benzyl or 2-α-Na-methylmethyl-5-dimethylamino-4-oxopentanoyl, 2-benzyl or 2-α-naphthylmethyl-5,5-dimethyl-4-oxohexanoyl, a , p-diamino phenylacetyl, α, p-diacylamino-phenylacetyl, such as ap-dibenzyloxycarbonylamino-phenylacetyl or a-pivaloylaminop-benzylxycarbony lamino-phenylacetyl, furthermore 2- (o, o-dichloroanilino) -phenylacetyl or 2- (o, o-dichloro-N-benzylanilino) -phenylacetyl, naphthylcarbonyl, eg α- or β-naphthylcarbonyl or 1,8-naphthalenedicarbonyl , Pyrrolylcarbonyl, for example 2- or 3-pyrrolylcarbonyl, cycloheptatblpyrrolyl-S-carbonyl, indolylcarbonyl, for example 2-, 3- or 5-indolylcarbonyl, 1-benzylindolyl-3-carbonyl, 4,5,6,7-tetrahydroindolyl-2 carbonyl, quinolylcarbonyl, eg 2-, 3- or 4-quinolylcarbonyl, or oxamoyl,

A is the bivalent radical of the amino acids leucine, norleucine, phenylalanine, N-methyl-phenylalanine, β-phenylserine, cyclohexylalanine, glutamine, histidine or N-methyl-histidine, R _{2 is} hydrogen, R ₃ isobutyl or cyclohexylmethyl, R 1 is hydroxy, R 5 isopropyl, Cyclohexylmethyl, a-decahydronaphthyl or dimethylamine and

R6 is lower alkylamino having 1-7 C atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, n-pentyl or isopentylamino, di-lower alkylamino, e.g. Dimethylamines, hydroxy-lower alkylamino, e.g. 2-hydroxyethylamino, 1-hydroxybut-2-ylamino or 5-hydroxypentylamino, 2-phenoxyethylamino, 2- (3-carbamoyl-4-

hydroxyphenoxy) ethylamino, carboxyalkylamino or amino-carboxyalkylamino wherein the carboxy radical is not in the 1-position of the alkyl radical, e.g. 4-carboxy-n-butyl-amino, S-amino-S-carboxy-n-pentylamino, 7-carboxy-n-heptylamino or 8-carboxy-n-octylamino, lower alkoxycarbonylalkylamino or acylamino-lower alkoxycarbonyl-alkylamino wherein the carbonyl radical is not in the 1-position the alkyl group is, for example 4-tert-butoxycarbonyl-n-butylamino, 5-tert-butoxycarbonylamino-S-methoxycarbonyl-n-pentylamino or 7-tert-butoxycarbonyl-n-heptylamino, 4-tris (hydroxymethyl) -methylcarbamoyl-n-butylamino, aminoloweralkylamino, eg 2-aminoethylamino, di-lower alkylaminoloweralkylamino, e.g. 2-dimethylaminoethylamino or 3-dimethylaminopropylamino, lower alkoxycarbonylaminoloweralkylamino, e.g. 2-tert-butoxycarbonylaminoethylamino, morpholinoloweralkylamino, e.g. 2-morpholino-ethylamino, cycloalkyl-lower alkylamino, e.g. Cyclopropylmethylamino or cyclohexylmethylamino, benzylamino, pyridylloweralkylamino, e.g. 2-pyridylmethylamino, or imidazolyl-lower alkylamino, e.g. 2- (4-itnidazolyl) ethylamino or 2- (2- [4-imidazolyl] ethylamino) ethylatnino; and pharmaceutically acceptable salts of these compounds with salt-forming groups.

More particularly, the invention relates to compounds of the formula I in which R 1 is phenoxy lower alkanoyl , for example phenoxyacetyl, naphthoxy lower alkanoyl , for example et- or β-naphthoxyacetyl, phenyl-lower alkanoyl , in which lower alkanoyl is unsubstituted or substituted, for example by acyloxy, such as lower alkanoyloxy, carboxy, esterified carboxy, such as lower alkoxycarbonyl, Carbatnoyl, substituted carbamoyl such as lower alkylcarbamoyl, cyano, esterified phosphono such as di-lower alkoxyphosphoryl, or lower alkyl and oxo or benzofuranyl and oxo and optionally branched, eg 3-phenylpropionyl, 2-acetoxy-3-phenyl-propionyl, 2-pivaloyloxy 3-phenyl-propionyl, 2-ethoxy- or -methoxycarbonyl-S-phenyl-propionyl, 2-tert-butylcarbamoyl-3-phenyl-propionyl, 2-benzyl-3-cyano-propionyl, 2-dimethoxy-phosphoryl-3-phenyl ρropionyl, 2-benzyl-5,5-dimethyl-4-oxo-hexanoyl, 2-benzyl-4,4-dimethyl-3-oxo-pentanoyl or 4- (2-benzofuranyl) -2-benzyl-4-oxo butyryl, naphthyl-lower alkanoyl,

wherein lower alkanoyl is unsubstituted or substituted, e.g. by acyloxy such as lower alkanoyloxy, carboxy, esterified carboxy such as lower alkoxycarbonyl, unsubstituted or substituted carbamoyl, cyano or lower alkyl and oxo, and optionally branched, e.g. 3-ce- or β-naphthyl-propionyl, 2-acetoxy-3-a-naphthyl-propionyl, 2-pivaloyloxy-3-a-naphthyl-propionyl, 2-ethoxy- or methoxycarbonyl-3-C-naphthyl-propionyl, 2- Carbamoyl-3-ct-naphthyl-propionyl, 2-tert-butylcarbamoyl-3-anaphthyl-propionyl, 2-carboxymethylcarbamoyl-3-alpha-naphthyl-p-pyronia, 3-cyano-2-alpha-naphthylmethyl-p-trionyl, 5.5- Dimethyl-2-a-naphthylmethyl-4-oxo-hexanoyl or 4,4-dimethyl-2-alpha-naphthylmethyl-3-oxopentanoyl, indolyl-2-carbonyl or cyclohepta [b] pyrrolyl-5-carbonyl, A is the bivalent radical the amino acid L-histidine, R 2 is hydrogen, R 3 is isobutyl or cyclohexylmethyl, R 1 is hydroxy, R 5 is isopropyl or cyclohexylmethyl and R 6 is lower alkylamino, eg Methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, n-pentyl or isopentylamino or amino-carboxy-lower alkylamino wherein the substituents are not in the 1-position of the lower alkyl group, e.g. 5-amino-5-carboxy-pentylamino, and the carbon atoms bearing the radicals R3 and Ri * have the S-configuration, and also pharmaceutically acceptable salts of these compounds.

The invention more particularly relates to compounds of the formula I in which R 1 in the lower alkanoyl radical is phenyl- or ct-naphthyl-lower alkanoyl which is substituted by lower alkanoyloxy, lower alkoxycarbonyl, lower-alkylcarbamoyl, lower-alkoxyphosphoryl or lower-alkyl and oxo, in which lower alkyl has 1 to 7 carbon atoms, for example 2 (S) - Pivaloyloxy-3-phenylpropionyl, 2 (R) - and 2 (S) -dimethoxyphosphoryl-3-phenyl-propionyl, 2 (R) - and 2 (S) -benzyl-5,5-dimethyl-4-oxo hexanoyl, 2 (R) - and 2 (S) -benzyl-4,4-dimethyl-3-oxo-pentanoyl, 2 (R) - and 2 (S) -tert-butylcarbamoyl-3-ct-naphthyl-propionyl or 2 (R) - and 2 (S) -ethoxycarbonyl-3-a-naphthyl-propionyl, furthermore indolyl-2-carbonyl or cycloheptatblpyrrolyl-S-carbonyl, A is the bivalent radical of the amino acid L-histidine, Ra is hydrogen, R3 is cyclohexylmethyl, R _{1 is} hydroxy, R 5 is isopropyl and R is lower alkylamino having 1 to 7 C atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl,

, 43 - ^{2 3 9 2}

Isobutyl, n-pentyl or isopentylamino, and the carbon atoms bearing the radicals R.3, Ri * and R5 have the S configuration, and also pharmaceutically acceptable salts of these compounds.

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

the compound of formula I, wherein Ri is 2 (S) -pivaloyloxy-3-phenylpropionyl, A is the bivalent radical of the amino acid L-histidine, R _{2 is} hydrogen, R _{3 is} cyclohexylmethyl, Ri * is hydroxy, R 5 is isopropyl and Re n-butylamino and the the R3, R4 and R5 bearing C atoms have the S configuration and their pharmaceutically acceptable salts,

the compounds of the formula I in which Ri 2 is (R, S) -, 2 (R) - or 2 (S) -dimethoxyphosphoryl-3-phenyl-propionyl, A den. bivalent radical of the amino acid L-histidine, R 2 is hydrogen, R 3 is cyclohexylmethyl, R 1 * is hydroxy, R 5 is isopropyl and R is n-butylamino and the carbon atoms bearing the radicals R ₃ , R ₁ and R 5 have the S configuration, and the pharmaceutically acceptable salts

the compounds of the formula I in which Ri 2 (R, S) -, 2 (R) - or 2 (S) -benzyl-5,5-dimethyl-4-oxo-hexanoyl, A is the bivalent radical of the amino acid L-histidine R2 is hydrogen, R3 is cyclohexylmethyl, Ri * is hydroxy, R5 is isopropyl and Re is n-butylamino, and the C atoms carrying the radicals R3, Ri * and R5 have the S configuration, and the pharmaceutically acceptable salts thereof,

the compound of the formula I in which Ri 2 is (R, S) -benzyl-4,4-dimethyl-3-oxo-pentanoyl, A is the bivalent radical of the amino acid L-histidine, R 2 is hydrogen, R 3 is cyclohexylmethyl, R 1 * is hydroxy, R 5 Isopropyl and Re n-butylamino and the carbon atoms bearing the radicals R3, Ri * and R5 have the S configuration, and the pharmaceutically acceptable salts thereof,

239 21

the compound of the formula I in which Ri 2 is (R, S) -ethoxycarbonyl-3-a-naphthyl-propionyl, A is the bivalent radical of the amino acid L-histidine, R _{2 is} hydrogen, R _{3 is} cyclohexylmethyl, R 1 * is hydroxy, R 5 isopropyl and Rn n-butylamino and the carbon atoms bearing the radicals R3, Ru and R5 have the S-configuration, and the pharmaceutically acceptable salts thereof,

the compound of the formula I in which Ri is cyclohepta [b] pyrrolyl-5-carbonyl, A is the bivalent radical of the amino acid L-histidine, R _{2 is} hydrogen, R _{3 is} cyclohexylmethyl, R _{2 is} hydroxyl, R 5 isopropyl and R 6 is n-butylamino and the radicals R ₃ , Ru and R 5 bearing C atoms have the S configuration, and their pharmaceutically acceptable salts,

and the compound of the formula I in which Ri 2 is (S) -pivaloyloxy-3-phenylpropionyl, A is the bivalent radical of the amino acid L-histidine, R _{2 is} hydrogen, R ₃ isobutyl, Ru is hydroxyl, R 5 is cyclohexylmethyl and R _{2 is} n-butylamino and the carbon atoms bearing the radicals R ₃ and Ru have the S configuration and their pharmaceutically acceptable salts.

Procedure :

The compounds of the formula I according to the invention and salts of such compounds having at least one salt-forming group are obtained by methods known per se, e.g. 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 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

-45- 239 21

b) for the preparation of compounds of formula I, wherein Rk is hydroxy, the keto group in a compound of formula

ι δ? 6

Ri-AX ₂ -N-CH-C-CH ₂ -CH-CR ₆ (II),

? ⁵ 6

-CH-C

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 to a hydroxy group by reaction with a suitable reducing agent, or

c) for the preparation of compounds of formula I, wherein Ri »is hydroxy, an aldehyde compound of the formula

Ri-AX ₂ -N-CH-CH (III),

in which the substituents have the meanings mentioned and free functional groups, with the exception of the aldehyde group, optionally present in slotted form, with an organometallic compound of the formula

M - CH ₂

-CH-CR ₆ (IV),

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

Ri-AN-CH-CH-CH ₂ -OH-CR ₆ (V),

wherein X is a nucleofuge leaving group, the other substituents have the meanings given above and free functional groups are optionally in protected form, the substituent X exchanged with a substituent Ri »in nucleophilic form introducing reagent against Ri ₊ , or

e) in a compound of the formula

R2 fci "$ 5 Ri-AN-CH-CH-CH ₂ -OH CN (VI)

in which the substituents have the meanings mentioned and existing functional groups are optionally in protected form, the cyano group is converted into an N-substituted carboxamido group - (C-O) Re, or

f) for the preparation of a compound of the formula I in which R 1 * is free hydroxy, an epoxide of the formula

Ri - A - N - CH - cfi - ciH - CH - C - R ₆ (VII)

wherein the sub-substituents have the meanings given and free functional groups are optionally present in protected form, with a regio-selective reducing agent reduced to the corresponding alcohol, and if desired

g) splits off protecting groups present in an available compound and / or, if desired, after carrying out one of the abovementioned processes a) -f) or any other process for preparing 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.

_47- i-w ^ i.i ^

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 carboxy-terminated compound of formula I which can be condensed with a fragment complementary to the compound of formula I to form an amide bond are e.g. Compounds of the formulas Ri-OH, Ri-A-OH or

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 ± n situ.

Activated esters, especially at the linking carbon atom of the esterifying radical, are unsaturated esters, e.g. vinyl ester type, such as vinyl esters (obtainable, for example, by transesterification of a corresponding ester with vinyl acetate, activated vinyl ester method), carbamoylvinyl esters (obtainable, for example, by treating the corresponding acid with an isoxazolium reagent, 1,2-oxazolium or 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 Ν, Ν'-disubstituted Carbodiimide, eg N, N * -dicyclohexylcarbodiimide; carbodiimide method), or Ν, Ν-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-attracting Substituents suitably substituted phenyl

239 21Q

ester (obtainable, for example, by treating the corresponding acid with a suitably substituted phenol, for example 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence 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 base, cyanomethyl ester method), thioesters, in particular, if appropriate, 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, activated thiolester method), 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-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3-dicarboximide, 1-hydroxybenzotriazole or 3 -Hydroxy-3,4-dihydro-l, 2,3-benzotriazin-4-one, for example by the anhydride or carbodiimide method, activated N-hydroxy ester method).

Anhydrides of acids may be symmetrical or preferably mixed anhydrides of these acids, e.g. Anhydrides with inorganic acids, such as acid halides, in particular acid chlorides (obtainable, for example, by treating the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride, acid chloride method), azides (obtainable, for example, from a corresponding acid ester via the corresponding hydrazide and its treatment with nitrous acid, azide method), Anhydrides with carbonic monoesters, eg Carbonic acid lower alkyl halides (obtainable, for example, by treating the corresponding acid with chloroformic acid lower alkyl esters or with a 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example 1-lower alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, mixed O-alkylcarbonic anhydride method) or 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.

239 21

vaten (eg those which can be obtained with phenyl-N-phenylphosphoramidochloridat) or with phosphorous acid derivatives, or 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 Phenylniederalkancarbonsäurehalogenid, eg Phenylacetic acid, pivalic acid or trifluoroacetic acid chloride; mixed carboxylic acid anhydride method) or with organic sulfonic acids (obtainable, for example, by treating a salt such as an alkali metal salt, the corresponding acid with a suitable organic sulfonic acid halide such as lower alkanoic or aryl, eg methane or p Toluenesulfonyl chloride; mixed sulfonic acid anhydride method) and symmetrical anhydrides (obtainable, for example, by condensation of the corresponding acid in the presence of a carbodiimide or of 1-diethylaminopropyne; symmetrical anhyrid method e).

Suitable cyclic amides are in particular amides with five-membered diazacycles of aromatic character, such as amides with imidazoles, e.g. Imidazole (obtainable, for example, by treating the corresponding acid with Ν, Ν'-carbonyldiimidazole; imidazole method), or pyrazole, e.g. 3,5-dimethylpyrazole (obtainable, for example, via the acid hydrazide by treatment with acetylacetone; pyrazolide method).

Fragments complementary to the compound of formula I having a free amino group are e.g. depending on the meaning of Re, a primary or secondary amine, furthermore compounds of the formulas

Rz Ru Rs O

HAN-CH-CH-CH ₂ -CH-CR ₆

R2 Rii Rs

or HN-CH-CH-CH ₂ -CH-C-R ₆

The amino 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 is present 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 chlorophosphite or tetraethylpyrophosphite. 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 is replaced by halocarbonyl, e.g. Chlorocarbonyl, substituted or modified as 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.

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

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, hydroxy and mercapto groups, may be protected by suitable protecting groups (conventional protecting groups), which are usually used in the synthesis of peptide compounds, but also of cephalosporins and penicillins are used. These protective groups may already be present in the precursors and are intended to protect the functional groups concerned against undesirable side reactions such as acylations, etherifications, 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.

239 21O

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 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, in "The Peptides"; Volume 3 (Ed. E. Gross and J. Meienhofer), Academic Press, London and New York 1981, as well as in "Methods of Organic Chemistry", Houben-Weyl, 4th Edition, Bd. 15/1, Georg Thieme Verlag, Stuttgart 1974, described.

A carboxy group is e.g. protected as an ester group which is selectively cleavable under gentle conditions. A carboxy group protected in esterified form is esterified primarily by a lower alkyl group which is branched in the 1-position of the lower alkyl group or substituted in the 1- or 2-position of the lower alkyl group by suitable substituents.

A protected carboxy group esterified by a lower alkyl group branched at the 1-position of the lower alkyl group is, for example, tert-lower alkoxycarbonyl, e.g. tert-butoxycarbonyl, 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. Chloro, and / or nitro mono-, di- or trisubstituted phenyl, for example benzyloxycarbonyl, substituted by said substituents benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl substituted by said substituents, e.g. Di (4-methoxyphenyl) -methoxycarbonyl.

A protected carboxy group esterified by a lower alkyl group 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. Methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl, 1-lower-alkylthio-lower alkoxycarbonyl, e.g. 1-methylthiomethoxycarbonyl or

2 3 9 2 ί Ο

1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl, e.g. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, and 2-tri-lower alkylsilyl-lower alkoxycarbonyl, e.g. 2-Trimethylsilyläthoxycarbonyl.

A carboxy group may also be protected as an organic silyloxycarbonyl group. An organic silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbonyl group, e.g. Trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group may also be represented by two lower alkyl groups, e.g. Methyl groups, and the amino group or the carboxy group of a second molecule of the formula I be substituted. Compounds with such protecting groups can be e.g. with dimethylchlorosilane as the silylating agent.

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

An amino group may e.g. be protected in the form of an acylamino, arylmethylamino, etherified mercaptoamino or silylamino group or as an azido group.

For example, in a corresponding acylamino group, acyl is the acyl radical of an organic carboxylic acid with e.g. up to 18 carbon atoms, in particular an optionally, e.g. by halogen or aryl, substituted lower alkanecarboxylic acid or optionally, e.g. by halogen, lower alkoxy or nitro, substituted benzoic acid, or preferably a carbonic monoester. Such acyl groups are, for example, lower alkanoyl such as Fonnyl, acetyl, propionyl or pivaloyl, halo-lower alkanoyl, e.g. 2-haloacetyl such as 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2-trichloroacetyl, optionally e.g. halo, lower alkoxy or nitro substituted benzoyl, e.g. Benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or in the 1-position of the lower alkyl

residual branched or in the 1- or 2-position suitably substituted lower alkoxycarbonyl, e.g. tert-lower alkoxycarbonyl such as tert-butoxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals optionally substituted, e.g. 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, e.g. Benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or di- (A-methoxyphenyl) -methoxycarbonyl, aroylmethoxycarbonyl, e.g. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, 2-tri-lower alkylsilyl-lower alkoxycarbonyl, e.g. 2-trimethylsilylethoxycarbonyl, or 2-triarylsilyl-lower alkoxycarbonyl, e.g. 2-Triphenylsilyläthoxycarbonyl.

An arylmethylamino group is e.g. Mono-, di- or in particular triphenylmethylamino, e.g. Benzyl, diphenylmethyl or tritylamino.

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

A silylamino group is, for example, a tri-lower alkylsilylamino group, e.g. Trimethylsilylamino. The silicon atom of the silylamino group may also be represented only by two lower alkyl groups, e.g. Methyl groups, and the amino group or carboxyl group of a second molecule of the formula I be substituted. Compounds with such protecting groups can be e.g. with dimethylchlorosilane as the silylating agent.

Preferred amino protecting groups are acyl radicals of carbonic monoesters, especially tert-butoxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, furthermore trityl or formyl.

239 21O

A hydroxy group may be exemplified by an acyl group, e.g. by halogen, e.g. Chlorine, substituted lower alkanoyl, e.g. 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, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or trityl. A hydroxy group can also be replaced by tri-lower alkylsilyl, e.g. Trimethylsilyl or dimethyl-tert-butylsilyl, an easily cleavable alkyl group such as tert-lower alkyl, e.g. tert-butyl, an oxa or a thiaaliphatic or cycloaliphatic hydrocarbon radical, for example 1-lower alkoxy-lower alkyl or 1-lower-alkylthio-lower alkyl, e.g. Methoxyethyl, 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, as well as 1-phenyl-lower alkyl, e.g. Benzyl, diphenylmethyl or trityl, the phenyl radicals being exemplified by halogen, e.g. Chlorine, lower alkoxy, e.g. Methoxy, and / or nitro may be substituted.

For example, two adjacent hydroxyl groups may be protected by a preferably substituted methylene group, e.g. by lower alkylidene, e.g. Isopropylidene, cycloalkylidene, e.g. Cj * clohexylidene, or benzylidene.

A mercapto group, e.g. in cysteine, may be particularly protected by S-alkylation with optionally substituted alkyl radicals, thioacetal formation, S-acylation or by the formation of asymmetric disulfide moieties. Preferred mercapto protecting groups are e.g. optionally in the phenyl radical, e.g. 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, tetrahydropyranyl, acylaminomethyl, benzoyl, benzyloxycarbonyl or lower alkylaminocarbonyl, such as ethylaminocarbonyl.

The condensation for the preparation of the amide bond can be carried out in a conventional manner, for example as in standard works, such as "Houben-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," Priciples of Peptide Synthesis ", Springer-Verlag, Berlin 1984, described.

The condensation can be carried out in the presence of one of the conventional condensing agents. Common condensing agents are e.g. Carbodiimides, for example diethyl, dipropyl, N-ethyl-N '- (3-dimethylaminopropyD-carbodiimide or, in particular, dicyclohexylcarbodiimide, furthermore suitable carbonyl compounds, for example carbonyldiimidazole, 1,2-oxazolium compounds, for example 2-ethyl-5-phenyl- 1,2-oxazolium-3'-sulphonate and 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, furthermore activated phosphates, eg diphenylphosphoryl azide, diethylphosphoryl cyanide or phenyl-N-phenylphosphoramidochloridate.

If desired, an organic base is added, e.g. a tri-lower alkylamine with bulky radicals, e.g. Ethyldiisopropylamine, or a heterocyclic base, e.g. Pyridine, 4-dimethylaminopyridine or preferably N-methylmorpholine.

The condensation of acid anhydrides with amines can e.g. in the presence of inorganic carbonates, e.g. Alkali metal carbonates or bicarbonates, such as sodium or potassium carbonate or bicarbonate (usually together with a sulfate).

239 2 1O

The condensation is preferably carried out in an inert, polar, aprotic, preferably anhydrous, solvent or solvent mixture, for example in a carboxamide, for example formamide or dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, cyclic ether, for example, tetrahydrofuran, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or in mixtures thereof, optionally at reduced or elevated temperature, for example in a temperature range from about -40 ⁰ C to about + 100 ⁰ C, preferably from about -10 ⁰ C to about +50 ⁰ C, and optionally under an inert gas, eg nitrogen atmosphere.

Reactive acid derivatives can also be formed in situ. So you can, for example Form Ν, Ν'-disubstituted amidinoesters in situ by mixing 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. Dicyclohexylcarbodiimid, implemented. 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 starting materials in the presence of a disubstituted carbodiimide, e.g. Dicyclohexylcarbodiimide, and an N-hydroxylamine or N-hydroxyamide, e.g. N-hydroxybenzene triazole, N-hydroxysuccinimide or N-hydroxy-5-norbornene-2,3-dicarboximide, optionally in the presence of a suitable base, for example 4-dimethylaminopyridine, N-methylmorpholine or ethyldiisopropylamine.

Process b) (reduction 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).

- 57- 239 2 1

For reducing 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 more rapidly than the amide groups present in compounds of the formula I.

First of all, suitable borohydrides, such as alkali metal borohydrides, especially sodium borohydride, lithium borohydride or sodium cyanoborohydride, or suitable aluminum hydrides, such as bulky group alkali metal-lower alkoxyaluminum hydrides, e.g. Lithium tris-tert-butoxyaluminum.

The reduction can also be carried out with hydrogen in the presence of suitable heavy metal catalysts, e.g. Raney nickel or platinum or palladium catalysts, e.g. Platinum or palladium activated carbon, or according to Meerwein-Ponndorf-Verley with the aid of aluminum alkanolates, preferably aluminum 2-propoxide or ethanolate.

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 -80 ⁰ C and the boiling point of the solvent, preferably between -20 ⁰ C and + 100 ⁰ C, if necessary under inert gas, for example nitrogen or argon. An excess of the reducing agent is necessary in particular if it also reacts with the solvent, for example the protons of a protic solvent.

