DE3819263A1 - Amino-acid derivatives - Google Patents

Abstract

Amino-acid derivatives of the formula I R<1>-Z-M-NR<2>-CHR<3>-CR<4>-(CHR<5>)n-CO-E-Q-Y An<-> in which R<1>, Z, M, R<2>, R<3>, R<4>, R<5>, n, E, Q, Y and An<-> have the meaning stated in Claim 1, and their salts inhibit the activity of human plasma renin.

Description

The invention relates to novel amino acid derivatives of Formula I

R¹-ZM-NR²-CHR³-CR⁴- (CHR⁵) _n -CO-EQY An⊖ (I)

wherein
R¹ R⁶, R⁶-OC _m H _{2 m} -CO-, R⁶-C _m H _{2 m} -O-CO-, R⁶-C _m H _{2 m} - CO-, R⁶-SO₂-, (R⁶-C _m H _{2 m} - (T) _x - (G) _y -C _r H _{2 r} ) -L (R⁷-C _p H _{2 p} ) -C _t H _{2 t} -CO-, R⁶- (NHCH₂CH₂) _m -NHCH₂CO-, or 9-fluorenyl-C _m H _{2 m} -O-CO-,
Z 0 to 3 peptide-like interconnected amino acid residues selected from the group consisting of Abu, Ada, Ala, Ala, Arg, Asn, Asp, Bia, Cal, Dab, Gln, Glu, Gly, His, N β (im) -A- His, Ile, Leu, tert.-Leu, Lys, Met, α Nal, β-Nal, Nbg, Nle, Orn, Phe, Pia, Pro, Pya, Ser, Thr, Tic, Trp, Tyr and Val,
M β Ala, Gly, Pia or Pya, or, if Y in the radical Y is an R⁸N⊕ group instead of an N atom of a het-ylene group, also His,
E 0 to 2 peptide-like linked amino acid residues selected from the group consisting of Abu, Ala, Cal, His, Ile, Leu, Met, Nle, Nva, Phe, Trp, Tyr and Val,
Q is O or NH,
Y is an alkylene chain in which also a CH₂ group can be replaced by an arylene group or het-ylengruppe, having a total of 1-20 C-atoms, which by a R⁸R⁹R¹⁰N⊕ group or an unsubstituted or one or more times by A , AO and / or Hal substituted pyridinium group is substituted, and / or in which instead of an N atom of a het-ylengruppen a R⁸N⊕ group,
An⊖ an anion, which may also be absent, if, instead, a carboxy group present in the compound of formula I carboxy is present,
R³, R⁶ and R⁷ are each H, A, Ar, Aralkyl, Het, Het-alkyl, unsubstituted or mono- or polysubstituted by A, AO and / or Hal, cycloalkyl having 3-7 C atoms, cycloalkylalkyl having 4- 11 C atoms, bicycloalkyl or tricycloalkyl having in each case 7-14 C atoms, bicycloalkylalkyl or tricycloalkylalkyl having in each case 8-18 C atoms,
R² and R⁵ are each H or A,
R⁴ (H, OH), (H, NH₂) or = O,
R⁸, R⁹ and R¹⁰ are each alkyl having 1-18 C atoms or Ar-alkyl, two of the radicals R⁸, R⁹ and R¹⁰ together also an alkylene group having 2-8 C-atoms, which by an O atom or by a NR¹- Group can be interrupted,
R¹¹ is H, A, Ar or Aralkyl,
L is CH or N,
T O, S, NH or NA,
G is CO, S, SO or SO₂,
n 1 or 2,
m, p, r and t are each 0, 1, 2, 3, 4 or 5,
x and y are each 0 or 1,
Ar unsubstituted or mono- or polysubstituted by A, AO, Hal, CF₃, OH, H₂NSO₂ and / or NH₂ substituted phenyl or unsubstituted naphthyl,
Het a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N-, O- and / or S-atoms, which condenses with a benzene ring and / or one or more times by A, AO, Hal, CF₃, HO, O₂N, carbonyl oxygen, H₂N, HAN, A₂N, AcNH, AS, ASO, ASO₂, HOOC, AOOC, CN, H₂NCO, H₂NSO₂, ASO₂NH, Ar, Ar-alkyl, aralkenyl, hydroxyalkyl and / or aminoalkyl, each with 1 -8 carbon atoms may be substituted and / or its N and / or S heteroatoms may also be oxidized,
Hal F, Cl, Br or J,
Ac A-CO, Ar-CO or A-NH-CO-,
alkyl- an alkylene group having 1-4 C atoms and
A is alkyl having 1-8 C atoms,