When sodium borohydride is used, polar protic solvents, e.g. Methanol, ethanol or isopropanol; when using the other reducing agents, the polar, aprotic solvents mentioned under process a), e.g. 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, a metal radical -M is e.g. -Li or -MgHaI, e.g. -MgCl, -MgBr or -MgJ.

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, for example in an ether, such as diethyl ether or tetrahydrofuran, or a hydrocarbon, such as benzene or toluene, or mixtures thereof, if appropriate with cooling, in particular after the beginning of the reaction, for example to about -30 ⁰ C, or with heating, for example up to the boiling temperature of the reaction mixture, optionally in an inert gas, eg 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-donating solvents, e.g. Water (ice-water mixture) or dilute aqueous acids, e.g. diluted mineral acids, such as dilute aqueous sulfuric acid, or dilute organic acids, e.g. 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 is e.g. from the corresponding halide, e.g. Chloride, by reaction with a metallating agent, e.g. 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 a mineral acid, e.g. Hydrohalic acid, such as hydrochloric, hydrobromic or hydroiodic acid, also sulfuric acid, or halogenated sulfuric acid, e.g. Fluorosulfuric acid, or with a strong organic sulfonic acid such as an optional, e.g. by halogen, such as fluorine, substituted lower alkanesulfonic acid or an aromatic sulfonic acid, e.g. an optionally substituted by lower alkyl, such as methyl, halogen, such as bromine and / or nitro substituted benzenesulfonic acid, e.g. a methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid or hydroxy esterified with hydrazoic acid.

A substituent Ri, in nucleophilic form introducing reagent depends on the meaning of Ri, a hydroxide-containing base, for example sodium or potassium hydroxide (Ri ₄ OH), an alcohol, for example methanol or ethanol (Ri, "etherified hydroxy) or the salt of a carboxylic acid, eg silver acetate (Ri, esterified hydroxy).

Preferably, the reaction conditions are chosen so that the reaction proceeds essentially as second order nucleophilic substitution (S _W 2). For example, a compound of formula V in which X is a leaving group with high polarizability of the electron shell, for example iodine, in a polar aprotic solvent, for example acetone, acetonitrile, nitromethane, dimethyl sulfoxide or dimethylformamide, with the silver salt of a carboxylic acid, eg Silver acetate, implement. The reaction with a hydroxide-containing base is preferably in water, which is optionally mixed as a solubilizer, an organic solvent such as ethanol, tetrahydrofuran or acetone, and the

Reaction with an alcohol in an excess of this alcohol, optionally in the presence of one of the above polar aprotic solvents. The substitution reaction is optionally 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 ° C to about +50 ⁰ C, and optionally under an inert gas, for example nitrogen atmosphere carried out.

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

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 give an N-substituted compound of the formula I.

Acid-catalyzed, preferably hydrogen chloride-catalyzed, addition of alcohols to the nitriles of the formula VI gives Carbonsaureesterimide yielding by thermal rearrangement at temperatures above about 80 ⁰ C amides of the formula I.

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).

Reducing agents may be used 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 sufficient and as large a 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 can be e.g. so that one adds to 1 mole of the compound of formula VII and an excess, e.g. 1.4-3 mol, sodium cyanoborohydride in tetrahydrofuran at elevated temperature, e.g. under reflux, a solution of boron trifluoride etherate, BF3'0 (CaHs) 2 »in tetrahydrofuran is added so that the pH of the reaction solution is kept close to the turnover point of the also added indicator bromocresol green. The reduction with lithium borohydride is preferably carried out in an ether, e.g. Tetrahydrofuran, 1,2-dimethoxyethane or Diäthylenglykoldimethyläther, carried out at temperatures between room temperature and reflux temperature.

Method g) (postoperations) ;

In an available compound of the formula I in which R 1, R 2, R 3, R 4, R 5 and R 6 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 form an esterified carboxy group in convert a carboxy or a carboxamide group.

Substitution of a carboxamide group or other amino group occurs e.g. by alkylation.

Suitable means of alkylating a carboxamide group in a compound of formula I are e.g. Diazo compounds, e.g. Diazomethane. Diazomethane can be decomposed in an inert solvent, the free methylene formed reacting with the carboxamide group in the compound of formula I. The decomposition of diazomethane is preferably carried out catalytically, e.g. in the presence of a noble metal in finely divided form, e.g. Copper, or a noble metal salt, e.g. Copper (I) chloride or copper (II) sulfate.

Further alkylating agents are the alkylating agents mentioned in German Offenlegungsschrift 2 331 133, e.g. Alkyl halides, sulfonic acid esters, sea salt or 1-substituted 3-aryl triazene. which can be reacted under the reaction conditions mentioned there with a compound of formula I with a carboxamide group.

For the esterification of a carboxy group in a compound of formula I, one can use the free acid or convert the free acid into one of the reactive derivatives mentioned under process a) and react with an alcohol, or the free acid or a reactive salt, e.g. 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 alkylating agents mentioned above for the substitution of the carboxamide group and under the same reaction conditions, e.g. with diazomethane, alkyl halides, sulfonic acid esters, sea salt, 1-substituted 3-aryl triazenes, etc.

For converting an esterified carboxy group in a compound of the formula I into a free carboxy group, one of the processes described under process a), cleavage of the carboxy protecting groups

- to -

Methods or, if desired, an alkaline saponification according to the reaction conditions mentioned in Organikum, 15th edition, VEB German publishing house of the sciences, Berlin (east) 1976, are used.

In a compound of the formula I, an esterified carboxyl group can be converted into an optionally substituted carboxamide group by aminolysis with ammonia or a primary or secondary amine. 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 other functional groups are optionally present in protected form, the free hydroxy group, for example the hydroxy group Ri 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, e.g. with diazomethane, alkyl halides, sulfonic acid esters, sea salt, 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 compound, e.g. 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 wherein one or more functional groups are protected, these groups, e.g. Carboxy-, amino, hydroxy and / or mercapto groups, in a conventional manner, by solvolysis, in particular hydrolysis, optionally enzymatic hydrolysis, alcoholysis or acidolysis, or by means of reduction, in particular hydrogenolysis, or chemical

Reduction, optionally in stages or simultaneously released. The deprotection is described in the standard works referred to earlier in the "protecting groups" section.

For example, protected carboxy, e.g. tert-lower alkoxycarbonyl, lower alkoxycarbonyl substituted in the 2-position by an organic silyl group or lower alkoxy or lower alkylthio substituted in the 1-position, or optionally substituted diphenylmethoxycarbonyl e.g. by treatment with a suitable acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol or anisole, into free carboxy. Optionally substituted benzyloxycarbonyl may be e.g. by means of hydrogenolysis, i. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. Further, suitably substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl may also be obtained by reduction, e.g. by treatment with an alkali metal, e.g. Sodium dithionite, or with a reducing metal, e.g. Zinc, or reducing metal salt, such as a chromium II 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. by hydroxy, substituted lower alkanecarboxylic acid, e.g. Acetic acid, formic acid, glycolic acid, diphenyl glycolic acid, lactic acid, mandelic acid, 4-chorormandic 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 obtained by treatment with one, the

Fluoride anion supplying salt of hydrofluoric acid, such as an alkali metal fluoride, e.g. 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 tetra-lower alkylammonium fluoride or tri-lower alkylarylammonium fluoride, e.g. Tetraäthylaimnoniumfluorid or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent such as dimethyl sulfoxide or Ν, Ν-dimethylacetamide, are converted into free carboxy. With an organic silyl group such as tri-lower alkylsilyl, e.g. Trimethylsilyl, esterified carboxy may be solvolytically, e.g. by treatment with water, an alcohol or acid, or also a fluoride, as described above. Esterified carboxy can also be cleaved enzymatically, e.g. esterified arginine or lysine, such as lysine methyl ester, by trypsin.

A protected amino group is set free in known per se and depending on the nature of the protective groups in various ways, preferably by solvolysis or reduction. 2-halo-lower alkoxycarbonylamino (optionally after conversion of a 2-bromo-lower alkoxycarbonylamino group to a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can 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, cleaved. Optionally substituted diphenylmethoxycarbonylamino, tert-loweralkoxycarbonylamino or 2-tri-lower alkylsilyl-lower alkoxycarbonylamino may be prepared by treatment with a suitable acid, e.g. Formic or trifluoroacetic acid, optionally substituted benzyloxycarbonylamino e.g. by means of hydrogenolysis, i. by treating with hydrogen in the presence of a suitable hydrogenation catalyst such as a palladium catalyst, optionally substituted triarylmethyland.no or formylamino e.g. by treating with

an acid such as mineral acid, e.g. Hydrochloric acid, or an organic acid, e.g. Formic, acetic or trifluoroacetic acid, optionally in the presence of water, and an amino group protected with an organic silyl group, e.g. be released by hydrolysis or alcoholysis. One by 2-haloacetyl, e.g. 2-chloroacetyl, protected amino group can 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 thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting condensation 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 also possible to cleave directly onto a heteroatom, such as nitrogen, bound silyl, 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 "medium, such as a halogenated Kolenwasserstoff, for example methylene chloride, or else in water or a mixture of water and an organic solvent such as an alcohol or dioxane, at about 20 ⁰ C to 25 ° 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 2,2-dichloroacetyl protected hydroxy or mercapto group is e.g. by basic hydrolysis, by a tert-lower alkyl or by a 2-oxa or 2-thia-aliphatic or -cycloaliphatic hydrocarbons

239 21O

hydrogen radical by acidolysis, e.g. by treatment with a mineral acid or a strong carboxylic acid, e.g. Trifluoroacetic acid, released. Two hydroxy groups taken together by means of a preferably substituted methylene group, such as lower alkylidene, e.g. Isopropylidene, cycloalkylidene, e.g. Cyclohexylidene, or benzylidene, can be released by acid solvolysis, especially in the presence of a mineral acid or a strong organic acid.

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 e.g. by treating with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, or with inorganic alkali or alkaline earth metal salts, e.g. Sodium bicarbonate, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of the formula I are obtained in a customary manner, e.g. by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of formula I which are e.g. a free carboxy group and a free amino group may e.g. 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 be converted into the free compounds in the usual way: metal and ammonium salts, e.g. by treatment with suitable acids, acid addition salts e.g. by treating with a suitable basic agent.

Stereoisomer mixtures, in particular mixtures of diastereomers, can be prepared in a manner known per se, e.g. by fractional crystallization, chromatography, etc., are separated into the individual isomers.

Racemates can be prepared in a manner known per se, e.g. 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-Ri ₄ -C-AtOm, the configuration can be specifically reversed. For example, the configuration on the CH-Ri ₄ -AtOm can be reversed by nucleophilic second order substitution according to method d) after conversion of the group Ri ₄ into a nucleofuge leaving group X and reaction with a reagent introducing the same substituent Ri ₄ .

The invention also relates to those embodiments of the process starting from a compound obtainable as 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. 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 carriers.

The pharmaceutical compositions according to the 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

239 21O

contain materials. 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.

To to warm blooded animals, including humans, of about 70 kg body weight, administered doses are between about 3 mg and about 3 g, preferably between about 10 mg and about 1 g, for example at approximately 300 mg per person per day, _v divided into preferably 1 to 3 single doses, which can be the same size, for example. 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. Pharmaceutical preparations according to the invention may e.g. in dosage unit 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.

Preferably, solutions of the active ingredient are used, as well as suspensions, in particular isotonic aqueous solutions or suspensions, these being e.g. for lyophilized preparations containing the active ingredient alone or together with a carrier material, e.g. Mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating oemotic pressure and / or buffers, and are prepared in a manner known per se, e.g. by conventional solution or lyophilization process. The solutions mentioned or

Suspensions may contain viscosity increasing agents such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

As an oily component, suspensions in oil contain the vegetable, synthetic or semisynthetic oils 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 of 8-22, especially 12-22, carbon atoms, e.g. Lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachic acid, behenic acid or corresponding unsaturated acids such as e.g. 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, e.g. mono-, di- or trihydric alcohol, e.g. 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 M 2735" (polyoxyethylene glycerol trioleate from Gattefosse, Paris), "myglyol 812" (triglyceride of saturated fatty acids of chain length Ce to C 12 from Chemische Werke Witten / Ruhr, 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 carried out in the usual way under sterile conditions, as well as the filling in ampoules or vials and the closure of 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 excipients, into tablets or dragee cores. They can also be incorporated into plastic carriers that release or diffuse the active ingredient.

239 21O

Suitable carriers are, in particular, fillers, such as sugars, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch pastes using e.g. 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, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or Calciurastearat, 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, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of enteric coatings, solutions of suitable cellulose preparations, such as ethyl cellulose phthalate or hydroxypropylmethylcellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, e.g. for the identification or labeling of different doses of active substance.

Starting materials :

New starting materials and / or intermediates, as well as processes for their preparation, are also the subject of the present invention. Preferably, such starting materials are used and the reaction conditions are chosen so as to arrive at the compounds listed as preferred.

239 21O

The starting materials for carrying out process a) can be prepared by methods known per se, e.g. from the relevant amino acids by condensation analogous to the method a) described above.

For example, one can use a compound of the formula

OH R ₅ 0 H ₂ N-CH-CH-CH ₂ -CH-C-R ₆ (VIII),

wherein R3, R5 and R _{6 have} the meanings mentioned under formula I, by reacting a compound of formula

- CH - I -

ZiHN-CH-C-H (IX),

wherein R3 has the meaning given and Zi is an amino protecting group, with a sulfur-ylide compound in an epoxide of the formula

ZiHN - CH - CH ₂ H ₂ (X),

wherein R3 and Zi have the abovementioned meanings, the obtainable compound (X) is reacted, if appropriate after separation of the isomers with a reagent introducing a nucleofuge leaving group X, the compound of the formula

? ZiHN - CH - CH - CH ₂ --X (XI),

wherein R3 and Zi have the meanings mentioned and X is a nucleofugic leaving group, with a Carbony! connection of the formula

- 73- 2 39 2 1 O

R - (C-O) -R, (XII), a b

wherein each of R and R independently represents hydrogen, lower alkyl, aryl or aryl-lower alkyl, R and R together represent optionally bridged alkylidene of 4 to 12 carbon atoms, or a reactive derivative of said carbonyl compound in the presence of an acidic reagent, the compound obtainable the formula

(XIII)

CH-CH Ra CH ₂ X

wherein the substituents have the meanings given, with a carboxylic ester salt of the formula

j R ₅ -CH-C-OZ ₂ 1 Y® (XIV),

wherein Rs has the meaning mentioned under formula I, Z _{2 is} a carboxy-protecting group and Y is a cation, for example an alkali metal, for example the sodium or preferably the lithium ion, and in an available compound of the formula

Z ₁ / R ₅ O (XV),

CH-CH CH -C-OZ ₂ R ₃ CfT ₂

3 ^ n ₂

in which the substituents have the meanings mentioned, the carboxy-protecting group Z _{2 is} split off and / or an isomer mixture which is obtainable is separated into the individual isomers, the available compound having a free carboxy group (Z ₂ "H) is amidated with an amine R 6 -H, and available in one Compound of the formula

R 0 (XVI),

HC ^ CH - C - R ₆

239 21O

wherein the substituents have the meanings mentioned, opens the ring with a suitable solvolysis reagent and optionally cleaves the protecting group Ζχ.

The process is carried out analogously to the process described in European Patent Application 143,746.

The gesarate reaction sequence for the preparation of the intermediates of formula VIII can be carried out in situ or after isolation of any or all of the process-available precursors.

Compounds of the formula II are prepared, for example, by reacting a carboxylic acid of the formula

R ₁ -AN-CH-C-OH (XVII)

or a suitable functional derivative thereof, in which the substituents have the meanings given and free functional groups, with the exception of the optionally modified carboxy group, optionally in protected form, with an organometallic compound of the formula IV, wherein R5 and Re, have the meanings mentioned and M is a Metal radical, for example -Li or -MgHaI, for example -MgCl, -MgBr or -MgJ, reacting and eolvolysiert the formed addition product.

Suitable functional derivatives of carboxylic acids of formula XVII are, for example, the corresponding lithium salt of the carboxylic acid, a carboxylic acid halide, e.g. Carboxylic acid chloride, an anhydride, e.g. the symmetrical carboxylic anhydride or a mixed carboxylic acid anhydride with a sterically hindered carboxylic acid, e.g. with pivalic acid, or a thioester, e.g. 2-pyridylthio.

The reaction of a carboxylic acid of formula XVII or a suitable functional derivative thereof with a compound of formula IV is carried out in the usual manner, e.g. according to the reaction conditions specified in process c), but optionally under

Cooling, for example at temperatures of about -5O ° C to about 0 ⁰ C. In a preferred embodiment of the method, a 2-pyridylthioester of the carboxylic acid of formula XVII is reacted with a Brornmagnesium compound of formula IV.

Compounds of formula III can be prepared by processes known per se, for example by reacting in a compound of formula XVII, wherein the substituents have the meanings mentioned and free functional groups are 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

Jh J -

Hal - CH ₂ - CH - C - R ₆ (XVIII),

e.g. of the chloride, with a metalating agent, e.g. Magnesium, lithium or tert-butyllithium, are produced.

Compounds of the formula V are prepared, for example, by reacting an aldehyde of the formula III with an organometallic compound of the formula IV according to process c) and the resulting hydroxy compound of the formula I, optionally after separation of the isomers, having a definition corresponding to X strong esterified organic or inorganic acid, for example as described above for the preparation of the compound of formula XI from the corresponding diol.

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

R2 Ru Rs - N - CH - CH - CH ₂ - CH -

Ri-A - N - CH - CH - CH ₂ - CH - Hal (XIX),

239 21O

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 Lösungsmitel so that a reaction can take place. Such salts are e.g. Ammonium cyanide, alkali metal or alkaline earth metal cyanides, e.g. Sodium or potassium cyanide, or transition metal cyanides, e.g. 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 e.g. the reaction is carried out with those 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 carboxamides, e.g. Dimethylformamide or dimethylacetamide, nitriles, e.g. Acetonitrile or propionitrile, or di-lower alkyl sulfoxides, e.g. 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 optionally in an inert gas, eg nitrogen atmosphere.

Epoxides of formula VII are e.g. prepared by reacting a compound of formula IX with a phosphoranylidene compound of formula

R ^C ^ P - CH - CH - C - OZ ₂ (XX),

R ^{C /}

- 77 - 239 2 1

wherein R 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-C-OZ ₂ (XXI),

-C-

converted with an oxygenating agent containing the peroxo group in 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 Ri-A and R6.

R is preferably phenyl. The reaction of a compound of the formula IX with a phosphoranylidene compound of the formula XX is carried out under the reaction conditions known for Wittig reactions and described, for example, in the organic compound. The thereby obtainable olefin of the formula XXI is optionally reacted in situ with the oxidizing agent, for example peracetic acid or m-chloroperbenzoic acid. The cleavage of the protective groups Zi and Z ₂ and the introduction of the groups Ri-A- or Re is described above under process a).

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 values are determined on silica gel thin layer plates in the following solvent systems:

Nl chloroform-methanol 9: 1

N2 chloroform-methanol 19: 1

N3 ethyl acetate-n-hexane 1: 1

N4 ethyl acetate-n-hexane 1: 4

N5 ethyl acetate-n-hexane 1: 9

N6 methylene chloride ether 4: 1

N7 methylene chloride ether 1: 1

N8 methylene chloride-methanol 9: 1

™ / ö

N9 methylene chloride-methanol

NlO methylene chloride-methanol

Nll methylene chloride-methanol

Nl2 methylene chloride-methanol

N13 Essigeater-n-Hexane

N14 ethyl acetate-n-hexane

N15 ethyl acetate-n-hexane

Nl6 methylene chloride-methanol-water

Nl7 ethyl acetate-n-hexane

N18 ethyl acetate-methanol

N19 ethyl acetate-methanol

N20 methylene chloride-methanol

N21 methylene chloride-methanol

N22 methylene chloride-methanol-water

Chloroform-methanol-ammonia conc.

B2 chloroform-methanol-ammonia conc.

B3 methylene chloride-methanol-Aimnoniak conc.

B4 methylene chloride-methanol-ammonia conc.

B5 methylene chloride-methanol-ammonia conc.

B6 methylene chloride-methanol-ammonia conc.

B7 methylene chloride-methanol-ammonia conc.

B8 methylene chloride-methanol-ammonia conc.

B9 methylene chloride-methanol-ammonia conc.

BIO methylene chloride-methanol-ammonia conc.

BIl methylene chloride-methanol-ammonia conc.

Bl2 methylene chloride-methanol-ammonia conc.

Bl3 methylene chloride-methanol-ammonia conc.

B14 methylene chloride-methanol-ammonia conc.

Bl5 methylene chloride-methanol-ammonia conc.

Bl6 methylene chloride-methanol-ammonia conc.

Bl7 ethyl acetate-pyridine-glacial acetic acid-water

Bl8 n-butanol-pyridine-glacial acetic acid-water

Bl9 pyridine-n-butanol-n-amyl alcohol

Methyl ethyl ketone-glacial acetic acid-formic acid-water

239 21 0 6: 1 20: 1 10: 1 5: 1 4: 1 2: 1 1: 2 300: 10: 1 1: 6 1: 1 4: 1 3: 1 4: 1 40: 10: 1 40: 10: 1 350: 50: 1 1000: 50: 1 350: 50: 1 140: 10: 1 105: 50: 1 90: 10: 1 80: 10: 1 65: 10: 1 50: 10: 1 40: 10: 1 40: 25: 1 30: 10: 1 25: 10: 1 20: 5: 1 10: 10: 1 62: 21: 6: 11 38: 24: 8: 30 25: 20: 15: 10: 3: 3: 25

B2O n-butanol-pyridine-formic acid-water 42: 24: 4: 20

B21 n-butanol-pyridine-glacial acetic acid-water 42: 24: 4: 30

B22 n-butanol-pyridine-formic acid-water 44: 24: 2: 20

B23 methylene chloride-methanol-ammonia conc. 700: 50: 1

B24 methylene chloride-methanol-ammonia conc. 60: 10: 1

B25 methylene chloride-methanol-ammonia conc. 370: 30: 1

B26 methylene chloride-methanol-ammonia conc. 300: 10: 1

B27 methylene chloride-methanol-ammonia conc. 70: 10: 1

B28 methylene chloride-methanol-ammonia conc. 800: 50: 1

B29 methylene chloride-methanol-ammonia conc. 500: 50: 1

B30 methylene chloride-methanol-ammonia conc. 750: 50: 1

B31 methylene chloride-methanol-ammonia conc. 200: 10: 1

B32 methylene chloride-methanol-ammonia conc. 5: 3: 1

B33 methylene chloride-methanol-ammonia conc. 100: 10: 1

51 ethyl acetate-pyridine-glacial acetic acid water 62: 21: 6: 11

52 ethyl acetate-methanol-glacial acetic acid-water 67: 10: 12: 23

53 chloroform-methanol-water-glacial acetic acid 300: 108: 20: 2

54 chloroform-methanol-water-glacial acetic acid 150: 54: 10: 1

55 chloroform-methanol-water-glacial acetic acid 140: 80: 20: 1

56 chloroform-methanol-water-glacial acetic acid 180: 20: 2: 1

57 chloroform-methanol-water-glacial acetic acid 110: 94: 26: 1

58 chloroform-methanol-water-glacial acetic acid - 80: 20: 3: 3

59 chloroform-methanol-water-glacial acetic acid 70: 30: 3: 3

510 methylene chloride-methanol-water-glacial acetic acid 750: 270: 50: 5

511 n-Butanol-glacial acetic acid-water 67:10:23

512 methylene chloride-methanol-water-glacial acetic acid 160: 30: 3: 9

513 ethyl acetate-n-hexane-glacial acetic acid 40: 60: 1

For example, the abbreviation "R _f (Nl)" means that the R _f value was determined in the system Nl. The ratio of the solvents to one another is given in parts by volume.

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

Abbreviations for amino acids and amino acid derivatives:

H-Ala-OH L-Alanine

H-Arg-OH L-arginine

H-Cha-OH L-cyclohexylalanine

H-GIn-OH L-glutamine

H-Glu-OH !, - glutamic acid

H-Glu (OR) -OH L-glutamic acid, wherein the carboxylic acid function

the side chain is esterified with the R radical

H-Gly-OH glycine

H-His-OH L-histidine

H- (N-methyl-His) -OH N ^a -methyl-L-histidine .H-IIe-OH L-isoleucine

H-Leu-OH L-Leucine

H-Lys-OH L-lysine

H-Lys (R) -OH L-lysine, wherein the amino function of the side chain is substituted with the radical R.

H-NIe-OH L-norleucine, (S) -a-aminohexanoic acid

H-Orn-OH L-ornithine, (S) -Ct, 6-valeric acid

H-Om (R) -OH L-ornithine, wherein the amino function of the

Side chain with the radical R is substituted.

H-Phe-OH L-phenylalanine

H- (N-methyl-Phe) -OH N-methyl-L-phenylalanine H- (p-amino-Phe) -OH L-p-aminophenylalanine

H-VaI-OH L-Valine

-NH2 instead of -OH: C-terminal (carboxylic acid) amide -OMe instead of -OH: C-terminal (carboxylic acid) methyl ester -NHMe instead of -OH: C-terminal (carboxylic acid) methylamide

The fragment labeled -Leu-Val- represents the divalent radical of (2S, 4S, 5S) -5-amino-2-isopropyl-4-hydroxy-7-methyloctanoic acid and has the formula

H OH ^N.