in which, instead of one or more -NH-CO groups, one or more NA-CO groups may also be present,
and their salts.

Similar compounds are known from EP-A-16 32 37, EP-A- 17 34 81 and EP-A-20 98 97 known.

The invention was based on the object, new compounds with valuable properties, in particular those used for the manufacture of medicines can be.

It has been found that the compounds of the formula I and their salts have very valuable properties. In front In particular, they inhibit the activity of human plasma renin. This effect can z. B. by the method of F. Fyhrquist et al., Clin. Chem. 22, 250-256 (1976) become. It is noteworthy that these compounds  are very specific inhibitors of renin; for the Inhibition of other aspartylproteinases (eg pepsin and Cathepsin D) are usually much higher concentrations necessary for these connections.

The compounds can be used as active pharmaceutical ingredients in of human and veterinary medicine, in particular for the prophylaxis and treatment of cardiac, Circulatory and vascular diseases, especially hypertension, Heart failure and hyperaldosteronism. also The compounds can be used for diagnostic purposes used to treat patients with hypertension or Hyperaldosteronism the possible contribution of renin activity to maintain the pathological condition to determine.

The above and below abbreviations of Amino acid residues stand for the radicals -NR'-R "-CO-, in usually -NH-CHR-CO- (where R, R 'and R "are each for each Amino acid known specific meaning) following Amino acids:

Abu 2-aminobutyric acid Ada 3- (1-adamantyl) alanine Ala alanine β Ala β- alanine bad arginine Asn asparagine Asp aspartic acid Bia 3- (2-benzimidazolyl) -alanine Cal 3-cyclohexylalanine Dab 2,4-diaminobutyric acid Gln glutamine Glu glutamic acid Gly glycine His histidine N (im) -A-His in the 1- or 3-position of the imidazole ring by A substituted histidine Ile isoleucine Leu leucine tert-Leut tert-Leucine Lys lysine mead methionine α Nal 3- ( α- naphthyl) alanine β Nal 3- ( β- naphthyl) alanine nbg (2-norbornyl) glycine Nle norleucine N-Me-His N-methyl-histidine N-Me-Phe N-methyl-phenylalanine Nva norvaline Orn ornithine Phe phenylalanine Pia 3- (piperidyl) alanine [e.g. B. 2-Pia 3- (2-piperidyl) alanine] Per proline Pya 3- (pyridyl) alanine [e.g. B. 3-Pya 3- (3-pyridyl) alanine] Ser serine Thr threonine Tic 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid Trp tryptophan Tyr tyrosine Val Valine.

Furthermore, below:

ADPA 2-amino-5,6-dimethyl-3-pyrazinyl-methylamino AMPA 4-amino-2-methyl-5-pyrimidinyl-methylamino BOC tert-butoxycarbonyl imi-BOM Benzyloxymethyl in the 1-position of the imidazole ring CBZ benzyloxycarbonyl DNP 2,4-dinitrophenyl imi-DNP 2,4-dinitrophenyl in the 1-position of the imidazole ring ETNC N-ethylcarbamoyl ETOC ethoxycarbonyl FMOC 9-fluorenylmethoxycarbonyl IPNC N-isopropyl IPOC isopropoxycarbonyl MAC -morpholinoacetyl MC morpholinocarbonyl OMe Methylester OEt ethyl ester POA phenoxyacetyl DCCI dicyclohexylcarbodiimide HOBt 1-hydroxybenzotriazole.