α A ^(s) A ^(s)

«Γ γ>

The fragment named -Leu-VaI- is derived from the fragment -Leu-Val- by bridging NH and OH by an isopropylidene group and has the formula

- N · ·

v ¹ ' ^r

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

H 5 (S>

ι ι

• ·

The fragment -Cha- ^ VaI- is derived from the fragment -Ha-Valaryl isopropylidene group.

Fragment -Cha-Val- by bridging NH and OH by a

- 82 - 239 2 1

The fragment named GIy (Ra) -Gy (R _1. ) Means the divalent radical of 2-R (.- 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

H OH R ₅

- \ A ⁸ A,

5 · · · - R ₃ A

The fragment named -GIy (R ₃ ) ^ GIy (Rs) - is derived from the fragment -GIy (R ₃ ) -Gly (Rs) - by bridging NH and OH by an isopropylidene group.

Other abbreviations ;

Section. absolutely (anhydrous) Ac acetyl BOC tert-butoxycarbonyl DCCI dicyclohexylcarbodiimide DCH '- dicyclohexylurea DMF dimethylformamide DMSO dimethyl sulfoxide HOBt 1-hydroxybenzotriazole Minute Minute (s) Sdp. - boiling point Mp. melting point Hours. Hour (s) THF tetrahydrofuran Z benzyloxycarbonyl example 1: N- (quinolyl-2-carbon

54 mg of N- (quinolyl-2-carbonyl) -L-phenylalanine, 41 mg of H-Leu-Val-NHMe and 26 mg of HOBt (Fluka purum, containing 11-13% of water) are dissolved in 2.5 ml of DMF at 0 ^° C cooled. After addition of 45 mg of DCCI is stirred for 15 hrs. With ice cooling and then for 2 days at room temperature. The crystalline DCH is filtered off with suction and the filtrate concentrated in a high vacuum. The residue is added in a mixture of methanol-water-glacial acetic acid (94: 3: 3) for 30 min

239

Stirred 60 ° C and then concentrated. The residue is separated by means of flash chromatography (35 g of silica gel 60, 40-63 μΐη, eluent system N10). The product-containing fractions are evaporated. After drying in a high vacuum, the title compound is obtained as a slightly yellowish powder. R- (N10) - 0.33; R (N13) - 0.08.

The starting material H-Leu-Val-NHMe can be prepared according to the following reaction scheme:

(S) ZHN - CH - CHO

Γ "

CH ₂ -

a)

H ₂ -CH (CH ₃ ) 2 (XXII)

(S)

ZHN -

OH

S) (R) CH-CH-CH ₂ J

CH ₂ -CH (CHa) ₂ (XXIV).

^(s) A

ZHN - CH - CH - CH ₂ CH ₂ --CH (CH ₃ ) ζ

(XXIII)

b)

c)

CH ₂ J

IH ₂ -CH (CH ₃ ) 2 (XXV)

d)

ZIf "O CH (CHa) ₂

(S) (S), H-CH-CH ₂ -CH-COOCh ₃

(R, S)! IH ₂ -CH (CH ₃ ) 2

(XXVI)

e)

Zf- '0 CH (CHa) ₂ (S) (S)

, H-CH-CH ₂ -CH-COOH (R, S)

! h ₂ -ch (ch ₃ ) ₂

f)

(XXVII) (S, S, S-isomer: Z-Leu ^ Val-OH)

f \ D CH (CHa) ₂ (S) (S)

} E -CH-CH ₂ -CH-CO-NHCh ₃ - ² ^ H-Leu-Val-NHMe (S)

! h ₂ -ch (ch ₃ ) ₂

(Z-Leu-Val-NHMe)

a) 8.75 g of sodium hydride (55% in OeI) in a dry sulfonating flask under argon by stirring three times in 85 ml of petroleum ether (bp 40-60 °) and then decanting the solvent freed from OeI. After drying in a high vacuum

obtained a gray powder, which is added dropwise with a solution of 44.1 g Trimethylsulfoxoniumiodid in 180 ml of dimethyl sulfoxide, wherein the temperature rises to about 40 °. The gray suspension is stirred at room temperature for 1 h and then within 50 min. At 10 ° with a solution of 43.4 g of (S) -2-benzyloxycarbonylamino-4-methyl-pentanal (XXII) (preparation: Helvetica Chimica Acta 6 pounds, 450 (1983)) in 180 ml of DMSO. The yellow suspension is stirred for 15 minutes at 10 ° and then for 1.5 hours at room temperature. The yellowish cloudy solution is poured onto 500 g of ice. The aqueous solution is extracted with ether, the organic phase washed with water and evaporated after drying over sodium sulfate. The oily residue is separated by flash chromatography on 2 kg of silica gel (40-63 μΐη) with a mixture of methylene chloride / n-hexane / ethyl acetate (5: 10: 3). The product-containing fractions are combined, evaporated and dried under high vacuum. The epoxide (XXIII) (diastereomer mixture, about 3: 1) is obtained as a slightly yellowish oil. _Rf (B1) - 0.57; R _f (N4) - 0.16.

b) 33.8 g of compound (XXIII) are taken up in 255 ml of acetonitrile and the resulting solution is cooled to 0 °. After adding 19.24 g of sodium iodide are added dropwise at 0 ° 16.27 ml of trimethylchlorosilane over 30 min. The mixture is stirred for 40 minutes at 0-3 ° and then poured onto 250 ml of ice-cold water, the aqueous mixture is extracted with ether and the organic phase is washed with 10% aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution After drying over sodium sulfate Evaporation gives an oily mixture of the desired alcohol (XXIV) and the corresponding trimethylsilyl ether (both diastereomer mixtures) The free alcohol is separated by flash chromatography (2 kg of silica gel 60, 40-63 μιη, eluent N 4) product-containing, combined fractions give the alcohol (XXIV) as OeI After combining and evaporating the fractions containing the trimethylsilyl ether, the residue is taken up in THF, treated with a solution of 2.67 g of tetrabutylammonium fluoride in water and

The resulting mixture is stirred for 3 days at room temperature. The solution is then extracted by shaking between water and ether. The organic phase is washed with water, dried over sodium sulfate and evaporated. After drying in a high vacuum, an additional amount of the diastereomer mixture of compound (XXIV) is obtained as OeI. The entire amount of the diastereomer mixture (XXIV) is separated for further purification in two parts by medium-pressure chromatography (1.4 kg Lichroprep® Si 60, 25-40 μΐη, eluent: ethyl acetate / n-hexane (1: 8), fractions of approx. 220 ml). By crystallization from petroleum ether (bp 40-60 °), the more polar component of the raw material and the mixed fractions can be partially enriched (mp. 104-106 °). The two diastereomers are obtained in a ratio of about 3: 1. The less polar, oily component is the desired compound (XXIV). _Rf (N4) - 0.16; _Rf (B1) - 0.54.

c) 66.6 g of compound (XXIV) and 1.62 g of p-toluenesulfonic acid monohydrate are refluxed in 1500 ml of 2,2-diraethoxypropane for 3 hours. After cooling to room temperature, the mixture is extracted by shaking between 1000 ml of ether and 500 ml of saturated, aqueous sodium bicarbonate solution. The organic phase is washed with water, dried over sodium sulfate and evaporated. The semi-crystalline crude product is purified by flash chromatography (2 kg of silica gel 60, 40-63 μιη, eluent N 17, fractions to about 400 ml). Evaporation of the combined, product-containing fractions gives the compound (XXV) as slightly yellowish crystals. _Rf (N4) - 0.48; R _f (N5) - 0.26.

d) 10.82 ml of diisopropylamine are dissolved in 100 ml of absolute tetrahydrofuran under argon and cooled to 0 °. The mixture is then added dropwise at 0-5 ° for 20 min. With a 1.6 M solution of n-butyllithium in hexane and stirred for 15 min. 10.1 ml of isovaleric acid methyl ester are then added dropwise at -70 ° to -75 ° and the mixture is stirred for 1.5 hours at -75 °. At -60 ° to -75 ° are added dropwise with stirring 190 ml of hexamethylphosphoric triamide. The resulting suspension is stirred for 10 min

Finally, at -70 ° to -75 ° in 5 min. Added dropwise with a solution of 30.0 g of the compound (XXV) in 50 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 2.5 hours and finally poured onto a mixture of 450 ml of saturated aqueous ammonium chloride solution and 500 g of ice. The aqueous phase is extracted with ether and the organic phase is washed with water and dried over sodium sulfate. Evaporation gives the diastereomeric mixture of compound (XXVI) as a yellow oil. R _f (N5) - 0.20; R _f (N4) - 0.40 (values for the less polar component).

e) 10.7 g of potassium tert-butoxide are added in 80 ml of ether at about 5 ° with 1.07 ml of water. The white suspension is stirred for 10 min. In an ice bath and then treated with 10.0 g of the compound (XXVI) (Diastereomerengemisch) in 80 ml of ether, the temperature is kept below 10 °. The reaction mixture is then stirred for 18 hours at room temperature and finally poured onto 1600 ml of saturated aqueous ammonium chloride solution. The aqueous phase is extracted with ether and the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The oily crude product is separated by medium-pressure chromatography (740 g Lichroprep® Si 60, 25-40 μιη, eluent ethyl acetate / n-hexane 1: 5).

Z-Leu ^ VaI-OH , the less polar component of the compound (XXVII) having the desired configuration of the C atom bonded to the isopropyl group (S configuration) is obtained as a yellow OeI. R (methylene chloride / methanol / water 500: 10: 1) - 0.13; R- (N6) - 0.58.

f) Z-Leu-VaI-NHMe: A mixture of 500 mg Z-Leu-VaI-OH,

10 ml of DMF, 245 mg of HOBt and 330 mg of DCCI are left to stand for 24 hours at 0 °. The mixture is treated with an excess of methylamine and stirred for 2 hrs. At 0 ° and 2 hrs. At room temperature. The crystallized DCH is filtered off, the filtrate is concentrated

and dried in a high vacuum. From the residue is obtained by flash chromatography (eluent system N3), the title compound as a colorless OeI. R- (methylene chloride / ether 2: 1) - 0.45.

g) H-Leu-Val-NHMe: 352 mg of Z-Leu-VaI-NHMe are hydrogenated to saturation in 30 ml of methanol-water 9: 1 in the presence of 70 mg of palladium-carbon (10% Pd) at normal pressure and room temperature , The reaction mixture is filtered and the filtrate stirred with 75 ml of water at room temperature. After evaporation of the solvent, the title compound is obtained as a colorless oil. R _f (B4) - 0.08; R _f (S4) - 0.27.

h) N- (quinolyl-2-carbonyl) -L-phenylalanine : To a solution of 0.50 g of L-phenylalanine in 3 ml of 1N sodium hydroxide solution, at the same time, 4.5 ml of 1N sodium hydroxide solution are added at 0 ° for 10 minutes. 78 g of quinolyl-2-carboxylic acid chloride (quinaldic acid chloride, mp 91-94 °, prepared according to the instructions of DL Haimnick & WP Dickinson, J. Chem., 1929 , 214) were added dropwise in 10 ml of methylene chloride. The mixture is stirred for 30 min. At room temperature, then treated with 7.5 ml of 1N hydrochloric acid and extracted with ethyl acetate. The extracts are dried over sodium sulfate and concentrated. The title compound crystallizes from methylene chloride-hexane mixture as a light pink powder, mp. 160-162 °. R _f (Bll) - 0.25.

Example 2 : N- (Quinolyl-2-carbonyl) -Phe-Leu-Val-7-tert- butoxycarbonyl-n-heptylamide

Analogously to Example 1, the title compound is prepared starting from 96 mg of N- (quinolyl-2-carbonyl) -L-phenylalanine (Example 1), 128 mg of H-leu-Val-7-tert-butoxycarbonyl-n-heptylamide in 5 ml of DMF, 46 mg HOBt and 80 mg DCCl after purification by flash chromatography (35 g of silica gel 60, 40-63 μΐη, eluent system N3). R _f (N10) - 0.31.

The starting materials are prepared as follows:

a) H-Leu-Val-7-tert-butoxycarbonyl-heptylamide is prepared by hydrogenation of 213 mg of Z-Leu- ^ Val-7-tert-butoxycarbonyl-heptylamide in the presence of 40 mg of palladium-carbon (10%) analogously to Example Ig receive. R _f (B2) - 0.13.

CX

b) Z-Leu-Val-7-tert-butoxycarbonylheptylamide is prepared analogously to Example 1 starting from 162 mg of Z-leu-VaI-OH and 103 mg of 8-aminooctanoic acid tert-butyl ester after addition of 61 mg of HOBt, 53 μΐ 4-methylmorpholine and 107 mg DCCI obtained. R _f (N4) - 0.20.

c) 8-aminooctanoic acid tert-butyl ester is obtained by hydrogenation of 1.5 g of tert-butyl S-benzyloxycarbonylaminoctanoate in 15 ml of methanol after addition of 0.10 g of palladium-carbon (10%) analogously to Example Ig as obtained colorless oil. R _f (B3) - 0.08.

d) tert-butyl S-benzyloxycarbonylamino-octanoate ; In an autoclave, 2 g of 8-benzyloxycarbonylamino-octanoic acid are reacted in 12 ml of dioxane in the presence of 1.2 ml of sulfuric acid with 7.5 g of isobutylene and allowed to stand for 48 hours at room temperature. The reaction mixture is mixed with ice and 40 ml of 1.8 N aqueous ammonia solution. The reaction mixture is extracted with ether. The organic phase is washed with water and saturated, aqueous common salt solution, dried over sodium sulfate and concentrated in vacuo. The title compound is obtained as a yellow, clear oil. R _f (N8) - 0.44.

e) S-Benzyloxycarbonylamino-octanoic acid : To 7 g of 8-aminooctanoic acid are added 25 ml of 2N NaOH solution. Subsequently, at the same time at about 0 ° -5 ° for 30 min. 17.1 g of benzyl chloroformate (50% in toluene) and 12.5 ml of 4N NaOH solution. One observes a voluminous white precipitate. The reaction mixture is mixed with 150 ml of ether and 60 ml of water. The aqueous phase is extracted with ether, admixed with ice and slowly brought to pH 2 with dilute aqueous HCl solution with stirring. The resulting suspension is extracted twice with ethyl acetate. One unites the

239 2

organic phases, washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The title compound is obtained with a melting point of 63 ° -64 °, R (Nl) -0.53.

Example 3 : N- (Quinolyl-2-carbonyl) -Phe-Leu-Val-7-carboxy-n- heptylamide

124 mg of N- (quinolyl-2-carbonyl) -Phe-Leu-Val-7-tert-butoxycarbonyln-heptylamide (Example 2) and 2.5 ml of trifluoroacetic acid are stirred at room temperature for 10 min. The solution is concentrated and the residue is purified by flash chromatography (35 g of silica gel 60, 40-63 μιη, eluent system BIl). The product-containing fractions are evaporated. After drying at 40 ° in a high vacuum, the title compound is obtained as an amorphous powder. R _f (Bll) - 0.30.

Example 4: N- (Indolyl-2-carbonyl) -Ne-Leu-Val-n-butylamide 56 mg Indole-2-carboxylic acid, 140 mg H-Nle-Leu-Val-n-butylamide and 54 mg HOBt (Fluka purum , contains 11-13% water) are cooled to 0 ^° C. in 4 ml DMF. After addition of 95 mg of DCCI is stirred for 24 hours with ice cooling and then for 2 days at room temperature. The crystalline DCH is filtered off with suction and the filtrate concentrated in a high vacuum. The residue is added in 4 ml of a mixture of methanol-water-glacial acetic acid (94: 3: 3) for 30 min

Stirred 60 ⁰ C and then concentrated. The residue is separated by means of flash chromatography (100 g of silica gel 60, 40-63 μιη, eluent system N 10). The product-containing fractions are evaporated. The title compound is obtained as a white powder from the residue by crystallization from acetonitrile. Mp 243-244 ° C; R _f (N 14) - 0.17.

The starting material is prepared as follows:

239 21

a) H-Nle-Leu-Val-n-butylamide: 188 mg of Z-Nle-Leu-Val-n-butylamide are dissolved in 10 ml of methanol-water 9: 1 in the presence of 30 mg of palladium-carbon (10% Pd). hydrogenated at atmospheric pressure and room temperature to saturation. The reaction mixture is filtered. After evaporation of the solvent, the residue is dried under high vacuum and the title compound is obtained as a colorless oil.

R _f (B4) - 0.41.

b) Z-Nle-Leu-Val-n-butylamide: Analogously to Example 1, the title compound is prepared starting from 138 mg of Z-NiE-OH, 150 mg of H-Leu-Val-n-butylamide in 6 ml of DMF, 80 mg of HOBt and 140 mg DCCI after purification by flash chromatography (100 g of silica gel 60, 40-63 μιη, eluent N3). R _f (N3) - 0.15.

c) H-Leu-Val-n-butylamide; 595 mg of Z-Leu - ^ Val-n-butylamide

in 40 ml of methanol-water 9: 1 in the presence of 100 mg of palladium-carbon (10% Pd) at atmospheric pressure and room temperature to saturation hydrogenated. The reaction mixture is filtered and the filtrate is stirred with 40 ml of water for 75 min. At room temperature. After evaporation of the solvent, the title compound is obtained as a slightly yellowish oil. R _f (ll) - 0.57; R _f (S4) - 0.42.

d) Z-Leu ^ Val-n-butylamide: A mixture of 122 mg of Z-Leu ^ Val-OH (example Ie), 2 ml DMF, 60 mg of HOBt and 80 mg DCCI is 3 days at 0 ⁰ C allowed to stand. The mixture is added with stirring with 120 ml of n-butylamine and 2 Sid. with ice cooling and 24 hours at room temperature. The crystalline DCH is filtered off with suction and the filtrate concentrated in a high vacuum. From the residue is obtained by flash chromatography (30 g of silica gel 60, 40-63 microns, eluent N4) the title compound as a slightly yellowish OeI.

_Rf (N3) - 0.52.

239 2 1 O

Example 5; Analogously to Example 4 are prepared:

a) N- (indolyl-2-carbonyl) -Ne-Leu-Val-NHMe, flash chromatography with eluant N 10; R _f (B4) - 0.61: R _£ (N8) - 0.46.

b) N- (indolyl-2-carbonyl) -Ne-Leu-Val-isopropylamide, flash chromatography with eluant N 14; R (N14) - 0.11; Mp 241-243 °.

c) N- (indolyl-2-carbonyl) -Ne-Leu-Val-n-propylamide, flash chromatography with eluant N 14; R (N14) - 0.14; Mp 220-224 °.

d) N- (indolyl-2-carbonyl) -Ne-Leu-Val-2-hydroxyethylamide, flash chromatography with eluant N 10; R (B 4) - 0.55; Mp 241-242 °.

e) N- (indolyl-2-carbonyl) -Ne-Leu-Val-benzylamide, flash chromatography with eluant N 3; R- (N 10) - 0.35; Mp. 231-234 °.

f) N- (indolyl-2-carbonyl) -Ne-Leu-Val-2-pyridylmethylamide; R _f (B 5) - 0.23; R _f (B7) - 0.46.

g) N- (indolyl-2-carbonyl) -Ne-Leu-Val-1-hydroxy-2 (S) -butylamide; R _f (B 23) - 0.243.

h) N- (indolyl-2-carbonyl) -Ne-Leu-Val-äthylamid, flash chromatography with eluant N 14; R. (N14) - 0.08; Mp 236-238 °.

i) N- (indolyl-2-carbonyl) -Ne-Leu-Val-2- (tert-butoxycarbonylamino) ethylamide, flash chromatography with eluant N 10; R _f (N 10) - 0.20; Mp 225-226 °.

Example 6: N- (Indolyl-2-carbonyl) -Ne-Leu-Val-2-aminoethylamide 30 mg N- (indolyl-2-carbonyl) -Ne-Leu-Val-tert-butoxycarbonylaminoethylamide (Example 5i) and 3 ml Trifluoroacetic acid are stirred for 20 min. At room temperature. The reaction solution is concentrated and the residue is separated by flash chromatography (35 g of silica gel 60, 40-63 μπι, eluent system B 8). The product-containing fractions are evaporated. From the residue is obtained by lyophilization in 5 ml of tert-butanol, the title compound as a white lyophilisate. R- (B 11) - 0.47.

Example 7: N- (Indolyl-2-carbonyl) -Phe-Leu-Val-2- (3-carbamoyl)

4-hydroxyphenoxy) -äthylamid

25 mg of 2-indolecarboxylic acid, 71 mg of H-Phe-Leu-Val-2- (3-carbamoyl-4-hydroxyphenoxy) ethylamide, 23 mg of HOBt and 40 mg of DCCI are reacted analogously to Example 1. After chromatography in system B 7, the title compound is obtained as a yellowish powder. R- (B 7) - 0.27; R _f (B 9) - 0.46.

The starting materials are prepared as follows:

a) H-Phe-Leu-Val-2- (3-carbamoyl-4-hydroxyphenoxy) ethyl amide is prepared by hydrogenation of 236 mg of Z-Phe-Leu-Val-2- (3-carbamoyl-4-hydroxyphenoxy) ethylamide in the presence of 40 mg of palladium-carbon (10%) as in Example 1 g. R (N 11) - 0.23.

b) Z-Phe-Leu-Val-2- (3-carbamoyl-4-hydroxyphenoxy) ethylamide

is obtained analogously to Example 1, starting from 113 mg of Z-L-phenylalanine, 140 mg of H-Leu-Val-2- (3-carbamoyl-4-hydroxyphenoxy) -äthylamid and 58 mg HOBt after addition of 99 mg DCCI. The product is purified by flash chromatography in system N11. R- (N 11) - 0.39.

c) H-Leu-Val-2- (3-carbamoyl-4-hydroxyphenoxy) ethyl amide is prepared by hydrogenation of 240 ml of Z-Leu ^ Val-2- (3-carbamoyl-4-hydroxyphenoxy) ethylamide in the presence of 40 mg of palladium-carbon (10%) was obtained analogously to Example 1 g. Purification by flash chromatography in system B 11. R _f (B 11) - 0.40; R _f (B 7) - 0.15.

d) Z-Leu-Val-2- (3-carbamoyl-4-hydroxyphenoxy) -äthylamid is analogous to Example 1, starting from 147 mg of Z-Leu ^ Val-OH (Example Ie), 107 mg 2- (3-carbamoyl) 4-hydroxyphenoxy) ethylamine [J. Med. Chem. 2! 7, 831 (1984)] and 61 mg HOBt after addition of 97 mg DCCI. The product is purified by flash chromatography in system N11. R- (N 11) - 0.38; R_ (B 7) - 0.46.

Example 8: N- (Indolyl-2-carbonyl) -His-Leu-Val-n-butylamide 29 mg indole-2-carboxylic acid, 75 mg H-His-Leu-Val-n-butylamide and 27 mg HOBt (FLUKA purum , contains 11-13% water) are cooled to 0 ^° C. in 2 ml DMF. After addition of 48 mg of DCCI is stirred for 24 hours with ice cooling and then for 2 days at room temperature. The crystalline DCH is filtered off with suction and the filtrate concentrated in a high vacuum. The residue is stirred in 2 ml of 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 means of flash chromatography (100 g of silica gel 60, 40-63 μιη, eluent system B23). The product-containing fractions are evaporated. From the residue is obtained by lyophilization in 6 ml of tert-butanol, the title compound as a white lyophilisate. R _f (B4) - 0.40.

The starting material is prepared as follows:

a) H-His-Leu-Val-n-butylamide: 98 mg Z-His-Leu-Val-n-butylamide are dissolved in 10 ml methanol-water 9: 1 in the presence of 20 mg palladium-carbon (10% Pd). hydrogenated at atmospheric pressure and room temperature to saturation. The reaction mixture is filtered. After this

239 21

Evaporation of the solvent, the residue is dried under high vacuum and the title compound as a slightly yellowish OeI. R _f (B 11) - 0.39.

b) Z-His-Leu-Val-n-butylamide; The title compound is prepared analogously to Example 1 starting from 72 mg of Z-His-OH, 72 mg of H-Leu-Val-n-butylamide (Example 4c) in 3 ml of DMF, 38 mg of HOBt and 68 mg of DCCI after purification by flash chromatography ( 100 g of silica gel 60, 40-63 μΐη, flow agent B 23). R _f (B 4) - 0.46.

Example 9: Analogously to Example 8 are prepared:

a) N- (indolyl-2-carbonyl) -His-Leu-Val-NHMe, flash chromatography with eluant B8; R _f (S4) - 0.60; R _f (B4) - 0.27.

b) N- (indolyl-2-carbonyl) -His-Leu-Val-benzylamide, flash chromatography with eluant B 23; R (B 4) 0.36.

c) N- (indolyl-2-carbonyl) -His-Leu-Val-isoamylatnid, flash chromatography with eluant B 23; R (B 4) - 0.48.

d) N- (indolyl-2-carbonyl) -His-Leu-Val-cyclopropylmethylaraid, flash chromatography with eluant B 23; R (B4) - 0.39.