If the aforementioned amino acids in several enantiomeric forms may occur, such as are below, z. B. as part of the compounds of Formula I, all these forms and also their mixtures (eg the DL forms) included. The L-forms are preferred. If individual compounds are listed below are, then the abbreviations of these amino acids refer each on the L-shape, unless expressly something another is indicated.  

The invention further provides a method for Preparation of an amino acid derivative of the formula I and of its salts, characterized in that it is from one of its functional derivatives by treatment with a solvolysing or hydrogenolyzing Relieves funds or that one is a carboxylic acid of formula II

R¹-G¹-OH (II)

wherein
G¹ (a) Z¹,
(b) Z,
(c) ZM,
(d) ZMW,
(e) ZMW-E¹,
(f) ZMWE and
W-NR²-CHR³-CR⁴- (CHR⁵) _n -CO- mean
with an amino compound of the formula III

H-G² (III)

wherein
G² (a) -Z²-MWEQY,
(b) -MWEQY,
(c) -WEQY,
(d) -EQY,
(e) -E 2 -QY,
(f) -NH-Y,
E¹ + E² together E and
Z¹ + Z² together Z mean
implements,
or treating a tertiary amine otherwise of formula I with a quaternizing agent,
and optionally in a compound of formula I, a functionally modified amino and / or hydroxy group by treatment with solvolysierenden or hydrogenolyzing agents in freedom and / or for the preparation of a compound of formula I, R⁴ = (H, OH) or (H , NH₂) a Aminoketosäurederivat of formula I, R⁴ = 0, reduced or reductively aminated and / or converted a compound of formula I by treatment with an acid in one of its salts and / or in a compound of formula I an anion An⊖ against a other anion exchanges.

Above and below have the radicals or parameters R¹ to R¹¹, Z, M, E, Q, Y, An⊖, L, T, G, m, n, p, r, t, x, y , Ar, Het , Hal, Ac, A, G¹, G², E¹, E², Z¹, Z² and W are as defined for the formulas I, II or III, unless expressly stated otherwise.

In the above formulas, A is 1-8, preferably 1, 2, 3 or 4 carbon atoms. A is preferably methyl, furthermore, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, and also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, Heptyl, octyl.  

Cycloalkyl is preferably cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl or cycloheptyl, but also z. B. 1-, 2- or 3-methylcyclopentyl, 1-, 2-, 3- or 4-methylcyclohexyl.

Accordingly, cycloalkyl is preferably cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2 Cyclobutylethyl, cyclopentylmethyl, 2-cyclopentylethyl, Cyclohexylmethyl, 2-cyclohexylethyl, but also z. Eg 1-, 2- or 3-methylcyclopentylmethyl, 1-, 2-, 3- or 4- Methylcyclohexylmethyl.

Bicycloalkyl is preferably 1- or 2-decalyl, 2-bicyclo [2,2,1] heptyl or 6,6-dimethyl-2-bicyclo- [3,1,1] heptyl.

Tricycloalkyl is preferably 1-adamantyl.

Hal is preferably F, Cl or Br, but also J.

Ac is preferably A-CO-, such as acetyl, propionyl or butyryl, Ar-CO- such as benzoyl, o-, m- or p-methoxybenzoyl or 3,4-dimethoxybenzoyl, A-NH-CO- and N- Methyl or N-ethylcarbamoyl.

Ar is preferably phenyl, furthermore preferably o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o- m- or p-bromophenyl, o-, m- or p-iodophenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-sulfamoylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, o-, m- or p-aminophenyl, 1- or 2-naphthyl.  