Example 10: N- (N-Benzyl-indolyl-2-carbonyl) -His-Leu-Val-NHMe 29 mg N-benzyl-indole-2-carboxylic acid, 40 mg H-His-Leu-VaI-NHMe, 18 mg HOBt and 28 mg DCCI are stirred in 1.5 ml of DMF for 1.5 days at room temperature. After evaporation of the solvent in a high vacuum, the residue in 4 ml of a mixture of methanol-water-glacial acetic acid (94: 3: 3) at 60 ° for 1 hr. Stirred. After evaporation to dryness, the product is obtained as a colorless, amorphous powder after medium-pressure chromatography (Lobar® finished column size B, 40-60 μm particle size, Merck No. 10401, solvent B8). R- (B 24) - 0.4.

The starting materials are prepared as follows:

239 21

a) N-Benzyl-indole-2-carboxylic acid is obtained by treating 300 mg of the corresponding ethyl ester (preparation see Synthesis 1984 , 738) with 2 ml of 1N NaOH in 2 ml of THF at room temperature for 2 days. After addition of 2 ml of 1N HCl, it is evaporated to dryness, partitioned between ether and water, the organic phase is dried and the crude product obtained after evaporation is separated by medium-pressure chromatography (Lobar® column Merck

No. 10401, eluent ethyl acetate / n-hexane 1:19). _Rf (N4) - 0.03; ¹ H-NMR (TMS, DMSO-dg): 11 ppm (IH), 7.7 (d, 1H), 7.54 (d, 1H), 7.34-7.0 (8H), 5.9 (a, 2H).

b) H-His-Leu-Val-NHMe is obtained by hydrogenation of 410 mg of Z-His-Leu-Val-NHMe in the presence of 50 mg of palladium-carbon (10%) in 20 ml of methanol-water (95: 5). under normal pressure and CC ^ absorption for 4 hrs. at room temperature. After filtering off the catalyst and evaporating to dryness, the product is obtained after lyophilization from tert-butanol as an amorphous powder. R _f (B 24) - 0.09.

c) Z-His-Leu-Val-NHMe: 326 mg Z-His-OH, 250 mg H-Leu-Val-NHMe

and 172 mg HOBt are added in 7 ml DMF at ice bath temperature with 274 mg DCCI. It is stirred overnight at 0 ° and then for 24 hrs. At room temperature. After evaporation of the solvent, the residue is stirred in 5 ml of a mixture of methanol-water-glacial acetic acid (94: 3: 3) at 60 ° for 1 hour. The solvent mixture is evaporated off under reduced pressure and the product is obtained as an amorphous powder after medium-pressure chromatography (1 Lobar® column Grosse B, Merck No. 10401, eluent B7). R_ (B8) «0.35.

Example 11: Prepared analogously to Example 10:

a) N- (2- [N-benzyl-o, o'-dichloro-anilino] -phenylacetyl) -His-Leu-Val-NHMe, R (N 8) - 0.35.

- 96 - 23 9 2 U

b) N- (quinolyl-2-carbonyl) -His-Leu-Val-NHMe, flash chromatography with eluant B4; R _f (B 4) - 0.31.

c) N-oxamoyl-His-Leu-VaI-NHMe, flash chromatography with eluant B4; R _f (B4) - 0.28; R _f (S8) - 0.27.

Example 12: N- (3 (R, S) -Benzyloxycarbonyl-4-a-naphthylbutyryl) -His Leu-Val-NHMe

Starting from 40.2 mg of 2 (R, S) - (a-naphthylmethyl) -succinic acid benzyl ester and 44 mg of H-His-Leu-Val-NHMe, the procedure of Example 10 is followed by flash chromatography (100 g of silica gel 60, 40 g). 63 μιη, eluent B 25), the title compound is obtained as a white solid R _f (B 4) - 0.30; R _f (S12) - 0.40.

The starting material is prepared as follows:

a) 2 (R, S) - (α-Naphthylmethyl) -succinic acid 1-benzyl ester: A solution of 480.5 mg of α-naphthylmethylsuccinic anhydride (for preparation see J. Chem. Soc. 1956 , 355-358) and 216 , 3 mg of benzyl alcohol in 5 ml of toluene is boiled for 6 1/2 hours and then evaporated. The residue is dissolved in 10 ml of diisopropyl ether, treated with 362 mg of dicyclohexylamine and stirred overnight. The precipitated white crystals of the dicyclohexylammonium salt are filtered off and recrystallized from diisopropyl ether, mp 120 ° -122 °. The mother liquor is used for the preparation of the isomeric 4-benzyl ester (Example 13a). The recrystallized dicyclohexylammonium salt is dissolved in 10 ml of THF, acidified with 0.5 ml of 1 N HCl, filtered, and the filtrate evaporated, then dissolved in 20 ml of toluene, filtered, and evaporated again. Crystallization of the residue from cyclohexanone gives the title compound as white needles, mp 122-124 °; R (S13) - 0.30.

239 21O

Example 13; N- (3-benzyloxycarbonyl-2 (R, S) -g-naphthylmethyl

propionyp-His-Leu-Val-NHMe

Starting from 36 mg of 2 (R, S) - (α-naphthylmethyl) -succinic acid 4-benzyl ester and 38.5 mg of H-His-Leu-Va1-NHMe, the title compound is obtained analogously to Example 10 after flash chromatography in system B 25 obtained as a white solid. R _f (B4) - 0.40; R _f (S12) - 0.51.

The starting material is prepared as follows:

a) 2 (R, S) - (ot-Naphthylmethyl) -succinic acid 4-benzyl ester: The mother liquor of the dicyclohexylammonium salt of Example 12a is evaporated, dissolved in 10 ml of THF, acidified with 1.5 ml of 1 N HCl, filtered and the filtrate evaporated. The residue is dissolved in ether, washed with 1 N HCl and brine, dried over Na 2 SO 4 and evaporated to give the title compound as a colorless oil. R _f (S 13) - 0.30.

Example 14: N- (Indolyl-2-carbonyl) -Leu-Leu-Val-NHMe 39 mg Indole-2-carboxylic acid, 78 mg H-Leu-Leu-Val-NHMe, 37 mg HOBt and 59 mg DCCI are incubated at room temperature stirred for 2 days in 1.5 ml of DMF. After evaporation of the solvent under high vacuum, the product is recovered by medium pressure chromatography (Lobar® column Grosse B, Merck No. 10401, eluent B 26) as an amorphous powder. R _f (B 24) - 0.53.

The starting material is prepared as follows:

a) H-Leu-Leu-Val-NHMe is obtained by hydrogenation of 115 mg of Z-Leu-Leu-Val-NHMe in 10 ml of methanol-water (95: 5) in the presence of 40 mg of palladium-carbon (10%). under normal pressure and CO2 absorption for 5 hours at room temperature. After filtering off

of the catalyst and evaporation to dryness, the product is obtained as an amorphous powder. R_ (BlI) - 0.8.

b) Z-Leu-Leu-Val-NHMe: 151 mg of Z-Leu-OH (dicyclohexylammonium salt), 75 mg of H-Leu-Val-NHMe and 52 mg of HOBt are mixed with 82 mg DCCI in 3 ml DMF at ice bath temperature , It is stirred for 8 hours in an ice bath and for 10 hours at room temperature. After evaporation of the solvent in a high vacuum, the product is obtained after medium pressure chromatography (Lobar® column, Merck No. 10401, eluent B8) as an amorphous powder. R _f (B 27) 0.38.

Example 15; Prepared analogously to Example 14:

a) N- (indolyl-2-carbonyl) -Cha-Leu-Val-NHMe, R (B 24) - 0.56.

b) N- (indolyl-2-carbonyl) -Gln-Leu-Val-NHMe, R _f (B 9) - 0.23.

c) N- (N- [indolyl-2-carbonyl] -L-threo-β-phenylseryl) -Leu-Val-NHMe, R _f (B 8) -0.47.

Example 16: N- (Indolyl-2-carbonyl) -His-Cha-Val-NHMe A mixture of 98.6 mg H-His-Cha-Va1-NHMe, 37.7 mg indole-2-carboxylic acid, 35.8 mg HOBt, 63.9 mg DCCI and 5.2 ml DMF is stirred for 50 hrs. At room temperature. The crystallized DCH is filtered off and the filtrate is evaporated. The crude product is purified by flash chromatography (110 g of silica gel 60, 40-63 μπι, solvent B4). Evaporation of the combined, product-containing fractions gives the title compound, R_ (B 4) «0.22.

The starting material is prepared as follows:

a) H-His-Cha-Val-NHMe: 130 mg of Z-His-Cha-Val-NHMe are dissolved in 5 ml of methanol-water 9: 1 in the presence of 20 mg of palladium-carbon (10% Pd) at normal pressure and room temperature hydrogenated to saturation. The reaction mixture is filtered and the filtrate with 5 ml of water at

Room temperature stirred. After evaporation of the solvent, the title compound is obtained as a colorless oil. R- (B 11) 0.38.

b) Z-Hia-Cha-Val-KHMe: A mixture of 150.8 ag H-Cha-Val-NHMe, 6 al DMF, 81.1 ag HOBt, 153.3 ag Z-His-OH and 144.2 ag DCCZ is stirred for 48 hrs. at Rauateaperatur. The DCH is filtered off, the filtrate is concentrated and dried aa high vacuum. The residue is separated by flash chromatography (145 g of gel gel 60, 40-63 μm, eluent: B 23). Evaporation of the combined, product-containing fractions gives the title compound. R _f (B 4) - 0.35; R _f (S 4) - 0.65.

H-Cha-Val-NHMe is prepared analogously to the diagram shown in Example 1 as follows:

c) 2 (S) -benzyloxycarbonyl-alaino-3-cyclohexyl-propionic acid ethyl ether 243 g of 2 (S) -benzyloxycarbonylamino-3-cyclohexyl-propionic acid (preparation: Helvetica Chiaica Acta _5_7, 2131 (1974)) are dissolved in 600 ml of toluene and 900 ml of ethanol submitted. The reaction mixture is cooled to 0 ° C. and 88.3 g of thionyl chloride are added dropwise within 30 minutes, 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 purified by flash chromatography (2 kg of silica gel 60, 40-63 μm, N3) The product-containing fractions are combined, concentrated by evaporation and dried in a high vacuum to give the title compound as a slightly yellowish oil R. (N 5) 0.2; R _f (N15) 0.52.

d) 2 (S) -Benzyloxycarbonylaalno-3-cyclohexyl-propanal: 116.1 g of ethyl 2 (S) -benzyloxycarbonylamino-3-cyclohexyl-propionate are initially charged in 2.2 l of toluene and cooled to -65 °. 836 μl of diisobutylaluminum hydride are added dropwise at -65 ° within 30 minutes and the mixture is stirred for 20 minutes. 84.2% methanol are then added dropwise at -65 ° within 10 min, followed by 825 al aqueous Kaliua natriua tartrate solution without cooling. The reaction mixture is added to 3 liters of potassium-sodium tartrate solution / ice

discharged and extracted with 5 1 ether. The ether phase is washed with 2 1 of water, then poured immediately into a solution consisting of 106 g of semicarbazide hydrochloride and 156.5 g Natriutnacetat in 620 ml of water and 620 ml of 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 χ 1.5 1 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, 40-63 μΐη, eluent N3). Evaporation of the combined, product-containing fractions gives the semicarbazone of the title compound, R- (N8) -0.51. 130 g of this semicarbazone are dissolved in 1 1 of THF, mixed with 282 ml of 37% formaldehyde solution and then at 10 ° with 143 ml of 0.5N HCl. The reaction mixture is stirred for 2 hrs. At room temperature, filtered and the filtrate washed with 0.5 1 of water, 0.5 1 NaHCCh and 0.5 1 of 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. This will be processed immediately.

e) (1 (S) -benzyloxycarbonylamino-2-cyclohexyl-ethyl) -oxirane: 18.9 g of sodium hydride dispersion (55% in OeI) are dissolved in 50 ml of petroleum ether (bp 40-60) in a dry mixing flask under argon °) and then decanting the solvent freed of OeI. 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 °. The gray suspension is boiled for 1 h at reflux and then admixed within a period of 50 min at -70 ° with a solution of 108.6 g of 2 (S) -benzyloxycarbonylamino-3-cyclohexylpropanal in 250 ml of THF. The yellow suspension is stirred for 2 hours at 0 °. The yellowish cloudy solution is poured onto 500 g of ice. The aqueous solution is extracted with 2.5 1 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 of silica gel 60, 40-63 μπι, solvent N4). The

product-containing fractions are combined, evaporated and dried under high vacuum. The title compound (diastereomer mixture, ca. 4: 1) is obtained as a slightly yellowish OeI. R- (N 16) 0.71; R _f (N4) - 0.16.

f) 3 (S) -benzyloxycarbonylamino-4-cyclohexyl-1-iodo-butan-2 (R, S) -ol: 42.3 g of (1 (S) -benzyloxycarbonylamino-2-cyclohexyl-ethyl) -oxirane are added in Acquired 200 ml of acetonitrile and the resulting solution was cooled to 0 °. After addition of 20.9 g of sodium iodide are added dropwise at 0 ° 17.7 ml of trimethylchlorosilane over 30 min. The mixture is stirred for 40 min. At 0-3 ° and then poured onto 700 ml of ice-cold water. The aqueous mixture is extracted with ether and the organic phase is 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.

g) 3-Benzyloxycarbonyl-4 (S) -cyclohexylmethyl-2,2-dimethyl-5 (R) -iodomethyl-1,3-oxazolidine: 49.3 g of Compound Example 16f) and 1.07 g of p-toluenesulfonic acid monohydrate in 140 ml of 2,2-dimethoxypropane and 450 ml of methylene chloride for 3 hrs. At room temperature. The mixture is partitioned between 1 l of 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 of silica gel 60, 40-63 μπι, eluent N17). Evaporation of the combined, product-containing fractions gives the title compound as a slightly yellowish oil. _Rf (N4) - 0.55; R _f (N 17) - 0.46.

h) 2 (R, S) - (3-Benzyloxycarbonyl-4 (S) -cyclohexylmethyl-2,2-dimethyl-1,3-oxazolidinyl-5 (S) -methyl) -3-methyl-butyric acid methyl ester: 14.3 ml of diisopropylamine are dissolved in 200 ml of absolute tetrahydrofuran under argon and cooled to 0 °. Subsequently, at 0-5 °, the mixture for 20 min. Dropwise with 65.8 ml of a 1.6M solution

of n-butyllithium in hexane and stirred for 20 min. Then 13.3 ml Isovaleriansauremethylester are added dropwise at -70 ° to -75 ° and the mixture stirred for 1.5 hours at -75 °. At -60 ° to -75 °, 320 ml of hexamethylphosphoric triamide are added dropwise with stirring. The resulting suspension is stirred for 10 min. And finally treated at -70 ° to -75 ° in 5 min. Dropwise with a solution of 43.4 g of the compound Example 16g) in 110 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 2.5 hours and finally poured onto a mixture of 1 1 of saturated, aqueous ammonium chloride solution and 500 g of ice. The aqueous phase is extracted with 2 1 ethyl acetate, the organic phase washed with water and dried over sodium sulfate. Evaporation gives the diastereomeric mixture of the title compound as a yellow oil. R _f (N 4) - 0.36; R _f (N5) - 0.21 (values for the less polar component).

i) 2 (R, S) - (3-Benzyloxycarbonyl-4 (S) -cyclohexylmethyl-2,2-dimethyl-1,3-oxazolidinyl-5 (S) -methyl) -3-methylbutyric acid; 16.5 g of potassium tert-butoxide are added in 250 ml of ether at about 5 ° 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 16h) (diastereomer mixture) in 250 ml of ether, the temperature is kept below 10 °. The reaction mixture is then stirred for 18 hours 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 flash chromatography (2.5 kg of silica gel 60, 40-63 μΐη, eluent N4). 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 OeI. R _f (N 16) - 0.20; R _f (N 6) - 0.35.

j) Z-Cha-Val-NHMe: A mixture of 311.9 mg Z-Cha-VaI-OH, 6.4 ml DMF, 138.2 mg HOBt and 186.1 mg DCCI will stand at 0 ° for 24 hrs calmly. The mixture is treated with an excess of methylamine and stirred for 2 hrs. At 0 ° and 2 hrs. 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 colorless OeI by flash chromatography (eluent system N3). R- (N3) - 0.45.

k) H-Cha-Val-NHMe: 243 mg of Z-Cha-Val-NHMe 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 until 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 (B 4) - 0.11; R _f (S 4) - 0.31.

Example 17: N- (2 (R, S) -acetoxy-3-a-naphthyl-propionyl) -His-Leu-Val

n-butylamide

A solution of 21.4 mg of 2 (R, S) -acetoxy-3-a-naphthyl-propionic acid, 35 mg of H-His-Leu-Val-n-butylamide and 12.7 mg of HOBt in 1.5 ml abs. DMF is added at 0 ° with stirring with 22.2 mg DCCI. The reaction mixture is further stirred for 12 hours at 0 ° and 48 hours at room temperature and then filtered. The filtrate is evaporated at 40 ° and the residue is kept in 2 ml of a mixture of methanol-water-glacial acetic acid (94: 3: 3) at 60 ° for 60 min. Thereafter, the solution is evaporated on a rotary evaporator, dried briefly in a high vacuum and the residue thus obtained chromatographed on silica gel with solvent system B28, the title compound being obtained as white crystals. R (B 4) - 0.415.

The starting material is prepared as follows: a) 2 (R, S) -acetoxy-3-q-naphthyl-propionic acid: A mixture of 0.21 g of 2-hydroxy-3-a-naphthyl-propionic acid and 0.2 ml of acetyl chloride stirred at room temperature for 40 min. and then on a rotary evaporator

evaporated below 50 °. The remaining title compound is dried over potash at 40 ° 16 hrs. Under high vacuum. R _f (N 18) - 0.63.

b) 2-Hydroxy-3-q-naphthyl-propionic acid: A solution of 1.4 g of 2-bromo-3-a-naphthyl-propionic acid and 1.4 g of calcium carbonate in 14 ml of water is refluxed for 10 hrs boiled, cooled, adjusted to pH 2 with 2 N hydrochloric acid and extracted with ethyl acetate. The organic phases are dried with sodium sulfate and evaporated. From the residue is obtained by chromatography on silica gel with eluant N.21 the crystalline title compound.

R _f (N 18) - 0.5.

c) 2-bromo-3-a-naphthyl-propionic acid: A solution of 10 g of ot-naphthylamine in 100 ml of acetone is added dropwise with stirring at room temperature with 39.2 ml of conc. HBr and then at 0-5 ° with 17.4 ml of a 4N aqueous solution of sodium nitrite. Subsequently, 70 ml of acrylic acid are added dropwise rapidly and 0.4 g of copper (I) bromide are added. The reaction mixture is adjusted to pH 3 at 60 ° with about 30 g of sodium acetate, stirred for a further 90 min. At 70 ° and then evaporated on a rotary evaporator. The residue is dissolved in ethyl acetate and extracted four times with sodium bicarbonate solution. The bicarbonate extracts are acidified with hydrochloric acid and extracted with ethyl acetate. The organic phases are washed with water and brine, dried over sodium sulfate and evaporated. Chromatography of the residue with toluene-ethyl acetate (9: 1) on silica gel gives the title compound as brownish crystals. R _f (Nl9) - 0.25.

Example 18: N- [4- (2-Benzofuranyl) -2 (R, S) -benzyl-4-oxo-butyryl] - His-Leu-Val-n-butylamide

Analogously to Example 17, from 50 mg of 4- (2-benzofuranyl) -2 (R, S) -benzyl-4-oxo-butyric acid, 50 mg of H-His-Leu-Val-n-butylamide, 25 mg of HOBt and

Obtained 36 mg DCCI the title compound and purified by flash chromatography with solvent system B7. R _f (B7) - 0.30.

The starting material is prepared as follows:

a) 4- (2-Benzofuranyl) -2 (R, S) -benzyl-4-oxo-butyric acid: 2.0 g (benzofuranyl-2-carbonylmethyl) benzyl malonic acid diethyl ester are dissolved in 10 ml of ethanol and taken in succession at room temperature with 10 ml of water and 7.4 ml of 2N sodium hydroxide solution. After stirring at room temperature for 16 hours, it is acidified to pH 3 with 1N HCl and extracted with methylene chloride. The crude diacid with mp. 154 ° crystallizes on concentration. This is decarboxylated in a round bottom flask for 10 min. At a temperature of 170 °. After cooling the melt is crystallized from ethyl acetate / hexane, the title compound of mp. 170-171 ° pure. R _f (Nl2) - 0.63.

b) (Benzofuranyl-2-carbonylmethyl) -benzyl malonic acid diethyl ester: 5.0 g of benzylmalonic acid diethyl ester are added dropwise at room temperature to a suspension of 870 mg of sodium hydride in 25 ml of DMF. After 20 min., 4.78 g bromomethyl-2-benzofuranyl ketone (prepared according to Liebigs Ann. Chem. 312, 332 (1900) dissolved in 25 ml DMF are added dropwise. After stirring for 2 h at room temperature, it is poured onto ice and IN HCl and extracted with methylene chloride. The crude product is purified by flash chromatography on 260 g of silica gel with methylene chloride as eluent to give the title compound as an OeI. R _f (CH ₂ Cl ₂ ) »0.23.

Example 19: N- (4-Cyano-2 (R, S) -a-naphthylmethyl-butyryl) -His Leu-Val-n-butylamide

Analogously to Example 17, 21.0 mg of 4-cyano-2 (R, S) -a-naphthylmethyl-butyric acid, 35.0 mg of H-His-Leu-Val-n-butylamide, 12.7 mg of HOBt and 22, 2 mg DCCI the title compound and purified by flash chromatography with solvent system B3. R _f (B4) 0.46 (slower diastomer).

The starting material is prepared as follows:

- 106 - 239 2 1 ö

a) 4-Cyano-2 (R, S) -ct-naphthylmethy! -butyric acid: 2.13 g of diethyl 2-cyanoethyl malonate are added to a suspension of 0.48 g of sodium hydride dispersion in 25 ml of DMF. The reaction mixture is stirred for 2 hours at 80 ° and then treated at room temperature with 1.77 g of α-chloromethylnaphthalene in 5 ml of DMF. The mixture is stirred for 16 hrs. At 50 ° and then evaporated. The residue is dissolved in ethyl acetate, washed with 0.1 N hydrochloric acid and water, dried over sodium sulfate and evaporated, leaving behind 2-cyanäthylot-naphthylmethyl-malonsäurediäthylester.

7.2 g of this intermediate are stirred in 36 ml of DMSO, 360 μΐ water and 1.73 g of lithium chloride for 3 hrs. At 180 °. The reaction mixture is evaporated in a high vacuum, the residue dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated to give 4-cyano-2 (R, S) -a-naphthylmethylbuttersäure ethyl ester.

For saponification, 0.45 g of this ester in 7 ml of methanol and 1.8 ml of 1N sodium hydroxide solution are stirred for 16 hours at 35 °. Thereafter, the reaction mixture is evaporated, the residue dissolved in water, washed with ethyl acetate, acidified with 2N sulfuric acid and extracted with ethyl acetate. After washing with water, drying over sodium sulfate and evaporation, the title compound is obtained as yellow OeI from these ethyl acetate extracts.

Example 20: N- (2 (R) - and 2 (S) -cyanomethyl-3-q-naphthyl-propionyl) - His-Leu-Val-n-butylamide

19.9 mg of 2 (R, S) -cyanomethyl-3-a-naphthylpropionic acid, 35.0 mg of H-His-Leu-Val-n-butylamide, 12.7 mg of HOBt and 22.2 mg DCCI the title compound as a diastereomer mixture and separated by flash chromatography with solvent system B28. R_ (B4) 0.46 (faster diastereomer); R- (B4) - 0.44 (slower diastereomer).

The starting material is prepared as follows.

- 107 - 239 21

a) 2 (R, S) -cyanomethyl-3-a-naphthyl-propionic acid: To a stirred suspension of 0.44 g of sodium hydride dispersion in 50 ml of DMF

3.0 g of ct-naphthylmethyl-malonic acid diethyl ester and after 30 min. Added 0.6 ml of chloroacetonitrile. The reaction mixture is stirred for 1 h. At 50 ° and then evaporated in a high vacuum. The residue is dissolved in ethyl acetate, washed with 0.1N hydrochloric acid and water, dried over sodium sulfate, evaporated and purified by chromatography on silica gel with toluene to give diethyl cyanomethyl (oj-naphthylmethyl) malonate.

Analogously to Example 19a), this malonate is hydrolyzed and decarboxylated, the resulting 2 (R, S) -cyanomethyl-3-a-naphthylpropionsäure ethyl ester purified by chromatography with solvent system N4 and saponified with sodium hydroxide in methanol, the title compound as a yellowish OeI is obtained.

Example 21; N-benzyloxycarbonyl- (p-benzyloxycarbonylamino-Phe) - His-Leu-Val-n-butylamide

The title compound is prepared analogously to Example 17 from 58 mg of N-benzyloxycarbonyl-p-benzyloxycarbonylamino-L-phenylalanine, 50 mg of H-His-Leu-Val-n-butylamide, 20 mg of HOBt and 32 mg of DCCI and by flash chromatography with solvent System B31 cleaned. R _f (B8) - 0.51.