Accordingly, Ar-alkyl is preferably benzyl, 1- or 2-phenylethyl, o-, m- or p-methylbenzyl, 1- or 2-o-, -m- or -p-tolylethyl, o-, m- or p-ethylbenzyl, 1- or 2-o-, -m- or -p-ethylphenylethyl, o-, m- or p-methoxybenzyl, 1- or 2-o-, -m- or -p- Methoxyphenylethyl, o-, m- or p-fluorobenzyl, 1- or 2-o-, -m- or -p-fluorophenylethyl, o-, m- or p-chlorobenzyl, 1- or 2-o-, -m- or -p-chlorophenylethyl, o-, m- or p-bromobenzyl, 1- or 2-o-, -m- or -p-bromophenylethyl, o-, m- or p-iodobenzyl, 1- or 2-o-, -m- or -p-iodophenylethyl, o-, m- or p-trifluoromethylbenzyl, o-, m- or p-hydroxybenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, o-, m- or p-aminobenzyl, 1- or 2-naphthylmethyl.

Het is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazole-1, -4- or -5-yl, 1,2,4-triazole-1, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4 or 5-yl, 1,2,4-oxadiazole 3 or 5-yl, 1,3,4-thiadiazol-2 or 5-yl, 1,2,4-thiadiazol-3 or -5-yl, 2,1,5-thiadiazole-3 or 4-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzoethienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzthiazolyl,  2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolyl. The heterocyclic Residues may also be partially or completely hydrogenated his. Het can so z. B. also mean 2,3-dihydro 2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, tetrahydro-2-or 3-thienyl, 2,3-dihydro-1, -2, -3, -4 or 5-pyrryl, 2,5-dihydro-1-, 2-, -3-, -4- or -5-pyrryl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, 2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydrofuran 1-, 3- or -4-pyrazolyl, 1,4-dihydro-1, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1, -2, -3, -4, -5- or -6-pyridyl, 1,2,3,6-tetrahydro-1, -2, -3, -4, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxane-2-, -4- or -5-yl, hexahydro-1, -3- or -4-pyridazinyl, hexahydro-1, -2-, -4- or -5- pyrimidyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4- Tetrahydro-1, -2, -3, 4, 5, 6, 7 or 8 isoquinolyl.

The heterocyclic radicals may also be substituted as indicated his. Het can z. B. preferably also mean: 2-amino-4-thiazolyl, 4-carboxy-2-thiazolyl, 4-carbamoyl 2-thiazolyl, 4- (2-aminoethyl) -2-thiazolyl, 2-amino-5,6- dimethyl-3-pyrazinyl, 4-carbamoylpiperidino, further e.g. B. 3-, 4- or 5-methyl-2-furyl, 2-, 4- or 5-methyl-3- furyl, 2,4-dimethyl-3-furyl, 5-nitro-2-furyl, 5-styryl 2-furyl, 3-, 4- or 5-methyl-2-thienyl, 2-, 4- or  5-methyl-3-thienyl, 3-methyl-5-tert-butyl-2-thienyl, 5-chloro-2-thienyl, 5-phenyl-2 or 3-thienyl, 1, 3, 4- or 5-methyl-2-pyrrolyl, 1-methyl-4 or 5-nitro- 2-pyrrolyl, 3,5-dimethyl-4-ethyl-2-pyrrolyl, 4-methyl-5 pyrazolyl, 5-methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 4- or 5-methyl-2-thiazolyl, 2- or 5-methyl 4-thiazolyl, 2- or 4-methyl-5-thiazolyl, 2,4-dimethyl 5-thiazolyl, 3-, 4-, 5- or 6-methyl-2-pyridyl, 2-, 4-, 5- or 6-methyl-3-pyridyl, 2- or 3-methyl-4-pyridyl, 3-, 4-, 5- or 6-chloro-2-pyridyl, 2-, 4-, 5- or 6-chloro 3-pyridyl, 2- or 3-chloro-4-pyridyl, 2,6-dimethyl-3 or -4-pyridyl, 2,6-dichloro-3 or 4-pyridyl, 2- Hydroxy-3-, 4-, 5- or -6-pyridyl (= 1H-2-pyridone) 3-, 4-, 5- or 6-yl), 2-hydroxy-4,6-dimethyl-3 pyridyl, 5-phenyl-1H-2-pyridone-3-yl, 5-p-methoxyphenyl 1H-2-pyridone-3-yl, 2-methyl-3-hydroxy-4-hydroxymethyl 5-pyridyl, 2-hydroxy-4-amino-6-methyl-3-pyridyl, 3-N ' Methylureido-1H-4-pyridone-5-yl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 2-, 5- or 6-methyl-4- pyrimidinyl, 2,6-dimethyl-4-pyrimidinyl, 2,6-dihydroxy 4-pyrimidinyl, 5-chloro-2-methyl-4-pyrimidinyl, 2-methyl-4-amino-5-pyrimidinyl, 3-methyl-2-benzofuryl, 2-ethyl-3-benzofuryl, 7-methyl-2-benzothienyl, 1, 2, 4-, 5-, 6- or 7-methyl-3-indolyl, 1-methyl-5- or 6-benzimidazolyl, 1-ethyl-5 or 6-benzimidazolyl, 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2-quinolyl, 2-oxo-pyrrolidino, 2-oxopiperidino, 2,5-dioxopyrrolidino, 3-benzyl-2,5-dioxopyrrolidino.

L is preferably CH. T is preferably O or S. G is preferably CO. The parameters m, p, r and t are preferably each 0, 1 or 2; n is preferably 1; x is preferably 0; y is preferably 0 or 1.

R¹ is preferably H, POA, alkoxycarbonyl such as ETOC, IPOC or BOC; Ar-alkoxycarbonyl such as CBZ; Het alkoxycarbonyl such as 2- (2-, 3- or 4-pyridyl) ethoxycarbonyl; Alkanoyl having preferably 2-7 C atoms such as acetyl, propionyl, butyryl, isobutyryl, pivaloyl (trimethylacetyl), hexanoyl, 3,3-dimethylbutyryl (tert-butylacetyl), heptanoyl, 2-propylvaleryl (dipropylacetyl); Amino-alkanoyl such as aminoacetyl (H-Gly), 3-aminopropionyl (H-β Ala), 4- aminobutyryl, 6-aminohexanoyl, 8-Aminooctanoyl; Dialkylaminoalkanoyl such as 4-dimethylaminobutyryl, 4-diethylaminobutyryl or 5-dimethylaminopentanoyl; Amidoalkanoyl, e.g. B. BOC-Gly, Gly-ETOC, IPOC-Gly, BOC-β Ala, 4-BOC-aminobutyryl, 6-BOC-aminohexanoyl, 8-BOC-aminooctanoyl, N-benzoyl-N-benzyl-aminoacetyl; Cycloalkylcarbonyl such as cyclopentylcarbonyl or cyclohexylcarbonyl; Ar-CO such as benzoyl; Ar-alkanoyl, such as phenylacetyl, 2- or 3-phenylpropionyl, 4-phenylbutyryl, 2-benzyl-butyryl, 2-benzyl-hexanoyl, 2-benzyl-5-methyl-hexanoyl, 2-benzyl-heptanoyl, 2- or 3- o-, -m- or -p-fluorophenylpropionyl, 2- or 3-o-, -m- or p-chlorophenylpropionyl; Oxo-Ar-alkanoyl, in particular groups of the formula R¹²-CO-CH₂ (CH₂C₆H₅) - CO-, wherein R¹² A, cycloalkyl having 3-7 C-atoms or cycloalkylalkyl having 4-11 C-atoms, z. Butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2,2-dimethylpropyl, hexyl, 4-methylpentyl, 3,3-dimethylbutyl, heptyl, 5-methylhexyl, cyclohexyl, cyclohexylmethyl or 2-cyclohexylethyl, such as 2-benzyl-4-oxo-5,5-dimethylhexanoyl, 2-benzyl-4-oxo-6,6-dimethylheptanoyl, 2-benzyl-4-oxo-6-methylheptanoyl, 2-benzyl 4-oxo-6-cyclohexylhexanoyl; by amino groups, in particular dialkylamino-substituted ar-alkanoyl, z. For example, 2-benzyl-4-dimethylaminobutyryl, 2-benzyl-5-dimethylaminopentanoyl; Di-Ar-alkanoyl such as 2-benzyl-3-phenylpropionyl, 2-benzyl-4-phenylbutyryl, 2- (2-phenylethyl) -4-phenylbutyryl, 2- (1- or 2-naphthylmethyl) -4-phenylbutyryl ; Hetalkanoyl such as pyrrolidinoacetyl, 