The starting material is produced as follows:

a) N-Benzyloxycarbonyl-p-benzyloxycarbonylamino-L-phenylalanine:

1.01 g of p-amino-L-phenylalanine (Bachern AG, Bubendorf) is taken up in 6 ml of H 2 O as the sodium salt. Thereupon, 3.35 ml of benzyl chloroformate (50% in toluene) and 5 ml of 2N NaOH are added dropwise while cooling with ice bath, and stirring is continued for 20 min. The white suspension is adjusted to pH 1 with 2N HCl, extracted with ethyl acetate and the organic phase dried over sodium sulfate and evaporated. The residue is purified by flash chromatography with solvent system BlI. The eluate is treated with 2N HCl

- 108 - 239 2 1 ö

acidified, extracted with ethyl acetate, the extracts dried and evaporated to give the title compound as white crystals. R _f (BIl) - 0.22.

Example 22: N-Pivaloyl- (p-benzyloxycarbonylamino-Phe) -His-Leu-Val

n-butylamide

The title compound is prepared analogously to Example 17 from 52 mg of N-pivaloyl-p-benzyloxycarbonylamino-L-phenylalanine, 50 mg of H-His-Leu-Val-n-butylamide, 20 mg of HOBt and 32 mg of DCCI and by flash chromatography with solvent System B31 cleaned. R_ (B8) - 0.41.

The starting material is prepared as follows:

a) N-Pivaloyl-p-benzyloxycarbonylamino-L-phenyl alanine: 2.22 g of N-pivaloyl-p-amino-L-phenylalanine are initially charged in 4 ml of 2N NaOH and 5 ml of H2O. With ice-bath cooling, 1.3 ml of benzyl chloroformate and 2.1 ml of 4N NaOH are added dropwise at the same time. The suspension is stirred for 30 min. And then with conc. HCl adjusted to pH. It is extracted with ethyl acetate, washed with water, dried and the solvent evaporated in vacuo to give beige crystals. ¹ H-NMR (DMSO-d ₆ , TMS): 1.0 ppm (s, 9H); 2.9-3.0 (dd, 2H); 4.4 (m, IH); 5.15 (s, 2H); 5.72 (s, 2H); 7.1 (d, IH); 7.3-7.5 (m, 5H); 14.6 (s, IH).

b) N-Pivaloyl-p-amino-L-phenylalanine: 2.73 g of N-pivaloyl-p-nitro-L-phenylalanine in 50 ml of methanol are dissolved in the presence of 270 mg of palladium-carbon (10% Pd) for 20 min. hydrogenated at atmospheric pressure and room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness leaving the title compound as a pink powder. ¹ H-NMR (DMSO-d _6, TMS): 1.05 ppm (s, 9H); 2.8-2.95 (m, 2H); 4.2-4.5 (m, IH); 6.45 (d, 2H); 6.9 (d, 2H); 7.25 (d, IH).

c) N-Pivaloyl-p-nitro-L-phenylalanine: 2.0 g of p-nitro-L-phenylalanine (Bachern AG, Bubendorf) are dissolved in 5 ml of 2N NaOH and 2 ml of THF and at 10-15 ° simultaneously with 1.2 ml of pivaloyl chloride in 1.3 ml

Toluene and 2.4 ml of 4N NaOH. It is stirred for 1 hr. At room temperature and then with conc. HCl adjusted to pH 1. The aqueous phase is extracted with ethyl acetate and the organic phase is dried and evaporated to give the title compound as a yellowish powder. R. (N20) - 0.23.

Example 23: Analogously to Example 17 are prepared:

a) N- (2 (R) - and 2 (S) -hydroxy-3-ct-naphthyl-propionyl) -His-Leu-Valn-butylamide, separation of the diastereomers by flash chromatography with solvent system B30; R (B4) «0.43 (slower diastereomer) and R. (B4)« 0.49 (faster diastereomer).

b) N- (3-ct-naphthyl-propionyl) -His-Leu-Val-n-butylamide, flash chromatography with eluant B28; R (B4) - 0.41.

c) N- (quinolyl-2-carbonyl) -His-Leu-Val-n-butylamide, medium pressure chromatography on Lobar®-finished column with flux B31; R _f (B8) - 0.64.

d) N-naphthylcarbonyD-His-Leu-Val-n-butylamide, flash chromatography with eluant B31; R (B8) »0.60.

e) N- (α-naphthoxyacetyl) -His-Leu-Val-n-butylamide, flash chromatography with eluant B23; R (B4) - 0.49.

f) N- (2 (R, S) -benzyl-5,5-dimethyl-4-oxo-hexanoyl) -His-Leu-Val-n-butylamine: R (B7) - 0.33. The starting material is described in Example 25a.

Example 24: N- (2 (R, S) -acetoxy-3-a-naphthyl-propionyl) -His-Cha-Val-

n-butylamide

The title compound is obtained analogously to Example 17 from 30 mg of 2 (R, S) -acetoxy-3-a-naphthylpropionic acid, 54 mg of H-His-Cha-Val-n-butylamide, 17.8 mg of HOBt and 31 mg of DCCI Purified flash chromatography with solvent system B28. R (B4) 0.5.

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 16a. _Rf (B4) - 0.05; R

(S4) - 0.16.

b) Z-His-Cha-Val-n-butylamide is analogous 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 Example 16b and purified by flash chromatography with solvent system B4. Mp 208-210 °. R (B4) - 0.49; R _f (S4) - 0.62.

c) H-Cha-Val-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 16k. R _f (B4) - 0.25.

d) Z-Cha-Val-n-butylamide is obtained starting 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 DCCI analogously to Example 16j and purified by flash chromatography with solvent system N4, R (N3) - 0.61.

Example 25: N- (2 (R, S) -, 2 (R) - and 2 (S) -benzyl-5,5-dimethyl-4-oxo)

hexanoyl) -His-Cha-Val-n-butylamide

40 mg of 2 (R, S) -, 2 (R) - or 2 (S) -benzyl-5,5-dimethyl-4-oxo-hexanoic acid, 50 mg of H-His-Cha-Val are prepared analogously to Example 24 n-butylamide, 25 mg HOBt and 36 mg DCCI, the corresponding title compound

~ 239 2ί · 0

and purified by flash chromatography with solvent system B5. R _f (B5) - 0.24; R (B7) - 0.35 (both diastereomers).

The starting materials are prepared as follows:

a) 2 (R, S) -benzyl-5,5-dimethyl-4-oxo-hexanoic acid: Starting from 5.0 g of benzylmalonic acid diethyl ester, 870 mg of sodium hydride and 3.58 g of bromomethyl tert, analogously to Example 18a and 18b Butyl ketone in DMF obtained the title compound. Mp 94-95 °. R (NIl) - 0.56.

b) 2 (R) - and 2 (S) -benzyl-5,5-dimethyl-4-oxo-hexanoic acid : 400 mg of the racemate from Example 25a, 370 mg of 2 (S) -amino-3-phenylpropanol (L-) Phenylalaninol), 272 mg HOBt and 500 mg DCCI are reacted analogously to Example 1. The diastereomers are separated by flash chromatography with solvent system N3. R_ (N3) - 0.23 (faster diastereomer) and R-. (N3) 0.17 (slower diastereomer). By boiling with acetic acid / 2N HCl 1: 1 for 10 hrs. At 80 °, the phenylalaninol residue is cleaved again, and the title compounds are isolated as pure enantiomers.

Example 26: N- (2 (R, S) -ethoxycarbonyl-3-a-naphthyl-propionyl) - His-Cha-Val-n-butylamide

The title compound is obtained from 42 mg of a-naphthylmethyl-malonic acid monoethylester, 60 mg of H-His-Cha-Val-n-butylamide, 26 mg of HOBt and 40 mg of DCCI analogously to Example 24 and purified by flash chromatography with solvent system B5. R_ (B5) - 0.22; R _f (B7) - 0.36.

The starting material is prepared as follows:

a) q-Naphthylmethyl-malonic acid monoethyl ester: 5.00 g of a-naphthylmethyl-malonic acid diethyl ester (J. Am. Chem. Soc. 62, 2335 (1940)) dissolved in 50 ml of water / ethanol 1: 1 with 16.5 ml of 1N NaOH are added. After 30 min. At room temperature, the saponification is completed. The reaction mixture is mixed with 16.5 ml of IN HCl and

²³⁹

extracted with methylene chloride. The extracts are evaporated and the residue is purified by flash chromatography with NIl solvent system. R _f (NIl) - 0.35; R _f (N7) - 0.25.

Example 27: N- (Cyclohepta [b] pyrrolyl-5-carbonyl) -His-Cha-Val- n-butylamide

The title compound is obtained analogously to Example 24 from 37 mg of cycloheptafibyryl-S-carboxylic acid, 60 mg of H-His-Cha-Val-n-butylamide, 32 mg of HOBt and 48 mg of DCCI and purified by flash chromatography with solvent system B7. R ,. (B7) ™ 0.35.

The starting material is prepared as follows:

a) Cycloheptafbipyrrol-S-carboxylic acid: 260 mg of cyclohepta [b] pyrrole-5-carbonitrile are refluxed in 16 ml of a 1: 1 mixture of ethanol and sodium hydroxide solution for 24 hours. Thereafter, with conc. Hydrochloric acid acidified, extracted with methylene chloride and the extracts evaporated. R _f (BIl) - 0.18; R _f (Nl2) - 0.55.

b) Cycloheptatblpyrrole-S-carbonitrile: 800 mg of cyclohepta- [b] pyrrole (prepared according to HeIv. Chim. Acta 61, 1647 (1984)) are added in portions at 0 ° to a solution of 1.1 ml of oxalyl chloride in 40 ml of DMF , The mixture is stirred for 30 min. At room temperature, then treated with 60 ml of saturated sodium acetate solution and acidified with conc. Ammonia adjusted to pH 9. The formed cycloheptafbipyrrol-S-carbaldehyde is extracted with methylene chloride and purified by flash chromatography with solvent system N6. R _f (N6) - 0.46.

300 mg of this aldehyde are stirred vigorously with 640 mg of hydroxylamine and 1.5 g of sodium acetate in 20 ml of methanol at room temperature. The reaction mixture is poured onto water and the resulting

Cyclohpetafbjpyrrol-S-carbaldoxime extracted with methylene chloride. _Rf (N6) - 0.35.

340 mg of this oxime are added in 20 ml of methylene chloride at room temperature with 371 mg Ν, Ν'-carbonyl-diimidazole. After 1 h., The reaction mixture is applied directly to 65 g of silica gel and eluted under slight excess pressure, the title compound with solvent system B6. R- (B6) - 0.70.

Example 28: N-f 2 (R, S) - (2-dimethylaminoethyl-carbamoyl) -3-α-

naphthyl-propionyl] -His-Cha-Val-n-b.utylamid

The title compound is obtained analogously to Example 24 from 49 mg of 2 (R, S) - (2-dimethylaminoethylcarbamoyl-S-naphthyl-propionic acid, 60 mg of H-His-Cha-Val-n-butylamide, 26 mg of HOBt and 40 mg of DCCI and flash Chromatography with solvent system B9, R _f (B9) - 0.27, R _f (B7) - 0.13.

The starting material is prepared as follows:

a) 2 (R, S) - (2-Dimethylaminoethyl-carbamoyl) -3-a-naphthyl-propionic acid: Analogously to Example 1, from 1.00 g of ci-naphthylmethyl-malonic acid monoethyl ester (Example 26a), 0.80 ml 2-Dimethylaminoethylamine, 0.67 g of HOBt and 1.14 g of DCCI 2 (R, S) - (2-dimethylaminoethyl-carbamoyl) -3-ot-naphthyl-propionsäureäthylester. R _f (B5) - 0.33; R _f (B7) - 0.46.

The ethyl ester is saponified analogously to Example 26a with sodium hydroxide solution in aqueous ethanol. The title compound crystallizes from water at 4 ° as thin, colorless crystals of mp. 102 ° · R _f (BIl) - 0.08.

Example 29: N- [2 (R, S) - (2-hydroxy-1 (S) -methyl-ethylcarbamoyl) -3-a-

naphthyl-propionyl} -His-Cha-Val-n-butylamide

47 mg of 2 (R, S) - (2-hydroxy-1 (S) -methylethylcarbamoyl) -3-a-naphthyl-propionic acid, 60 mg of H-His-Cha-valn-butylamide, 26 mg of HOBt are obtained analogously to Example 24 and 40 mg DCCI the title compound and purified by flash chromatography with solvent system B7. R _f (B7) - 0.22; R _f (B9) - 0.31.

The starting material is prepared as follows:

a) 2 (R, S) - (2-hydroxy-l (S) -methyl-ethylcarbarooyl) -3-a-naphthylpropionic acid is starting from 2.00 g of ct-naphthylmethyl-malonic acid monoethyl ester (Example 26a), 0.69 g 2 (S) -Amino-l-propanol, 1.46 g HOBt and 2.27 g DCCI prepared analogously to Example 28a. R _f (BIl) - 0.18; R _f (S 0) - 0.52.

Example 30: N- [2 (R, S) - (2'-dimethoxy-ethylcarbamoyl-S-a-

naphthyl-propionylj-His-Cha-Val-n-butylamide

Analogously to Example 24 is from 51 mg of 2 (R, S) - (2,2-dimethoxy-a'thylcarbamoyl) -3-a-naphthyl-propionic acid, 60 mg H-His-Cha-Val-n-butylamide, 26 mg HOBt and 40 mg DCCI the title compound and purified by flash chromatography with solvent system B7. R _f (B7) - 0.35; R (B5) - 0.20.

The starting material is prepared as follows:

a) 2 (R, S) - (2,2-dimethoxy-ethylcarbamoyl) -3-ct-naphthyl-propionic acid is starting from 1.00 g of a-naphthylmethyl-malonic acid monoethyl ester (Example 26a), 0.48 ml of aminoacetaldehyde dimethyl acetal, 0.73 g HOBt and 1.14 g DCCI prepared analogously to Example 28a. R (BIl) - 0.28; R _f (S 0) - 0.65.

239 21O

Example 31; N-f2 (R, S) - (tert-butoxycarbonyl »ethylcarbaaoyl) -3-o-

naphthyl-propionyll-Hia-Cha-Val-n-butylaaid

The title compound is prepared analogously to Example 24 from 92 mg of 2 (R, S) - (tert-ButoxycarbonylaethylcarbaaoyD-S-ct-naphthyl-propionic acid, 100 ag H-His-Cha-Valn-butylaaid, 43 ag HOBt and 67 ag DCCI purified by flash chromatography on solvent Systea B5 R _f (BS) -0.21; R _f (B7) -0.34.

The starting material is prepared as follows:

a) 2 (R, S) - (tert-butoxycarbonyl-ethylcarbamoyl) -3-q-naphthylpropionic acid is obtained from 1.00 g of α-naphthylethyl salonic acid monoethyl ether (Example 26a), 1.73 g of glycine tert-butyl ester dibenzene sulphide salt, m.p. , 73 g HOBt and 1.14 g DCCI prepared analogously to Example 28a and purified by flash chromatography on a solvent Systea N12. R _f (N12) - 0.38.

Example 32; S-f2 (R, S) -Carboxyaethylcarbaaoyl-3-a-naphthyl

propionyll-His-Cha-Val-n-butylaaid

90 g of N-f2 (R, S) - (tert-butoxycarbonyl-ethylcarbamoyl) -3-a-naphthylpropionyl] -His-Cha-Val-n-butylaaid (Example 31) are dissolved in 0.5 g of trifluoroacetic acid and stirred for 1 h left standing at Rauateaperatur. The mixture is then evaporated to dryness and the product is purified by flash chromatography with solvent Systea BIl. R _f (BU) - 0.34; R _f (B9) - 0.21.

Example 33: N- (5,5-Diaethyl-2 (R, S) -a-naphthylmethyl-4-oxo-hexanoyl) - His-Cha-Val-n-butylaaid

Analogously to Example 24 from 46 ag of 5,5-Diaethyl-2 (R, S) - (a-naphthylaethyl) -4-oxo-hexanoic acid, 60 g of H-His-Cha-Val-n-butylaaid, 26 h HOBt and 40 g of DCCI, the title compound and purified by flash chromatography on the solvent Systea B5. R _f (B5) - 0.21; R _f (B7) - 0.37.

- 116 The starting material is prepared as follows:

a) 5,5-dimethyl-2 (R, S) -ct-naphthylmethyl-4-oxo-hexanoic acid: Starting from 5.0 g of ct-Naphthylmethylmalonsäure-diethyl ester (J. Am. Chem. Soc 62, 2335 (1940)), 730 mg of sodium hydride and 2.9 g of bromomethyl tert-butyl ketone in DMF and subsequent saponification and decarboxylation gave the title compound. Mp. 93-93.5 °. R _f (NIl) - 0.50.

Example 34; N- (ethoxycarbonyl-ct-naphthoxy-acetyl) -His-Cha-Val-n-

butylamide

The title compound is prepared analogously to Example 24 from 29.6 mg of a-naphthoxy-malonic acid monoethyl ester, 50.0 mg of H-His-Cha-Val-n-butylamide, 16.5 mg of HOBt and 28.8 mg of DCCI and by flash Chromatography with solvent system B3 purified. R _f (B4) - 0.54.

The starting material is prepared as follows:

a) a-Naphthoxy-malonic acid monoethyi ester: 2.0 g of a-naphthoxymalonic acid diethyl ester are dissolved in 5 ml of absolute ethanol and with stirring with the solution of 0.41 g of potassium hydroxide in 5 ml of abs. Ethanol added. The reaction mixture is stirred for 16 h at room temperature and then evaporated to dryness. The residue is dissolved in water, washed with ether, acidified with 5N hydrochloric acid and extracted with ethyl acetate. From these ethyl acetate extracts, after washing with brine, drying over sodium sulfate and evaporation, the title compound is obtained as a light brown oil.

Example 35: N- (4-Cyano-2 (R, S) -a-naphthoxy-butyryl) -His-Cha-Val- n-butylamide

Analogously to Example 24 is from 27.6 mg of 4-cyano-2 (R, S) -ct-naphthoxybuttersäure, 50.0 mg H-His-Cha-Val-n-butylamide, 16.5 mg HOBt unc 28.8 mg DCCI produced the title compound and by

Purified flash chromatography with solvent system B28. R _f (B4) - 0.52.

The starting material is prepared as follows:

a) 4-cyano-2 (R, S) -a-naphthoxy-butyric acid: A mixture of 5.0 g of a-naphthoxy-malonic acid-diethyl ester and 1.09 ml of acrylonitrile is added under stirring at 0 ° with 0.11 ml a 50% aqueous KOH solution. The reaction mixture is stirred for 5 days at room temperature and then dissolved in ethyl acetate. The ethyl acetate solution is washed with 2N sodium bicarbonate solution, 2N hydrochloric acid and brine, dried over sodium sulfate and evaporated, leaving behind (2-cyanoethyl) -ci-naphthoxy-malonic acid diethyl ester.

7.84 g of this malonic ester are stirred in 39.2 ml of DMSO, 398 μl of water and 1.87 g of lithium chloride for 3 hours at 180 °. The reaction mixture is evaporated in a high vacuum, the residue is dissolved in ethyl acetate and extracted with water. The water extracts are adjusted to pH 2 with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracts are washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a light brown oil.

Example 36: N- (4-tert-Butoxycarbonyl-2 (R _> S) -a-naphthoxy-butyryl) -

His-Cha-Val-n-butylamide Analogously to Example 24, 35.7 mg of 4-tert-butoxycarbonyl-2 (R, S) -Ct-

naphthoxy butyric acid, 50.0 mg H-His-Cha-Val-n-butylamide, 16.5 mg HOBt and 28.8 mg DCCI, the title compound was prepared and purified by flash chromatography with solvent system B28. R _f (B4) - 0.33.

The starting material is prepared as follows:

a) 4-tert-butoxycarbonyl-2 (R, S) -O! -naphthoxy-butyric acid: To a solution of 7.6 g of sodium hydride in 300 ml of DMF is slowly added dropwise a solution of 25 g of 1-naphthol in 50 ml of DMF , The

239 21O

Suspension is stirred for 30 min and then treated dropwise with 41.5 g of bromomalonic acid diethyl ester in 50 ml of DMF. The reaction mixture is stirred for 16 hrs. At room temperature and then evaporated in a high vacuum. The residue is dissolved in ethyl acetate and washed with 2N sodium hydroxide solution, water and brine, dried over sodium sulfate and evaporated. The residue is distilled at 145-170 ° / 2.6 Pa and gives a-naphthoxy-malonic acid diethyl ester as orange OeI.

A solution of 3.0 g of this malonic acid ester and 1.45 ml of tert-butyl acrylate in 5 ml of acetonitrile is mixed with 1.49 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene and 24 hrs. At Room temperature stirred. The reaction mixture is mixed with 25 ml of water, adjusted to pH 2 with about 12 ml of 2N hydrochloric acid and extracted with ether. The ether phases are washed with brine and water, dried over sodium sulfate and evaporated, leaving (2-tert-Butoxycarbonyläthyl) -a-naphthoxy ~ malonic acid diethyl ester as a light brown OeI remains.

This ester is hydrolyzed and decarboxylated analogously to Example 35a with lithium chloride and water in DMSO at 180 °. The crude acid is purified by solvent B4 chromatography to give the title compound as a white foam.

Example 37; N- (2 (R, S) -Aethylaminocarbonyloxy-3-a-naphthyl-propionyl) - His-Cha-Val-n-butylamide

Analogously to Example 24, 15.5 mg of 2 (R, S) -ethylaminocarbonyloxy-3-ct-naphthyl-propionic acid, 25.0 mg of H-His-Cha-Val-n-butylamide, 8.3 mg of HOBt and 14, 4 mg DCCI the title compound and purified by flash chromatography with solvent system B28. R _f (B29) - 0.25.

The starting material is prepared as follows:

a) 2 (R, S) -ethylaminocarbonyloxy-3-a-naphthyl-propionic acid: A solution of 50 mg of 2-hydroxy-3-a-naphthyl-propionic acid (Example 17b) in 2 ml of DMF is admixed with 54 μl of ethyl isocyanate. The reaction mixture is stirred for 3 hrs. At 100 ° and then evaporated on a rotary evaporator under high vacuum. The residue is dissolved in ethyl acetate, washed with 0.1 N hydrochloric acid, water and brine, dried over sodium sulfate, evaporated and purified by chromatography on silica gel with solvent system BlI. Yellow OeI, R _f (BIl) - 0.27.

Example 38: N- [2 (R, S) - (2-Benzyloxycarbonylamino-2-methyl-

propionyloxy) -3-a-naphthyl-propionyl] -His-Cha-VALN-butylamide

47.0 mg of 2 (R, S) - (2-benzyloxycarbonylamino-2-methylpropionyloxy) -3-α-naphthyl-propionic acid, 50.0 mg of H-His-Cha-Val-n, are obtained analogously to Example 24. butylamide, 16.5 mg HOBt and 28.2 mg DCCI, the title compound and purified by flash chromatography with solvent system B30. R- (B29) - 0.38.

The starting material is prepared as follows:

a) 2 (R, S) - (2-Benzyloxycarbonylamino-2-methyl-propionyloxy) -3-anaphthyl-propionic acid: To a stirred suspension of 0.14 g of sodium hydride (55% in mineral oil) in 10 ml of DMF is added at room temperature a solution of 0.77 g of α-benzyloxycarbonylamino-isobutyric acid in 5 ml of DMF and after 30 min. Dropped 1 g of 2-bromo-3-a-naphthylpropionsäure ethyl ester in 5 ml of DMF. The reaction mixture is stirred for 16 hours at room temperature and then evaporated in a high vacuum. The residue is dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel with toluene / ethyl acetate (95: 5) gives the ethyl ester of the title compound.

For saponification, 230 mg of the ester are dissolved in 5 ml of THF / water (9: 1) and treated at 0 ° with 20.8 mg of LiOH'HaO. The reaction mixture is stirred for 20 hours at 0 ° and then three times with ethyl acetate

extracted. The ethyl acetate phases are washed with water and brine, dried over sodium sulfate and evaporated. From the residue obtained after chromatography on silica gel with solvent system BIl the title compound as a yellow OeI, R _f (BIl) - 0.34.

Example 39: N- (3-phenyl-2 (S) -pivaloyloxy-propionyl) -His-Cha-Val

n-butylamide

Analogously to Example 24, the title compound is prepared from 30 mg of 3-phenyl-2 (S) -pivaloyloxy-propionic acid, 50 mg of H-His-Cha-Val-n-butylamide, 18 mg of HOBt and 29 mg of DCCI and purified by medium-pressure chromatography a Lobar® finished column with methylene chloride-methanol-ammonia conc. 150: 10: 1 cleaned. R (B8) »0.45.

The starting material is prepared as follows:

a) 3-phenyl-2 (S) -pivaloyloxy-propionic acid: 3.01 g of 3-phenyl-2 (S) -pivaloyloxy-propionic acid benzyl ester are dissolved in 35 ml of methanol in the presence of 300 mg of palladium-carbon (10%). hydrogenated at room temperature under normal pressure for 30 min. The catalyst is filtered off and the filtrate is evaporated in vacuo. The title compound is obtained as a clear colorless oil. R _f (N21) - 0.74. ¹ H-NMR (DMSO-de): 12.5 (IH); 7.25 (s, 5H); 5.1 (dxd, 1H); 3.15 (m, 2H); 1.1 ppm (s, 9H).

b) Benzyl 3-phenyl-2 (S) -pivaloyl-propionate: 0.24 ml of pivalic acid chloride in 2 ml of methylene chloride are added to a cooled to 0 ° C solution of 250 mg of 3-phenyl-2 (S) -hydroxy-propionic acid benzyl ester (L-ß-phenylmilchsäure-benzyl ester) and 0.408 ml of triethylamine in 5 ml of methylene chloride added dropwise. The mixture is stirred for 30 hrs. At room temperature and then poured onto ice. The organic phase is washed with 1N hydrochloric acid and water and dried over sodium sulfate. The solvent is evaporated in vacuo and the residue is purified by medium pressure chromatography

(Lobar® finished column Merck, Grosse B, eluent petroleum ether / ether 11: 1). The title compound is obtained as a colorless oil. R _f (N4) - 0.52.

c) 3-phenyl-2 (S) -hydroxypropionic acid benzyl ester: 23 ml of a 20% aqueous solution of cesium carbonate (pH 7) are added at room temperature to a solution of 4.0 g of L-.beta.-phenyl lactic acid (3-phenyl-2 (S) -hydroxypropionic acid) in 65 ml of methanol and 6.5 ml of water was added dropwise. The solvent is evaporated and the residue is dried for 24 hours at room temperature under high vacuum. The dried cesium salt is taken up in 37 ml of anhydrous DMF, cooled to 0 ⁰ C and treated dropwise with 3.15 ml of benzyl bromide. The resulting white suspension is stirred for 24 hours at room temperature and then filtered. The filtrate is evaporated under high vacuum, the residue taken up in ether, washed with water and saturated aqueous NaHCO3 solution and dried over sodium sulfate. After evaporation of the solvent in vacuo, the title compound is obtained as a yellowish OeI. R _f (N4) - 0.2. ¹ H-NMR (DMSO-d ₆ ): 7.3 (s, 5H); 7.2 (s, 5H); 5.6 (d, 1H); 5.15 (s, 2H); 4.4 (m, 1H), 3.0 ppm (m, 2H).

Example 40: N- (2 (R, S) -, 2 (R) - and 2 (S) -dimethoxyphosphoryl-3

phenyl-propionyl) -His-Cha-Val-n-butylamide

Analogously to Example 24 is from 31 mg of 2 (R, S) -dimethoxyphosphoryl-3-phenyl-propionic acid, 50 mg of H-His-Cha-Val-n-butylamide, 18 mg of HOBt and 29 mg DCCI Titelverbindving prepared as a mixture of diastereomers and Medium pressure chromatography (Lobar® ready column, eluent methylene chloride-methanol-ammonia concentrated 120: 10: 1). R- (B8) - 0.46 (faster diastereomer); R _f (B8) 0.41 (slower diastereomer). The diastereomers can be separated by chromatography.

The starting material is prepared as follows:

, _^122-239

a) 2 (R, S) -dimethoxyphosphoryl-3-phenyl-propionic acid: 6.66 g of methyl 2-dimethoxyphosphoryl-3-phenylpropionate (trimethyl a-benzylphosphonoacetate) are initially introduced in 20 ml of MeOH and treated at room temperature with 8 ml of H 2 O and 12.14 ml of 2N KOH and stirred for 90 min. It is then neutralized with 12.14 ml of 2N HCl, evaporated to 20 ml, extracted with ethyl acetate, dried and evaporated again. ¹ H-NMR (DMSO-d ₆ ):

2.8-3.2 ppm (m, 2H); 3.6 (s, 3H); 3.75 (s, 3H); 7.2 (s, 5H).

b) ot-benzyl-phosphonoacetic acid trimethyl ester : 2.4 g of NaH (50% in OeI) are placed in 250 ml of dimethoxyethane and treated under ice-bath cooling with 10 g of trimethyl phosphonate in 40 ml of dimethoxyethane. It is stirred for 90 min. At room temperature and then treated with 6.52 ml of benzyl bromide in 40 ml of dimethoxyethane. After 4.5 hours of stirring at room temperature, the reaction mixture is poured onto 100 ml of a 2N aqueous solution of NaHzPOi, and ice, extracted with ether, the organic phase dried and evaporated. The crude product is purified by medium-pressure chromatography (1400 g Lichoprep® Si 60, 25-40 pm, eluent ethyl acetate-n-hexane 2: 1 and pure ethyl acetate). ¹ H-NMR (DMSO-de):

2.9-3.4 ppm (m, 2H); 3.60 (s, 3H); 3.61 (s, 3H); 3.85 (s, 3H); 7.22 (s, 5H).

Example 41: Ammonium N- (2 (R, S) -methoxy-oxidophosphoryl-3-phenylpropionyl) -His-Cha-Val-n-butylanide and Diammonium-N- (3-phenyl-2 (R, S) -phosphonato) propionyl) -His-Cha-VALN-butylamide

43 mg of N- (2 (R, S) -dimethoxyphosphoryl-3-phenyl-propionyl) -His-Cha-valn-butylamide (Example 40) are mixed in 1 ml of chloroform at room temperature with 45 μM trimethylbromosilane and stand for 30 hours calmly. The reaction mixture is evaporated, treated with 1 ml of 1N hydrochloric acid, stirred for 1 hour at room temperature and evaporated again. The residue is separated by flash chromatography (eluent methylene chloride-methanol-ammonia conc., Initially 10: 5: 1, then 5: 3: 1).

Methyl ester ammonium salt: R (B32) - 0.38 (faster diastereomer); R (B32) «0.33 (slower diastereomer) ♦ diammonium salt: R. (B32) 0.32 (faster diastereomeric); R- (B32) - 0.26 (slower diastereomer).

Example 42; H- (2 (R, S) -benzyl-S-diäthoxyphosphoryl-propionyl-His- Cha-Val-n-butylaaid

The title compound is prepared analogously to Example 24 from 93 g of 2 (R, S) -benzyl-3-diethoxyphosphoryl-propionic acid, 130 g of H-His-Cha-Val-n-butylaaid, 47 g of HOBt and 75 g of DCCI Plash-Chroaatographie «it solvent Systea B5 cleaned. R _f (B8) - 0.37 (faster diastereoere); R _f (B8) - 0.32 (slower diastereoere).

The starting material is prepared as follows:

a) 2 (R, S) -benzyl-3-diethoxy-3-phosphoryl-propionic acid: 745 g of 2-benzyl-3-diethylphosphoryl-propionic acid ethyl ester are initially charged in 5% ethanol and 4% water, a 1.13 g of 2N ROH is added and Stirred for 4 hours at Rauateaperatur, then ait 1.13 al 2N HCl neutralized and evaporated. The residue is purified by flash chromatography on a solvent Systea N10. R _f (N8) - 0.46. ¹ H NMR (DMSOd _n ): 1.2 ppa (t, 6H); 1.7 (a, IH); 2.05 (a, IH); 2.7-3.0 (a, 3H); 3.95 (q, 4H); 7.15-7.35 (a, 5H).

b) ethyl 2-benzyl-3-dietethoxy-pho-3-propyl-3-propionate: 30% of ethanol is obtained at room temperature with 4 % of a 1 % sodium ethoxide solution, 1.0 g of α-benzylacrylic acid ethyl ester and 0.68% of diethylphosphite (diethylphosphoric acid ester) in 5 al ethanol added. The Gisch is stirred for 24 hours at Rauacaarperatur, then with 200 ag NaH? POu in 1 al water added and eingedaapft. Ee is partitioned between ether and water, the organic phase is dried, poured in and purified by flash chromatography on methylene chloride ether 7: 1. ¹ H-NMR (DMSO-dft): 1.05 pp · (t, 3H); 1.18 (t, 6H); 1.8-2.2 (m, 2H); 2.9 (a, 3H); 3.95 (a, 6H); 7.2 (a, 5H).

c) ethyl ct-benzylacrylate: 20 g Benzylmalonsaurediathylester in 40 ml of ethanol are added at room temperature with 4.0 g of KOH in 50 ml of ethanol, stirred overnight at room temperature, evaporated, mixed with 7.1 ml of water and in an ice bath with 6 , 3 ml conc. Acidified hydrochloric acid, It is partitioned between water and ether, dried the organic phase 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 °) for 90 min, 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, IN HCl, water, sat. NaHCO 3 solution and brine. The title compound is recovered by distillation. ¹ H-NMR (DMSO-de): 1.2 ppm <t, 3H); 3.6 (d, 2H); 4.1 (q, 2H); 5.6 (m, IH); 6.15 (m, IH); 7.25 (m, 5H).

Example 43: N- (3-Benzyloxycarbonyl-2 (R, S) -a-naphthoxy-propionyl) - His-Cha-Val-n-butylamide

The title compound is prepared analogously to Example 24 from 135 mg of 3-benzyloxycarbonyl-2 (R, S) -Ctnaphthoxy-propionic acid, 181 mg of H ^ His-Cha-Val-n-butylamide, 60 mg of HOBt and 105 mg of DCCI. Chromatography with solvent system B23 purified. R _f (B23) - 0.34.

The starting material is prepared as follows:

a) 3-Benzyloxycarbonyl-2- (R, S) -ot-naphthoxy-propionic acid: 0.35 g of sodium hydride (55% in OeI) are added at 0 ° to 1.04 g of ct-naphthoxy -succinic acid in 20 ml of DMF Stirred for 4 hrs. At room temperature, then treated with 1.08 ml of benzyl bromide and stirred for 20 hrs. The reaction mixture is evaporated, dried under high vacuum, taken up in 1N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over MgSO 4 and evaporated. The residue is purified by flash chromatography

²³⁹

Ethyl acetate-n-hexane-methanol 20: 10: 1 to give the title compound as a beige OeI. R_ (Sl3) - 0.48.

b) q-Naphthoxysuccinic Acid: 23 g of a-naphthol in 700 ml of DMF and 200 ml of THF are added in portions with stirring at 0 ° in portions with 20.2 g of sodium hydride (55% in OeI). After 15 min. At 10 ° 29.6 g of bromosuccinic acid in 100 ml of DMF in 30 min. Dropwise. The reaction mixture is stirred for 2 hrs. At room temperature and 15 hrs. At 100 °, whereby distilling off THF. It is then concentrated under high vacuum and partitioned between 1N hydrochloric acid and ethyl acetate. The organic phase is dried, evaporated and purified by flash chromatography with solvent system BIO. By crystallization from ethyl acetate-n-hexane 1: 2, the title compound is obtained as a beige powder of mp. 161-162 °. R _f (SIO) - 0.17.

Example 44: N- (4-Carbamoyl-2 (R) - and 2 (S) -ct-naphthoxy-butyryl) - His-Cha-Val-n-butylamide

Analogously to Example 24, from 14.8 mg of 4-carbamoyl-2 (R, S) -ct-naphthoxybutyric acid, 25.0 mg of H-His-Cha-Val-n-butylamide, 8.3 mg of HOBt and 14.4 mg DCCI the title compound prepared as a diastereomer mixture and separated by flash chromatography with solvent system B29. R- (B4) 0.35 (faster diastereomer) and R_ (B4) »0.25 (slower diastereomer).

The starting material is prepared as follows:

a) 4-Carbamoyl-2 (R, S) -ot-naphthoxybutyric acid: A solution of 3 g of diethyl α-naphthoxymalonate (Example 36a) and 0.71 g of acrylamide in 5 ml of acetonitrile is charged with 1.49 ml of 1 , 8-diazabicyclo [5.4.O] undec-7-ene and stirred for 24 hrs. At room temperature. The reaction mixture is mixed with 25 ml of water, adjusted to pH 2 with 2N hydrochloric acid and extracted with ether. The ether phases are washed with water and brine, dried over sodium sulfate and evaporated, leaving (2-carbamoylethyl) -a-naphthoxy-malonsäurediäthylester remaining.

This ester is hydrolyzed and decarboxylated analogously to Example 35a with lithium chloride and water in DMSO at 180 °. The crude acid is purified by chromatography with solvent system BIl to give the pure title compound.

Example 45: Prepared analogously to Example 24:

a) N- (2 (R) - and 2 (S) -cyanomethyl-3-a-naphthyl-propionyl) -His-Cha-Valn-butylamide; Separation by flash chromatography with eluant B28; R (B4) - 0.43 (faster diastereomer) and R (B4) - 0.38 (slower diastereomer).

b) N- (indolyl-2-carbonyl) -His-Cha-Val-n-butylamide; Flash chromatography with eluant B23; R _f (B4) - 0.43;

R _f (B4) - 0.59.

c) N-phenoxyacetyl-His-Cha-Val-n-butylamide; Flash chromatography with eluant B23; R _f (B4) - 0.48; R _f (S4) - 0.62.

d) N-iB-naphthylcarbonyD-His-Cha-Val-n-butylamide; Flash chromatography with eluant B23; R (B4) - 0.44; R _f (S4) - 0.67.

e) N-ict-naphthoxyacetyl-His-Cha-Val-n-butylamide; Flash chromatography with eluant B23; R (B4) - 0.52.

f) N- (3-Benzyloxycarbonyl-2 (R, S) -a-naphthylmethyl-propionyl) -His-Cha-Val-n-butylamide; Flash chromatography with eluant B3; R _f (B23) - 0.21; R _f (S6) - 0.23.

g) N- (2 (R, S) -Benzyl-4-oxopentanoyl) -His-Cha-Val-n-butylamide; R _f (B7) - 0.43.

h) N- (2 (R, S) -Benzyl-4,4-dimethyl-3-oxopentanoyl) -His-Cha-Valn-butylamide; R _f (B7) - 0.35.

i) N- (5-dimethylamino-2 (R) - and 2 (S) -a-naphthylmethylpentanoyl) -His-Cha-Val-n-butylamide; R _f , (BlI) - 0.63 (faster diastereomer) and R- (BH) "0.18 (slower diastereomer).

j) N- (2 (R, S) -benzyl-5,5-dimethyl-4-oxo-hexanoyl) -His-Cha-valmethylamide; R _f (B7) - 0.30.

k) N- (2- (R, S) -tert-butylcarbamoyl-3-a-naphthyl-propionyl) -His-Cha-Val-n-butylamide; R _f (B5) - 0.20; R _{ (B7) - 0.30.

Example 46: N- (3-Carboxy-2 (R) - and 2 (S) -ct-naphthylmethyl-

propionyl) -HJ3-Cha-Val-n-butylamide

60 mg of N- (3-benzyloxycarbonyl-2 (R, S) -a-naphthylmethyl-propionyl) -His-Cha-Val-n-butylamide (Example 45f) are dissolved in 6 ml of methanol and dissolved in the presence of 100 mg of palladium Charcoal (10% Pd) hydrogenated to saturation. The residue is separated by chromatography on 30 g of silica gel with methylene chloride-methanol-water (initially 110: 10: 1, then 50: 10: 1). R (SlO) - 0.66 and R- (N22) - 0.37 (faster diastereomer); R _f (SlO) - 0.48 and R (N22) - 0.17 (slower diastereomer).

Example 47: N- (Quinolyl-2-carbonyl) -N-methyl-His-Cha-Val-n-

butylamide

50 mg H-Cha-Val-n-butylamide (Example 24c), 55 mg N ^a - (quinolyl-2-carbonyl) -N-methyl-L-histidine and 26 mg HOBt are dissolved in 2 ml DMF in an ice bath with 41 mg DCCI offset. The mixture is stirred for 6 hours in an ice bath and for 3 days at room temperature. After evaporation of the solvent in a high vacuum, the residue in .5 ml of a mixture of methanol-water-glacial acetic acid (94: 3: 3) for 60 min. At 60 ⁰ C heated and evaporated again. The residue is purified by medium pressure chromatography on a Lobar® finished column, Grosse B, with solvent system B26

purified and isolated from tert-butanol by lyophilization. R _f (B8) - 0.36.

The starting material is prepared as follows:

a) ^ - (Quinolyl) -carbonyU-N-ethyl-L-histidine: 321 mg

N - (quinolyl-2-carbonyl) -N-methyl-L-histidine methyl ester are dissolved in 3 ml of THF and treated at room temperature with 1.42 ml of 1N NaOH. After 1.5 hours, it is neutralized with 1.42 ml of 1N HCl and evaporated to dryness. R- (B8) - 0.02.

b) N, ^Ct - (quinolyl-2-carbonyl) -p-methyl-L-histidine methyl ester: 400 mg N ^a -methyl-L-histidine methyl ester dihydrochloride, 298 mg quinoline-2-carboxylic acid, 263 mg HOBt, 0.531 ml of ethyldiisopropylamine and 418 mg of DCCI are stirred in 2 ml of DMF for 5 days at room temperature and then evaporated. The residue is stirred for 1 hour in a mixture of methanol-water-glacial acetic acid (94: 3: 3) at 60 °, evaporated again and purified by medium-pressure chromatography on a Lobar® finished column with solvent system B31. R _f (B8) - 0.63.

c) N ^a -methyl-L-histidine methylester dihydrochloride: 2 g N ^a -methyl-L-histidine hydrochloride (Bachem AG, Bubendorf) are dissolved in 30 ml of methanol and treated with ice bath cooling with 1.2 ml of SOCl 2. It is stirred overnight at room temperature and then evaporated to dryness. ¹ H-NMR (DMSO-d ₆ , TMS): 2.65 ppm (s, 3H); 3.45 (dd, 2H); 3.7 (s, 3H); 4.4 (m, IH); 7.55 (3, H); 9.1 (s, IH).

Example 48: N-Methyl-N- (3-phenyl-2 (S) -pivaloyloxy-propionyl) - His-Cha-Val-n-butylamide

Analogously to Example 47 is from 68 mg of N ^a- methyl-N ^a - (3-phenyl-2 (S) -pivaloyloxy-propionyl) -L-histidine, 50 mg H-Cha-Val-n-butylamide, 26 mg HOBt and 41 mg DCCI the title compound and prepared by

239 21

Medium pressure chromatography on a Lobar® finished column with B26 solvent system. R (B8) - 0.29.

The starting material is prepared as follows:

a) N ^Ci -Methvl-N ^0t - (3-phenyl-2 (S) -pivaloyloxy-propionyl) -L-histidine: Analogously to Example 47a, the corresponding methyl ester is saponified with sodium hydroxide solution. R (B8) «0.01.

b) N ^Ct -Methyl N ° ^t - (3-phenyl-2 (S) -pivaloyloxy-propionyl) -L-histidine methyl ester ; Analogously to Example 47b, the title compound is prepared from N-methyl-L-histidine methyl ester dihydrochloride and 3-phenyl-2 (S) -pivaloyloxy-propionic acid (Example 39a) and purified by flash chromatography with eluant N10, then medium pressure chromatography (Lichroprep® Si60, 25-40 μιη, eluant B33). R _f (B8) - 0.59.

Example 49: N- (Indolyl-2-carbonyl) -N-methyl-His-Cha-Val-n-

butylamide hydrochloride

The title compound is prepared analogously to Example 47 from 53 mg of N- (indolyl-2-carbonyl) -N-methyl-L-histidine, 50 mg of His-Cha-Val-n-butylamide, 26 mg of HOBt and 41 mg of DCCI. Chromatography (Lichroprep® Si60, 25-40 μπι, eluant B33) and lyophilized from tert-butanol. R. (B8) 0.57.

T ^ λ + .j-, »τ <* / τ ι ·, t ι L, _s " α-methyl-L-histidine The starting material N - (indolyl-2-carbonyl) -N

is prepared analogously to Example 47a.

Example 50: N- (Naphthalene-1, S-dicarbonyl-Phe-Cha-Val-n-Butyl

amide

Starting from 110 mg of naphthalene-1,8-dicarbonyl-L-phenylalanine (Egypt. J. Chem., 24, 127 (1981)), 80 mg of H-cha-val-n-butylamide (Example 24c) are prepared analogously to Example 1, 49 mg HOBt and 81 mg DCCI gave the title compound and by flash chromatography

- 130- 2 39 2 1

it solvent Systea N6 cleaned. R (N7) «0.41; R _f (N6) - 0.17.

Example 51; W- (indolyl-2-carbonyl) ~ Phe-Cha-Val-n-butylanide A mixture of 39 g of indole-2-carboxylic acid, 114 g of H-Phe-Cha-Valn-butylaaid, 37 g of HOBt and 66 g of DCCI in 6 al DHF is stirred for 24 hrs. At room temperature. The crystallized DCH is filtered off and the filtrate is evaporated. The crude product is purified by flash chromatography (100 g silica gel 60, 40-63 μm, N6 runner). Evaporation of the combined, product-containing fractions gives the title compound. R- (B3) -0.46; R _f (S9) - 0.89.

The starting material is prepared as follows:

a) H-Phe-Cha-Val-n-butylaaid: 144 g of Z-Phe-Cha-Val-n-butylamide are dissolved in 5: 1 methanol: 9: 1 in the presence of 20 g of palladium carbon (10% Pd). hydrogenated at atmospheric pressure and room temperature to saturation. The reaction mixture is filtered and the filtrate is stirred at room temperature as water. After dea vaporization of the solvent, the title compound is obtained as a colorless oil. R _f (B2) - 0.62; R _f (S9) - 0.85.

b) Z-Phe-Cha-Val-n-butylaaid: A mixture of 150 parts of Z-Phe-OH, 164 parts of H-Cha ² Val-n-butylaaid, 76 parts of HOBt and 134 parts of DCCI in 6 as DMF becomes 48 Std. Stirred at room temperature. The DCH is filtered off, the filtrate is concentrated and dried aa high vacuum. The residue is separated by flash chromatography (185 g of silica gel 60, 40-63 et al., N6). By evaporation of the

united, product-containing fractions gives the title compound. R _f (B4) - 0.80; R _f (N7) - 0.37.

Example 52: N-dinolyl-carbonyl-Nle-Cha-Val-n-butylamide Analogously to Example 51, 40 mg of indole-2-carboxylic acid, 110 mg of H-Nle-Cha-Val-n-butylamide, 38 mg of HOBt and 68 mg DCCI in 6 ml of DMF, the title compound and purified by flash chromatography with solvent system N7. R (B2) - 0.38; R. (S9) - 0.89.

The starting material is prepared as follows:

a) H-Nle-Cha-Val-n-butylamide is analogously to Example 51a by hydrogenation of 144 mg of Z-Nle-Cha-Val-n-butylamide in 5 ml of methanol-water 9: 1 in the presence of 20 mg of palladium-carbon (10% Pd). R _f (B2) - 0.57; R _f (S9) - 0.69.

b) Z-Nle-Cha-Val-n-butylamide is prepared analogously to Example 51b starting from 133 mg of Z-NiE-OH, 163 mg of H-Cha-Val-n-butylamide, 77 mg of HOBt and 134 mg of DCCI in 6 ml of DMF manufactured. R _f (B2) - 0.80; R _f (N7) - 0.31

Example 53: N- (Indolyl-2-carbonyl) -His-Cha-Val-3-dimethyl

aminopropylamide

Analogously to Example 17, the title compound is obtained from 15 mg of indole-2-carboxylic acid, 43 mg of H-His-Cha-Val-3-dimethylaminopropylamide, 14 mg of HOBt and 25 mg of DCCI in 2 ml of DMF and by flash chromatography with solvent system BlI cleaned. R _f (Bl) = 0.32; R _f (S9) - 0.12.

The starting material is prepared as follows:

a) H-His-Cha-Val-S-dimethylaminopropylamide is prepared by hydrogenating 57 mg of Z-His-Cha-Val-S-dimethylaminopropylamide in 18 ml

Methanol-water 9: 1 in the presence of 15 mg of palladium-carbon (10% Pd) prepared analogously to Example 16a. R _f (Bl) - 0.085.

b) Z-His-Cha-Val-B-dimethylaminopropylamide is starting from

136 mg of Z-His-OH, 167 mg of H-Cha-Val-3-dimethylaminopropylamide, 72 mg of HOBt and 128 mg of DCCI in 6 ml of DMF were obtained analogously to Example 16b. _Rf (B1) - 0.32; R _f (S9) - 0.14.

c) H-Cha-Val-S-dimethylaminopropylamide: 247 mg of Z-Cha-Val-3-dimethylaminopropylamide are dissolved in 10 ml of methanol-water 9: 1 in the presence of 40 mg of palladium-carbon (10% Pd) at normal pressure and room temperature hydrogenated to saturation. The reaction mixture is filtered and the filtrate is stirred with 10 ml of water at room temperature. After evaporation of the solvents, the title compound is obtained as a colorless oil. R (Bl) - 0.13.

d) Z-Cha-Val-3-dimethylaminopropylamide: A mixture of 357 mg of Z-Cha-Val-OH (Example 16i), 8.5 ml of DMF, 153 mg of HOBt and 206 mg of DCCI is kept at 0 ° for 24 hours calmly. The mixture is mixed with 337 mg of dimethyl-3-amino-propylamine and stirred for 2 hrs. At 0 ° and 39 hrs. 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 colorless OeI by flash chromatography (eluent system B4). R _f (B4) - 0.32; R _f (N12) - 0.24.

Example 54: N- (Indolyl-2-carbonyl) -His-Cha-Val-2-morpholino-

äthylamid

Analogously to Example 17, the title compound is obtained from 26 mg of indole-2-carboxylic acid, 83 mg of H-His-ChaSval-2-morpholinoethylamide, 25 mg of HOBt and 43 mg of DCCI in 4 ml of DMF and purified by flash chromatography with eluant B4 , R (B2) - 0.19; R _f (S9) - 0.41.

The starting material is prepared as follows:

a) H-Hi3-Cha-Val-2-aorpholino * ethylamine is prepared by hydrogenation of 104 mg of Z-His-Cha ^ Val ^ -aorpholinoäthylaaid in 10 el methanol-water 9: 1 in the presence of 40 ag Palladiua coal (10 % Pd) was prepared analogously to Example 16a. _Rf (B1) - 0.43; R _f (S9) - 0.13.

b) Z-His-Cha-Val-2-aorpholinoethylaaid is prepared from 174 ag Z-His-OH, 230 ag H-Cha-Val-2-aorpholinoethyl aldehyde, 92 g HOBt and 163 mg DCCI in 8 al DM? obtained analogously to Example 16b.

R _f (B2) - 0.28; R _f (S9) - 0.39.

c) H-Cha-Val-2-aorpholinoäthylaaid is hydrogenated by 340 g of Z-Cha ^ Val-2-aorpholinoäthylaaid in 10 al methanol Waseer9: 1 in the presence of 50 mg Palladiua coal (10% Pd) analogously to Example 53c manufactured. R _f (Bl) - 0.48; R _f (S9) - 0.21.

d) Z-Cha-Val-2-aorpholinoäthylanld is analogous to Example 53d from 267 mg of Z-Cha ^ Val-OH, 98 ag 4- (2-aminoethyl) morpholine, 115 ag HOBt and 155 eg DCCI in 7 al DMF manufactured. R. (NI) - 0.68;

R _f (N6) - 0.10.

Example 55: N- (Indolyl-2-carbonyl) -His-Cha-Val- (5-tert-butyl)

butoxycarbonyl-amino-S-methoxycarbonyl-pentyd-aide Analogously to Example 17, 31 g of indole-2-carboxylic acid, 124 mg of H-His-Cha-Val- (S-tert-butoxycarbonyl-amino-S-aethoxycarbonylpenty-D-aaid, 29 mg of HOBt and 52 TLCCI in 3% DMF, the title compound was obtained and purified by flash chromatography on solution Systea B23 R _f (34) - 0.42; R _f (S9) - 0.71.

The starting material is prepared as follows:

a) H-His-Cha-Val- (S-tert-butoxycarbonyl-amino-S-methoxycarbonylpentyl) -aldehyde is prepared by hydrogenation of 143 g of Z-His-Cha-Val- (5-tert-butoxycarbonyl-amino-5-aethoxycarbonyl-pentyD-) aaid in 10 al

- 134- 2 39 21 O

Methanol-water 9: 1 in the presence of 25 mg of palladium-carbon (10% Pd) prepared analogously to Example 16a. R (B4) - 0.10; R _f (BIl) - 0.66.

b) Z-His-Cha-VaI- (S-tert-butoxycarbonylamino-S-methoxycarbony1-pentyl) -amide is prepared from 197 mg of Z-His-OH, 349 mg of H-Cha-Val- (S-tert-butoxycarbonylamino S-methoxycarbonyl-pentyD-amide, 104 mg HOBt and 183 mg DCCI in 11 ml DMF analogously to Example 16b. R _f (B4) - 0.59.

c) H-Cha-Val- (5-tert-butoxycarbonylamino-5-methoxycarbonylpentyl) -amide is prepared by hydrogenating 469 mg of Z-Cha-Val- (5-tert-butoxycarbonylamino-S-methoxycarbonyl-pentyD-amide in 7 ml Methanol-water 9: 1 in the presence of 100 mg of palladium-carbon (10% Pd) prepared analogously to Example 53c R- (B4) 0.16.

d) Z-Cha-Val- (5-tert-butoxycarbonylamino-5-methoxycarbonylpentyl) -amide is analogous to Example 53d from 446 mg of Z-Cha-VaI-OH, 320 mg of N-tert-butoxycarbonyl-L-lysine methyl ester , 153 mg HOBt and 278 mg DCCI in 14 ml DMF. _Rf (N3) - 0.48;

R _f (N10) - 0.63.

Example 56: N- (Indolyl-2-carbonyl) -His-Cha-Val- ^ -amino-5-carboxy-

pentyl) -amide hydrochloride

102 mg of N- (indolyl-2-carbonyl) -His-Cha-Val- (5-tert-butoxycarbonylamino-5-methoxycarbonyl-pentyl) -amide, 1.9 ml of 0.1 N NaOH and 1 ml of water are dissolved in 5 ml of methanol stirred at room temperature for 16 hrs. The reaction mixture is neutralized with 1.9 ml of 0.1 N HCl, evaporated and extracted with ethyl acetate. The extracts are evaporated, treated with 1.5 ml of trifluoroacetic acid and allowed to stand at room temperature for 20 min. The trifluoroacetic acid is evaporated and the crude product is purified by flash chromatography (160 g of silica gel 40-63 μιη, eluent S4). The residue is taken up in 1N HCl, completely evaporated and from tert-butanol

lyophilized, leaving the title compound as a light beige powder. R _f (B32) - 0.76.

Example 57: N- (α-Naphthoxyacetyl) -His-Cha-Val-2-hydroxyethylamide Analogously to Example 53, starting from 59 mg of C-naphthoxyacetic acid, 146 mg of H-His-Cha ^£ Val-2-hydroxyethylamide, 45 mg HOBt and 78 mg DCCI the title compound was prepared and purified by flash chromatography with solvent system B4. R _f (B4) «0.30.

Example 58; N- (3-phenyl-2 (S) -pivaloyloxy-propionyl) -His-Leu-Gly (R-

and S-cyclohexylmethyl) -n-butylamide

40 mg of 3-phenyl-2 (S) -pivaloyloxypropionic acid (Example 39a), 70 mg of H-His-Leu-Gly (R- and S-cyclohexylmethyl) -n-butylamide, 25 mg of HOBt and 39 mg are obtained analogously to Example 17 DCCI, the title compounds prepared, purified by medium pressure chromatography on a Lobar® finished column with solvent system B31 and isolated by lyophilization from tert-butanol. R_ (B8) 0.64 (diastereomer A) and R. (B8) 0.55 (diastereomer B).

The starting material is prepared as follows:

a) H-His-Leu-Gly (R- and S-cyclohexylmethyl) -n-butylamide are obtained by hydrogenation of Z-His-Leu-Gly (R- and S-cyclohexylmethyl) -n-butylamide analogously to Example 16a. R _f (B8) - 0.17 (diastereomer A) and R - (B8) 0.11 (diastereomer B).

b) Z-His-Leu-Gly (R- and S-cyclohexylmethyl) -n-butylamide are prepared starting from Z-His-OH and H-Leu-Gly (R- and S-cyclohexylmethyl) -n-butylamide analogously to Example 16b and purified by flash chromatography with solvent N10. R (N8) - 0.33 (diastereomer A) and R- (N8) 0.43 (diastereomer B).

c) H-Leu-Gly (R- and S-cyclohexylmethyD-n-butylatnid are obtained by hydrogenation of Z-leu-Gly (R- and S-cyclohexylmethyD-n-butylamide analogously to Example 16k R_ (BIO) - O, 64 (diastereomer A) and R (BIO) - 0.61 (diastereomer B).

d) Z-Leu-GIy (R- and S-cyclohexylmethyD-n-butylamide are obtained from Z-Leu ^ Gly (R- and S-cyclohexylmethyp-OH and n-butylamine analogously to Example 16j and by flash chromatography with eluant N4 R. (N3) 0.65 (diastereomer A) and R (N3) 0,5 0.59 (diastereomer B).

e) Z-Leu ^ Gly (R- and S-cyclohexy! methyl) -OH (3- [3-Benzyloxycarbonyl-2,2-dimethyl-4 (S) -isobutyl-1,3-oxazolidine-5 (S) -yl] -2 (R, S) -cyclohexylmethyl-propionic acid) is prepared analogously to Example 16i by hydrolysis of the corresponding methyl ester.

R. (N4) - 0.05 (mixture of diastereomers).

f) Methyl 3- (3-benzyloxycarbonyl-2,2-dimethyl-4 (S) -isobutyl-1,3-oxazolidine-5 (S) -yl) -2 (R _t S) -cyclohexylmethyl-propionate is analogous Example Id was prepared from the compound (XXV) and methyl 3-cyclohexylpropionate and purified by medium-pressure chromatography over a Lobar®-finished column with n-hexane-ethyl acetate 19: 1. R _f (N5) - 0.14 and 0.17.

g) Methyl S-cyclohexylpropionate: 20 g of cyclohexyl-propionic acid are allowed to stand in 200 ml of 5N HCl in methanol overnight at room temperature. The solvent is evaporated, the residue taken up in ether, washed with saturated NaHCO 3 solution and brine and dried. Distillation at 121-125 ° / 2.0-2.5 "10 ~ ² bar gives the title compound.

Example 59; N- (3-phenyl-2 (S) -pivaloyloxy-propionyl) -His-Leu-Gly

(R- and S-g-decahydronaphthyD-n-butylamide

Analogously to Example 17, 29 mg of 3-phenyl-2 (S) -pivaloyloxypropionic acid (Example 39a), 55 mg of H-His-Leu-Gly (R- and S-adecahydronaphthyl) -n-butylamide, 18 mg of HOBt and 28 mg DCCI the title compounds and purified by medium pressure chromatography on a Lobar® finished column with solvent system B31. R (B8) »0.53 (Diastereomer A) and R (B8) - 0.45 (Diastereomer B).

The starting materials are prepared as follows:

a) H-His-Leu-Gly (R- and S-ct-decahydronaphthyl) -n-butylamide are obtained by hydrogenation of Z-His-Leu-Gly (R- and Sa-decahydronaphthyl) -n-butylamide analogously to Example 16a , R (B8) »0 (both diastereomers).

b) Z-His-LeU-Gly (R- and S-ot-decahydronaphthyl) -n-butylamide are analogous starting from Z-His-OH and H-Leu-Gly (R- and Sa-decahydronaphthyl) -n-butylamide Example 16b obtained and purified by medium pressure chromatography with eluant B31. R (B8) - 0.59 (diastereomer A) and R- (B8) - 0.48 (diastereomer B).

c) H-Leu-Gly (R- and Sa-decahydronaphthyl) -n-butylamide are obtained by hydrogenation of Z-Leu-Gly (R- and Sa-decahydronaphthyl) -n-butylamide analogously to Example 16k and by medium-pressure chromatography with Purifier N8 followed by purified pure methanol. R- (B8) -0 (both diastereomers).

d) Z-Leu-Gly (R- and Sa-decahydronaphthyl) -n-butylamide are obtained from Z-Leu-Gly (R, Sa-decahydronaphthyl) -OH and n-butylamine analogously to Example 16j and by flash chromatography with eluant N4 separated. R- (N3) -0.68 (diastereomer A) and _Rf (N3) -0.61 (diastereomer B).

e) Z-Leu-Gly (R, Sa-decahydronaphthyl) -OH (3- [3-Benzyloxycarbonyl-2,2-dimethyl-4 (S) -isobutyl-1,3-oxazolidin-5 (S) -yl] -2 (R, S) -a-decahydronaphthyl-propionic acid) is prepared analogously to Example 16i by hydrolysis of the corresponding methyl ester and purified by medium-pressure chromatography with n-hexane-ethyl acetate 19: 1. R (N4) - 0.13 and 0.18.

f) Methyl 3- [3-benzyloxycarbonyl-2,2-dimethyl-4 (S) -isobutyl-l, 3-oxazolidine-5 (S) -yl] -2 (R, S) -a-decahydronaphthyl-propionate is prepared analogously to Example Id from the compound (XXV) and a-decahydronaphthyl-acetic acid methyl ester and purified by medium-pressure chromatography with n-hexane-ethyl acetate 19: 1.

g) ct-Decahydronaphthyl-acetic acid methyl ester is prepared by esterification of a-Decahydronaphthyl-acetic acid analogously to Example 58g. ¹ H-NMR (DMSO-ds, TMS): 3.58 ppm (s, 3H) and others.

h) ct-Decahydronaphthylacetic acid: 25 g of ct-naphthylacetic acid are dissolved in 120 ml of water and 134 ml of 1N sodium hydroxide solution and dissolved in the presence of 1.3 g of platinum-rhodium catalyst (PtO ₂ ¹ HzO-Rh ₂ O ₃ - 54: 46) for 31 hours at room temperature and atmospheric pressure. The catalyst is filtered off, the filtrate with conc. Hydrochloric acid acidified to pH 1 and extracted with ether. The title compound is obtained by drying and evaporating the ether extract.

Example 60; N- (3-phenyl-2 (S) -pivaloyloxy-propionyl) -His-Leu-Gly

(R- and S -dinethylanino) -n-butylaaid

3-Phenyl-2 (S) -pivaloyloxypropionic acid (Example 39a), 27 g of H-His-Leu-Gly (R- and S-diaethylaaino) -n-butylaaid, 12 g of HOBt and 20 g of Ag are analogously to Example 17 DCCI, the title compounds prepared, purified by medium pressure chromatography on a Lobar® - finished column altalt Altaltaltelsystea B5 and isolated by lyophilization from tert-butanol. R- (B8) x 0.36 (diastereomer A) and R, (BS) 0.30 (diastereomeric B).

The starting materials are prepared as follows:

a) H-His-Leu-Gly (R- and S-dinethylamino) -n-butylaaid are obtained by hydrogenation of Z-Hia-Leu-Gly (R- and S-diaethylaaino) -nbutylamid analogous to Example 16a. R. (B8) - 0.01 (both Dlastereoaere).

b) Z-Hia-Leu-Gly (R- and S-diaethylaaino) -n-butylaaid are obtained analogously to Example 16b starting from Z-His-OH and H-Leu-Gly (R- and S-diaethylaaino) -butylaaid and purified by medium-pressure chroaatography old fluid B33. R- (B8) -0.36 (diastereomer A) and R- (B8) 0.15 (diastereomeric B).

c) H-Leu-Gly (R- and S-diaethylaalno) -n-butylaaid are by hydrogenation of Z-Letr ^ Gly (R, S-dimethylaaino) -n-butylaaid analogous to Example 16k and separation by medium-pressure Chroaatographie old Fliessaittel B33 received. R- (B8) -0.28 (diastereoaerea A) and R. (B8) -0.19 (diastereomeric B).

d) Z-Leu-Gly (R, S-dimethylamino) -n-butylaaid is obtained from Z-Leu- ^1- Gly- (R, S-dimethylamino) -OH and n-butylamine analogously to Example 16j and by flash chromatography old fluid methylene chloride

- 140 - 2 3 9 21

Methanol-ammonia conc. 500: 10: 1 cleaned. R (B31) - 0.91 and 0.95.

e) Z-Leu-Gly (R, S-dimethylamino) -OH (3- [3-Benzyloxycarbonyl-2,2-dimethyl-4 (S) -isobutyl-1,3-oxazolidin-5 (S) -yl] -2 (R, S) -dimethyl-amino-propionic acid) is prepared analogously to Example 16j by hydrolysis of the corresponding ethyl ester and purified by medium-pressure chromatography with eluant N8. R (N3) = 0.21 and 0.10.

f) 3- (3-Benzyloxycarbonyl-2,2-dimethyl-4 (S) -isobutyl-l, 3-oxazolidin-5 (S) -yl) -2 (R, S) -dimethylamino-propionic acid ethyl ester is analogous Example Id from the compound (XXV) and ethyl dimethylaminoacetate prepared and purified by medium pressure chromatography with eluant N3. R _f (N3) - 0.52 and 0.35.

Example 61: N- (Indolyl-2-carbonyl) -His-Leu-Val-4- [tris- (tert-

butyldimethylsilyloxymethyl) -methyl] butylamide

21 mg of indole-2-carboxylic acid, 20 mg of HOBt and 23 .mu.ΐ Aethyldiisopropylamin be cooled to 0 ⁰ C in 2 ml of DMF. After addition of 116 mg of H-His-Leu-Val-4- [tris- (tert-butyldimethylsilyloxymethyl) -methylcarbamoylj-butylamide and 34 mg of DCCI is stirred for 24 hrs. With ice cooling and then for 2 days at room temperature. The crystalline DCH is filtered off with suction and the filtrate concentrated in a high vacuum. The residue is purified by flash chromatography with solvent system B23. By lyophilization in 20 ml of tert-butanol, the title compound is obtained as a slightly yellowish lyophilisate. R (B4) - 0.49.

The starting material is prepared as follows:

a) H-His-Leu-Val ^ cis-tert-butyldimethylsilyloxymethyl-methylcarbamoyl] -butyl amide is obtained from the corresponding N-benzyloxycarbonyl compound by hydrogenation analogously to Example 4a.

R _f (B4) - 0.11.

b) Z-His-Leu-Val-4- [tris (tert-butyldimethylsilyloxymethyl) methylcarbamoyl] butylamide: 58 mg of Z-His-OH, 155 mg of H-Leu-Val-4- tris- (tert-butyldiraethylsilyloxymethyl) -methylcarbamoyl] -butylamide (prepared according to EP-A 143 746), 35 μΐ ethyldiisopropylamine, 31 mg HOBt and 54 mg DCCI in 4 ml DMF, the title compound and purified by flash chromatography with eluant B23. R _f (B4) - 0.42.

Example 62: N- (Indolyl-2-carbonyl) -His-Leu-Val-4- [tri8-

(Hydroxymethyl) -methyl] butylamide

36 mg of N- (indolyl-2-carbonyl) -His-Leu-Val-4- [tris- (tert-butyldimethylsilyloxymethyl) -methylcarbamoyl] -butylamide and 2 ml of acetic acid-water 2: 1 are stirred for 2 hours at room temperature and then evaporated. The residue is purified by flash chromatography with solvent system BlI to give the title compound as a white powder. R _f (BIl) 0.27.

Example 63: N- (1-Benzyl-indolyl-3-carbonyl) -His-Leu-Val-2-picolyl-

amide

Analogously to Example 4, the title compound is obtained starting from 30 mg of N-benzyl-indole-3-carboxylic acid, 45 mg of H-His-Leu-Val-2-picolylamide, 19 mg of HOBt and 30 mg of DCCI and purified by flash chromatography with solvent. System B7 cleaned. R _f (B7) - 0.31; R _f (B9) - 0.43.

The starting materials are prepared as follows:

- 142 - 2 3921

C.,

a) H-His-Leu-Val-2-picolylamide is obtained by hydrogenation of 430 mg of Z-His-Leu-Val-2-picolylamide in the presence of 50 mg of palladium-carbon (10%) analogously to Example 1 g. R (BIl) - 0.18; R _f (B7) - 0.12.

b) Z-His-Leu-Val-2-picolylamide is obtained analogously to Example 1 starting from 225 mg of Z-His-OH, 350 mg of H-Leu-Val-2-picolylamide, 130 mg of HOBt and 218 mg of DCCI and by flash Chromatography with solvent system B7 purified. R (B7) - 0.30; R _f (BIl) - 0.63.

c) H-Leu-Val-2-picolylamide is obtained by hydrogenation of 1.69 g of Z -leu-Val-2-picolylamide in the presence of 170 mg of palladium-carbon (10%) analogously to Example Ig. R _f (B7) - 0.25.

d) Z-Leu- ^ Val-2-picolylamide is obtained analogously to Example 1 starting from 1.50 g of Z -Leu.RTM.VAL -OH, 0.76 ml of 2-aminomethylpyridine, 680 mg of HOBt and 1.070 g of DCCI and Purified with solvent system N7 chromatography. R (N7) - 0.32.

Example 64: Analogously to Example 8 are prepared:

a) N- (indolyl-2-carbonyl) -His-Leu-Val-n-pentylamide; Flash chromatography with eluant B4; R (B4) 0.42.

b) N- (indolyl-2-carbonyl) -His-Leu-Val-cyclohexylmethylamide; Flash chromatography with eluant B23; R (B4) - 0.34.

c) N- (indolyl-2-carbonyl) -His-Leu-Val-5-hydroxypentylamide; Flash chromatography with eluant B4; R (B4) - 0.18.

d) N- (α-naphthoxyacetyl) -His-Leu-Val-2-hydroxyethylamide; Flash chromatography with eluant B4; R (B4) »0.27.

Example 65: Analogously to Example 4 are prepared:

23 9 2 1

a) N- (a-naphthoxyacetyl) -Phe-Leu-Val-n-butylamide; Flash chromatography with eluant N10; R _f (N10) - 0.15.

b) N-methyl-N-α-naphthoxyacetyl-Phe-Leu-Val-n-butylamide; Flash chromatography with eluant N7; R (N7) - 0.26.

Example 66: According to one of the preceding examples can be prepared:

N- [2- (2-amino-2-methyl-propionyloxy) -3-ct-naphthyl-propionyl] -His-Cha-Val-n-butylamide;

N- (2-acetoacetoxy-3-a-naphthyl-propionyl) -His-Cha-Val-n-butylamide; N- (2-cyano-3-a-naphthyl-propionyl) -His-Cha-Val-n-butylamide; N- (2-acetyl-3-a-naphthyl-propionyl) -His-Cha-Val-n-butylamide; N- (2-acetonyl-3-a-naphthyl-propionyl) -His-Cha-Val-n-butylamide; N- (5-dimethylamino-2-a-naphthoxy-pentanoyl) -His-Cha-Val-n-butyl

N- (4-carboxy-2-a-naphthoxy-butyryl) -His-Cha-Val-n-butylamide; N- (2-a-naphthyloxy-4-oxo-pentanoyl) -His-Cha-Val-n-butylamide; N-iCyano-a-naphthoxy-acetyD-His-Cha-Val-n-butylamide; N- (3-phenyl-2-pivaloyloxy-propionyl) -His-Cha-Gly (dimethylamino) -n-butylamide;

N- (2-benzyl-J

amino) -n-butylamide;

N- (3-Phenyl-:

äthylamid; ^

N- (2-Ben2yl-5,5-dimethyl-4-oxo-hexanoyl) -His-Cha-Val-2- (4-imidazoIy1) -äthylamid;

N- (3-phenyl-2-pivaloyloxy-propionyl) -His-Cha-Val-2- [2- (4-imidazoIy1) ethylamino] -äthylamid;

N- (2-benzyl-5,5-dimethyl-4-oxo-hexanoyl) -His-Cha-Val-2- [2- (4-imidazoIy1) -äthylamino] -äthylamid;

N- (2-benzyl-5,5-dimethyl-4-oxo-hexanoyl) -His-Cha-Val-4-carboxybutylamid;

N- (2-benzyl-5,5-dimethyl-4-oxo-hexanoyl) -His-Cha-Gly (dimethyl-

N- (3-phenyl-2-pivaloyloxy-propionyl) -His-Cha-Val-2- (4-imidazolyl

N- [2- (2-Dimethylaminoäthylcarbamoyl) -3-phenyl-propionyl] -His-Cha-Val-4-carboxybutylamid; N- (2-dimethoxyphosphoryl-3-phenyl-propionyl) -His-Cha-Val-4-carboxybutylamid; N- [2- (5-amino-S-carboxy-pentylcarbamoyl] -3-phenylpropionyl] -His-Cha-Val-n-butylamide; N- (2-dimethylaminomethyl-3-a-naphthyl-propionyl) - His-Cha-Val-4-carboxybutylamide; N- (2-Benzyl-5-dimethylamino-4-oxopentanoyl) -His-Cha-Val-methyl-

N- (2-acetoxy-4-phenyl-butyryl) -His-Cha-Val-n-butylamide; N- (2-cyanomethyl-4-phenyl-butyryl) -His-Cha-Val-n-butylamide; N- (2-Aethylaminocarbonyloxy-4-phenyl-butyryl) -His-Cha-Val-nbutylamid; N- (3-a-naphthyl-2-neopentyloxy-propionyl) -His-Cha-Val-n-butylamide; N- (2-benzyl-5,5-dimethyl-4-oxo-hexanoyl) -His-Cha-Gly (cyclohexylmethyl) -n-butyl-amide; N- [4,4-dimethyl-3-oxo-2- (2-phenylethyl) pentanoyl] -His-Cha-Val-nbutylamid; N- (2-dimethoxyphosphoryl-4-phenyl-butyryl) -His-Cha-Val-nbutylamid; N- (2-dieth (butylamide; N- [5,5-dimethyl-4-oxo-2- (2-phenylethyl) hexanoyl] -His-Cha-Val-n-butylamide; N- (2-tert-butylcarbamoyl) 4-phenylbutyryl) -His-Cha-Val-n-butylamide; N-C-C-tert-butylcarbamoyl-S-phenyl-propionyl-D-His-Cha-Val-n-butylamide; N- (2-tert-butylcarbamoyl-3-oxy) naphthyl-propionyl) -His-cha-valmethylamide; N- (2-benzyl-5,5-dimethyl-4-oxo-hexanoyl) -His-Cha-Val-methyl-amide; N- (2-benzyl-5,5- dimethyl-4-oxo-hexanoyl) -His-Leu-Gly (cyclohexylmethyl) -n-butyl-amide;

N- (2-Diäthoxyphosphorylmethyl-4-phenyl-butyryl) -His-Cha-Val-n-

- 145 - 239

N- (2-benzyl-4,4-diraethyl-3-oxo-pentanoyl) -His-Leu-Gly (cyclohexylmethy1) -n-butyl-amide;

N- (2-tert-butylcarbamoyl-3-phenyl-propionyl) -His-Leu-Gly (cyclohexylmethyl) -n-butyl-amide.

Example 67: Gelatin solution

A sterile filtered aqueous solution of N- (2 (R, S) -benzyl-5,5-dimethyl-4-oxo-hexanoyl) -His-Cha-Val-n-butyl-amide is added with warming with a sterile gelatin solution, which serves as a preservative Containing phenol, mixed under aseptic conditions so that 1.0 ml of solution has the following composition:

N- (2 (R, S) -benzyl-5,5-dimethyl-4-oxo-hexanoyl) -

His-Cha-Val-n-butylamide 3 mg

Gelatin 150.0 mg

Phenol 4.7 mg

least. Water up to 1.0 ml

The mixture is filled under aseptic conditions in vials to 1.0 ml.

Example 68: Sterile dry substance for injection Dissolve 5 mg of N- (2 (R, S) -benzyl-5,5-dimethyl-4-oxo-hexanoyl) -His-Cha-Val-n-butylamide in 1 ml of an aqueous Solution with 20 mg 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 69 : Nasal Spray

In a mixture of 3.5 ml of "Myglyol 812" and 0.08 g of benzyl alcohol, 500 mg of finely ground (<5.0 μπι) N- (2 (R, S) -benzyl-5,5-dimethyl-4- oxo-hexanoyl) -His-Cha-Val-n-butylamide suspended.

This suspension is filled into a container with metering valve.

There are 5.0 g of "Freon 12" filled under pressure through the valve in the container. By shaking, the "freon" in the myglyol-benzyl alcohol mixture is dissolved. This spray container contains about 100 single doses, which can be applied individually.

Claims (15)

239 21O claims 1. A process for the preparation of compounds of the formula R 1-AN-CH-CH-CH ₂ -CH-CR ₆ (I), wherein Ri is hydrogen or acyl except for an optionally N-substituted acyl radical of a natural amino acid, A is an optionally N-alkylated a-amino acid residue which is N-terminal with Ri and C-tenninal is attached 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, Ri ₁ hydroxy, etherified or esterified hydroxy, Rj lower alkyl having 2 and more C atoms, 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 and Re substituted amino except one of of α-amino acid derived amino radicals, furthermore salts of such compounds with salt-forming groups and of pharmaceutical preparations containing such compounds, characterized in that a) a fragment of a compound of the 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 a reactive derivative thereof with activated amino group, wherein in the Reaktionskomponen- " optionally existing free functional groups, except for the groups participating in the reaction, may be in protected form, condensed to form an amide bond, or b) for the preparation of compounds of formula I, wherein Ri »is hydroxy, the keto group in a compound of formula fl? ⁵ ft -CH-C-CH ₂ -CH-C-Rs (II), Ri-AX ₂ - 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 Ri, hydroxy, an aldehyde compound of the formula Ri-AX ₂ -N-CH-CH (III), 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 8 ⁵ 8 - CH - C - R ₆ M-CH ₂ -CH-CR ₆ (IV), 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 Ri-AN-CH-CH-CH ₂ -CH-CR ₆ (V), wherein X is a nucleofugic leaving group, the other substituents have the meanings given above and optionally free functional groups are in protected form, the substituent X exchanged with a substituent Ri »in nucleophilic form introducing reagent against Ri ₄ , or e) in a compound of the formula JU Rz Rs Ri - A - N - CH - CH - CH ₂ - CH - CN (VI) in which the substituents have the meanings mentioned and existing functional groups are optionally in protected form, the cyano group is converted into an N-substituted carboxamido group - (CO) R ₆ , or f) for the preparation of a compound of the formula I in which R 1 is free hydroxy, an epoxide of the formula Ri - A - Ϊ-CH-di-cV-CH-δ-R ₆ (VII), wherein the substituents have the meanings given and free functional groups are optionally present in protected form, with a regio-selective reducing agent reduced to the corresponding alcohol, and if desired g) splits off protecting groups present in an available compound and / or, if desired, after carrying out one of the abovementioned processes a) -f) or any other process for preparing 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 obtainable compound of the formula I and / or converting a compound of the formula I into another inventive compound Compound of formula I converts, and 23921 if desired, mixing an available compound or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier. 2. Method according to item 1 for the preparation of compounds of the formula I, characterized in that a fragment of a compound of the 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 a reactive amino-functional derivative thereof, wherein free functional groups present in the reaction components except optionally in protected form are condensed to form an amide bond and optionally protecting groups present in an available compound by treatment with acid or base or split off by hydrogenolysis and / or converted 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 receives separates 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 item 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 Dihydroquinoline or an activated phosphate, and if desired in the presence of an organic base or alkali metal carbonates in an inert, 239 2 polar aprotic solvents in a temperature range of -40 ⁰ C to + 100 ⁰ C condensed, wherein activated esters of the amino or amido ester type, if desired, formed in situ by addition of an N-hydroxyamino or N-hydroxyamido compound, and if desired protecting groups present in an available compound by treatment with acid or with base or by hydrogenolysis and / or converting an available compound of formula I with a salt-forming group into its salt or an available salt into the free compound or into 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. 4. Process according to one of the items 1-3, characterized in that one selects such starting materials, the 3 compounds of the formula I, wherein Ri is hydrogen or acyl having the sub-formulas R-CO-, R-O-C0- or (R) (R) N-CO-C0-, wherein R is an unsubstituted or substituted, saturated or unsaturated, aliphatic, cycloaliphatic, cycloaliphatic aliphatic hydrocarbon radical up to and including 18, preferably up to and including 10, carbon atoms or an unsubstituted or substituted aromatic, heteroaromatic, aromatic-aliphatic or heteroaromatic-aliphatic hydrocarbon radical up to and including 18, preferably up to and including 10, C atoms or an unsubstituted or substituted, saturated five - or six-membered heterocycle and R is hydrogen or has the meanings of R, with the exception of an optionally N-substituted acyl radical of a natural amino acid, A is an optionally N-alkylated ct-amino acid residue, the N-terminal with Ri and C-terminal with the Group -NR2-linked, R2 is hydrogen or lower alkyl, R3 Wa or lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower, lower alkylcarbamoyl, lower alkyl, lower alkylcarbamoyl, lower alkyl, lower alkylcarbamoyl, lower alkyl, lower alkylcarbamoyl, lower cycloalkyl, lower alkylcarbamoyl, lower cycloalkyl, lower alkylcarbamoyl, lower cycloalkyl, lower alkylcarbamoyl, dilower alkylamino, aryl or aryl-lower alkyl and Re is an amino group which is substituted by one or optionally two unsubstituted or substituted, saturated or unsaturated, aliphatic Kohlenwassertoffreste up to and including 18, preferably up to 10, C-atoms or an unsubstituted or substituted aromatic, heteroaromatic, aromatic-aliphatic or heteroaromatic-aliphatic hydrocarbon radical up to and including 18, preferably up to and including 10, C atoms, with the exception of an amino radical derived from an α-amino acid, and pharmaceutically acceptable salts of such compounds with salt-forming groups. 5. The method according to any one of items 1-3, characterized in that one selects such starting materials that compounds of formula I, wherein Ri is hydrogen, lower alkanoyl having 1-7 C-atoms, Hydroxyniederalkanoyl, Niederalkoxyniederalkanoyl, Phenoxyniederalkanoyl, Naphthoxyniederalkanoyl, Niederalkanoyloxyniederalkanoyl, Carboxyniederalkanoyl , Lower alkoxycarbonyl-lower alkanoyl, carbamoyl-lower alkanoyl, lower alkylcarbamoyl-lower alkanoyl, di-lower alkylcarbamoyl-lower alkanoyl, ct-naphthoxy-carboxy-lower alkanoyl, ö-naphthoxy-lower alkoxycarbonyl-lower alkanoyl, a-naphthoxybenzyloxycarbonyl-lower alkanoyl, a-naphthoxy-carbamoyl-lower alkanoyl, a-naphthoxy-cyano-lower alkanoyl, o-naphthoxy lower alkylamino-lower alkanoyl, a-naphthoxy-oxo-lower alkanoyl, lower alkenoyl having 3-7 C atoms, lower alkynyl having 3-7 C atoms, cycloalkylcarbonyl having 4-9 C atoms, bicycloalkylcarbonyl having 6-11 C atoms, tricycloalkylcarbonyl with 9-11 C atoms, monocycloalkenylcarbonyl with 4-9 C atoms, bicycloalkene ylcarbonyl having 6-11 C atoms, cycloalkyl-lower alkanoyl having 5-11 C atoms, cycloalkyl-lower alkenoyl having 6-11 C atoms, cycloalkenyl-lower alkanoyl having 5-11 C atoms, benzoyl, unsubstituted, mono- or polysubstituted by lower alkyl, halogen, hydroxy Lower alkoxy and / or nitro, phenyl, α-naphthyl or β-naphthyl-lower alkanoyl wherein phenyl is unsubstituted, mono- or poly-substituted by lower alkyl, halogen, hydroxy, lower alkoxy and / or nitro and lower alkanoyl unsubstituted or substituted by hydroxy, lower alkoxy, acyloxy, carboxy, esterified carboxy, carbamoyl, substituted carbamoyl, cyano, phosphono, esterified phosphono, benzofuranyl and / or oxo and optionally branched, substituted anilinophenylacetyl, phenyl-lower alkenoyl, naphthylcarbonyl, indenylcarbonyl, indanylcarbonyl, Phenanthrenylcarbonyl, optionally substituted pyrrolylcarbonyl, furylcarbonyl, thienylcarbonyl, pyridylcarbonyl, optionally substituted indolylcarbonyl, 4,5,6,7-tetrahydroindolyl-2-carbonyl, cyclohepta- [b] pyrrolyl-5-carbonyl, optionally substituted quinolylcarbonyl, optionally substituted isoquinolylcarbonyl, 2 -Quinoxalinylcarbonyl, 2-benzofuranylcarbonyl, benz [e] indolyl-2-carbonyl, β-carbolinyl-3-carbonyl, pyrrolidinyl-3-carbonyl, hydroxypyrrolidinylcarbonyl, oxopyrrolidinylcarbonyl, piperidinylcarbonyl, indolinylcarbonyl, 1,2,3,4-tetrahydroquinolylcarbonyl, 1 , 2,3,4-tetrahydrosoquinolylcarbonyl, arylnied eralkoxycarbonyl, oxamoyl or lower alkyloxamoyl, A is a bivalent residue of natural α-amino acid of the L-configuration normally found in proteins, a homolog of such an amino acid wherein the amino acid side chain is extended or shortened by one or two methylene groups and / or one methyl group is replaced by hydrogen substituted phenylalanines or phenylglycines, wherein the substituent may be lower alkyl, halogen, hydroxy, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, lower alkoxycarbonylamino, arylmethoxycarbonylamino and / or nitro and one or more times, a benzannellierten phenylalanines or phenylglycine, a hydrogenated Phenylalanine or phenylglycine, 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 ataidierter form, an amino group of the side chain in acylierter Form or a hydroxy group of the side chain in etherified or esterified form or an epimer of such an amino acid, i. having the unnatural D configuration, optionally substituted by lower alkyl on the N atom, R 2 is lower or lower alkyl, R 3 is lower alkyl, cycloalkyl, lower alkylalkyl, lower cycloalkyl, lower alkyl or phenyl and Re alkylamino of 1 to 10 carbon atoms, di-lower alkylamino, hydroxy-lower alkylamino, di (hydroxylowkyl) amino, lower alkoxy-lower alkylamino, lower alkanoyloxy-lower alkylamino, phenoxy-lower alkylamino or phenoxyhydroxy-lower alkylamino 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 alkoxycarbonylmethylamino, physiologically cleavable esterified carboxyalkylamino, in which the Ester function is not in the 1-position of the alkyl radical, carbamoyl or Hydroxiliederalkylcarbamoylalkylamino, wherein the carbamoyl radical is not in the 1-position of the alkyl radical, further dicarbaaoylmethylamino, di (lower alkylcarbam oyl) -raethylamino, di- (hydroxy-lower alkylcarbamoyl-dimethylamino or bis (lower alkylcarbamoyl) -methylamino, amino-lower alkylamino, lower-alkylaminoloweralkylamino, di-lower alkylaminoloweralkylamino, lower alkoxycarbonylaminoloweralkylamino, guanidinoloweralkylamino, saturated five- or six-membered heterocyclyl-lower alkylamino, lower alkenylamino, lower alkynylamino, cycloalkyl-lower alkylamino, phenylamino or Phenyl-lower alkylamino, wherein phenyl is optionally substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, carboxy, lower alkoxycarbonyl, 239 21O Carbamoyl, amino, lower alkylamino, di-lower alkylamino, acylamino and / or monosubstituted or polysubstituted by nitro, pyridyl-lower alkylamino, imidazolyl-lower alkylamino or indolyl-lower alkylamino, as well as pharmaceutically acceptable salts of these compounds having salt-forming groups. 6. The method according to any one of items 1-3, characterized in that one selects such starting materials that compounds of formula I, wherein Ri is lower alkanoyl, lower alkenoyl, lower alkynyl, cycloalkylcarbonyl, benzoyl, unsubstituted, mono- or Mehrfachsubstituiert by lower alkyl, halogen, hydroxy , Lower alkoxy and / or nitro, phenyl-lower alkanoyl wherein phenyl is unsubstituted, mono- or poly-substituted by lower alkyl, halogen, hydroxy, lower alkoxy, and / or nitro and lower alkanoyl may be unsubstituted or substituted by hydroxy, acyloxy, carboxy or esterified carboxy Anilinophenylacetyl, phenyl-lower alkenoyl, naphthylcarbonyl, naphthyl-lower alkanoyl wherein lower alkanoyl may be substituted by hydroxy, acyloxy, carboxy or esterified carboxy, indenylcarbonyl, indanylcarbonyl, phenanthrenylcarbonyl, optionally substituted pyrrolylcarbonyl, furylcarbonyl, thienylcarbonyl, pyridylcarbonyl, optionally substituted indolylca rbonyl, 4,5,6,7-tetrahydroindolyl-2-carbonyl, optionally substituted quinolylcarbonyl, optionally substituted isoquinolylcarbonyl, 2-quinoxalinylcarbonyl, 2-benzofuranylcarbonyl, benz [e] indolyl-2-carbonyl, β-carbolinyl-3-carbonyl, Indolinylcarbonyl, 1,2,3,4-tetrahydroquinolylcarbonyl, 1,2,3,4-tetrahydroisoquinolylcarbonyl, arylmethoxycarbonyl having one or two aryl radicals, wherein aryl is optionally mono-, di- or by lower alkyl, lower alkoxy, hydroxy, halogen and / or nitro trisubstituted phenyl, oxamoyl or lower alkyloxamoyl, A is the bivalent radical of the amino acids alanine, valine, norvaline, leucine, norleucine, serine, proline, phenylalanine, β-phenylserine, ct-naphthylalanine, cyclohexylalanine, indoline-2-carboxylic acid, 1,2, S-tetrahydroisoquinoline-S-carboxylic acid , Aspartic acid, 239 21O Asparagine, aminomalonic acid, aminomalonic acid tetononamide, 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 ct 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 _{1 is} hydroxy and R _{2 is} lower-alkyl having 2 to 7 C atoms, cycloalkyl, cycloalkyl-lower alkyl, 1-adamantyl, benzyl, carbamoyl or lower-alkylcarbamoyl, and Re is amino, alkylamino, di-lower alkylamino, hydroxy-lower alkylamino, carboxyalkylamino, wherein the carboxy radical is not in the 1-position of the alkyl radical, furthermore dicarboxymethylamino, lower alkoxycarbonylalkylamino, wherein the carbonyl radical is not in the 1-position of the alkyl radical, furthermore di-lower alkoxycarbonylmethylamino, physiologically cleavable esterified carboxyalkylamino, wherein the ester function is not in the 1-position of the alkyl radical, carbamoyl or hydroxy-lower alkylcarbamoylalkylamino, in which the carbamoyl radical is not in the 1-position of the alkyl radical, furthermore dicarbamoylmethylamino, di- (lower alkylcarbamoyl) -methylamino, di (hydroxy-lower alkylcarbamoyl) -methylamino or bis ( lower alkylcarbamoyl) -methylamino, amino-lower alkylamino, lower alkylaminoloweralkylamino, di-lower alkylaminoloweralkylamino, lower alkoxycarbonylaminoloweralkylamino, guanidinoloweralkylamino, cycloalkylloweralkylamino, benzylamino, pyridylloweralkylamino, imidazolylloweralkylamino or indolyl-lower alkylamino, as well as pharmaceutically acceptable salts of these compounds with salt-forming groups. - ₁₅ 7- 239 21 O 7. The method according to any one of the items 1-3, characterized in that one selects such starting materials that compounds of formula I, wherein Ri is lower alkanoyl, 2- (o, o-dichloroanilino) phenylacetyl, 2- (o, o-dichloro -N-benzylanilino) -phenylacetyl, optionally substituted pyrrolylcarbonyl, furylcarbonyl, thienylcarbonyl, pyridylcarbonyl, optionally substituted indolylcarbonyl, 4,5,6,7-xetrahydroindolyl-2-carbonyl, optionally substituted quinolylcarbonyl, optionally substituted isoquinolylcarbonyl, 2-quinoxalinylcarbonyl, 2- Benzofuranylcarbonyl, benz [e] indolyl-2-carbonyl, β-carbolinyl-S-carbonyl, indolinylcarbonyl, 1,2,3,4-tetrahydroquinolylcarbonyl, 1,2,3,4-tetrahydroisoquinolylcarbonyl, A is the bivalent radical of the amino acids norleucine, phenylalanine, cyclohexylalanine, glutamic acid, glutamine, N-dimethyl-glutamine, ornithine or N-pivaloyl-ornithine, R 2 is hydrogen, R 3 isobutyl, cyclohexylmethyl or 1-adamantylmethyl, R 1 -hydroxy, R 5 isopropyl, cyclohexyl , Cyclohexylmethyl or methylcarbamoyl and Re lower alkylamino, di-lower alkylamino, hydroxy-lower alkylamino, carboxyalkylamino, wherein the carboxy radical is not in the 1-position of the alkyl radical, lower alkoxycarbonylalkylamino wherein the carbonyl radical is not in the 1-position of the alkyl radical, amino-lower alkylamino, guanidinoloweralkylamino, benzylamino or pyridyl-lower alkylamino, and pharmaceutically acceptable salts of These compounds are formed with salt-forming groups. 8. The method according to any one of items 1-3, characterized in that one selects such starting materials that compounds of formula I, wherein Ri is lower alkanoyl having 1 to 7 carbon atoms, Phenoxyniederalkanoyl, Naphthoxyniederalkanoyl, a-naphthoxy-carboxyniederalkanoyl, a-naphthoxy lower alkoxycarbonyl-lower alkanoyl, ct -naphthoxy-benzyloxycarbonyl-lower alkanoyl, o-naphthoxy-carbamoyl-lower alkanoyl, a-naphthoxy-cyano-lower alkanoyl, ct-naphthoxy-diallyl-lower alkylamino-lower alkanoyl, a-naphthoxy-oxo-lower alkanoyl, phenyl-, ot- Naphthyl or β-naphthyl lower alkanoyl wherein lower alkanoyl is unsubstituted or substituted by hydroxy, Lower alkoxy, acyloxy, carboxy, esterified carboxy, carbamoyl, substituted carbamoyl, cyano, phosphono, esterified phosphono, benzofuranyl and / or oxo and optionally branched, 2- (o, o-dichloroanilino) -phenylacetyl, 2- (o, o-dichloro-N-benzylanilino) -phenylacetyl, naphthylcarbonyl, pyrrolylcarbonyl, cyclohepta [b] pyrrolyl-5-carbonyl, indolylcarbonyl, 1-benzyl-indolyl-3-carbonyl, 4,5,6,7-tetrahydroindolyl-2-carbonyl , Quinolylcarbonyl or oxamoyl, A is the bivalent radical of the amino acids leucine, norleucine, phenylalanine, N-methyl-phenylalanine, β-phenylserine, cyclohexylalanine, glutamine, histidine or N-methyl-histidine, R _{2 is} hydrogen, R ₃ isobutyl or cyclohexylmethyl, Ri »hydroxy, Rs isopropyl , Cyclohexylmethyl, a-decahydronaphthyl or dimethylamino, and Rs lower alkylamino having 1-7 C atoms, di-lower alkylamino, hydroxy-lower alkylamino, 2-phenoxyethylamino, 2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino, carboxyalkylamino or amino-carboxyalkylamino, wherein the carboxy radical is not in the 1-position of the alkyl radical 4-tris- (hydroxymethyl) -methylcarbamoyl-n-butylamino, amino-lower alkylamino, di-lower alkylaminoloweralkylamino, loweralkoxycarbonylaminoloweralkylamino, morpholinoloweralkylamino, cycloalkyl-lower-alkylamino, benzylamino, pyridyl-lower-alkylamino or Imidazolylniederalkylamino, as well as pharmaceutically acceptable salts of these compounds are formed with salt-forming groups. 9. The method according to any of items 1-3, characterized in that one selects such starting materials that compounds of the formula I, wherein Ri Phenoxyniederalkanoyl, Naphthoxyniederalkanoyl, Phenylniederalkanoyl, wherein lower alkanoyl unsubstituted or substituted by acyloxy, carboxy, esterified carboxy, carbamoyl, substituted Carbamoyl, cyano, esterified phosphono or lower alkyl, and oxo or benzofuranyl and oxo and may be , _1S9 - ^{239 2! 0} when branched, naphthyl-lower alkanoyl wherein lower alkanoyl may be unsubstituted or substituted by acyloxy, carboxy, esterified carboxy, unsubstituted or substituted carbamoyl, cyano or lower alkyl and oxo and optionally branched, indolyl-2-carbonyl or cyclohepta [b] pyrrolyl-5 carbonyl, A is the bivalent radical of the amino acid L-histidine, R 2 is hydrogen, R 3 isobutyl or cyclohexylmethyl, R i * hydroxy, Rs isopropyl or cyclohexylmethyl and Re is lower alkylamino or amino-carboxy-lower alkylamino, wherein the substituents are not in the 1-position of the lower alkyl radical , and the carbon atoms bearing the radicals R3 and Ri * have the S configuration, and furthermore pharmaceutically acceptable salts of these compounds are formed. 10. A process according to any one of items 1-3, characterized in that starting materials are selected such that compounds of the formula I wherein R 1 in the lower alkanoyl radical is phenyl- or α-naphthyl-lower alkanoyl substituted by lower alkanoyloxy, lower alkoxycarbonyl, lower alkylcarbamoyl, lower-alkoxy-phosphoryl or lower-alkyl and oxo, wherein lower alkyl has 1 to 7 carbon atoms, indolyl-2-carbonyl or Cycloheptafblpyrrolyl-S-carbonyl, A is the bivalent radical of the amino acid L-histidine, R2 is hydrogen, R3 is cyclohexylmethyl, Ri, hydroxy, Rs isopropyl and Re Niederalkylamino with 1 to 7 carbon atoms and the carbon atoms bearing the radicals R3, Ri ₁ and R5 have the S-configuration, furthermore pharmaceutically acceptable salts of these compounds are formed. 11. The method according to any one of items 1-3, characterized in that one selects such starting materials, that the compound of formula I, wherein Ri 2 (S) -pivaloyloxy-3-phenyl-propionyl, A is the bivalent radical of the amino acid L- Histidine, R2 is hydrogen, R3 is cyclohexylmethyl, Ri * is hydroxy, R5 is isopropyl and Re n-butylamino, and the carbon atoms bearing the radicals R3, Ri and R5 have the S configuration and their pharmaceutically acceptable salts are formed. 239 21O 12. The method according to any one of items 1-3, characterized in that one selects such starting materials that the compounds of formula I, wherein Ri is 2 (R, S) -, 2 (R) - or 2 (S) -dimethoxyphosphoryl- 3-phenyl-propionyl, A is the bivalent radical of the amino acid L-histidine, R 2 is hydrogen, R 3 is cyclohexylmethyl, R 1 is hydroxy, R 5 is isopropyl and R 9 is n-butylamino, and the C atoms carrying the radicals R 3, R 1 * and R 5 are the S And their pharmaceutically acceptable salts are formed. 13. The method according to any one of the items 1-3, characterized in that one selects such starting materials that the compounds of formula I, wherein R _{1 is} 2 (R, S) -, 2 (R) - or 2 (S) -Benzyl -5,5-dimethyl-4-oxo-hexanoyl, A is the bivalent radical of the amino acid L-histidine, Rj is hydrogen, R3 is cyclohexylmethyl, Ri * is hydroxy, Rs isopropyl and Re n-butylamino and the radicals R3, Ri * and R5-bearing C-atoms have the S-configuration, and their pharmaceutically acceptable salts are formed. 14. The method according to any one of items 1-3, characterized in that one selects such starting materials that the compound of
Formula I, wherein Ri 2 (R, S) -Benzyl-4,4-dimethyl-3-oxo-pentanoyl, A is the bivalent radical of the amino acid L-histidine, R 2 is hydrogen, R 3
Cyclohexylmethyl, Ri »hydroxy, R5 isopropyl and Re n-butylamino and the C atoms carrying the radicals R3, Ri * and R5 denote the
S-configuration, and their pharmaceutically acceptable salts are formed. > 15. The method according to any one of items 1-3, characterized in that one selects such starting materials that the compound of
Formula I, wherein Ri 2 is (R, S) -ethoxycarbonyl-3-ce-naphthyl-propionyl, A is the bivalent radical of the amino acid L-histidine, R 2 is hydrogen, R 3 is cyclohexylmethyl, R 1 * is hydroxy, R 5 is isopropyl and R 9 is n-butylamino
and the radicals R3, Ri * and Rs carry the C atoms
S-configuration, and their pharmaceutically acceptable salts are formed.