4-pyrrolidinobutyryl, piperidinoacetyl, 4-aminopiperidinoacetyl, MAC; Di-hetalkanoyl such as 2- (2,5-dioxopyrrolidino) -3- (3-indolyl) -propionyl, 2- (3-benzyl-2,5-dioxopyrrolidino-3- (3-indolyl) -propionyl; cycloalkylalkanoyl such as cyclohexylacetyl, 2- or 3-cyclohexylpropionyl; FMOC; heterocyclic-substituted arylalkanoyl such as 2-benzyl-4- (2-, 3- or 4-pyridyl) -butyryl, 2-benzyl-4- (2-oxopyrrolidino ) -butyryl, 2- (2,5-dioxopyrrolidino) -3-phenylpropionyl, 2- (2,5-dioxopyrrolidino) -3-p-hydroxyphenylpropionyl, 2- (2,5-dioxopyrrolidino) -3-p- hydroxyphenylpropionyl, 2- (2,5-dioxopyrrolidino) -3- (1- or 2-naphthyl) propionyl, 2- (3-benzyl-2,5-dioxopyrrolidino) -3-phenylpropionyl, 2- (3 Benzyl-2,5-dioxopyrrolidino) -3-hydroxyphenyl-propionyl, 2- (3-benzyl-2,5-dioxopyrrolidino) -3- (1- or 2-naphthyl) -propionyl; N-substituted carbamoyl such as ETNC , IPNC, N-benzylcarbamoyl, N- (2-, 3- or 4-pyridylmethyl) -carbamoyl; N, N-disubstituted carbamoyl, such as N, N-dibenzylcarbamoyl, N -benzyl-N-2-phenylethylcarbamoyl, N-benzyl-N-butyl-carbamoyl, N-benzyl-N-isopentyl-carbamo yl, N, N-bis-2-phenylethylcarbamoyl, N-2-morpholinoethyl-N-1-naphthylmethylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, 4-aminopiperidinocarbonyl, MC; alkoxycarbonyl-substituted arylalkanoyl, such as 2-benzyl-3-ethoxycarbonylpropionyl, 2- (1-naphthylmethyl) -3-ethoxycarbonylpropionyl; substituted carbamoyl-substituted arylalkanoyl such as 2-benzyl-3- (N-isopropyl-carbamoyl) -propionyl, 2- (1-naphthylmethyl) -3- (N-isopropyl-carbamoyl) -propionyl, 2- (1-naphthylmethyl) - 3- (N-2-phenylethylcarbamoyl) -propionyl, 2-benzyl-3-piperidino-carbonyl-propionyl, 2-benzyl-3-morpholinocarbonyl-propionyl, 2- (1-naphthylmethyl) -3-morpholinocarbonyl-propionyl; acyl-substituted arylakanoyl such as 2-benzyl-4-oxo-hexanoyl, 2-benzyl-4-oxo-5,5-dimethyl-hexanoyl, 2-benzyl-4-oxo-6-methyl-heptanoyl, 2-benzyl-4 oxo-4-phenylbutyryl, 2-benzyl-4-oxo-4- (2-, (3- or (4-pyridyl) -butyryl; alkylsulfonyl such as tert-butylsulfonyl; arylalkanoyl substituted by alkylsulfonyl such as 2-tert. Butylsulfonylmethyl-3-phenylpropionyl.

Some particularly preferred radicals R¹ are BOC, further Pivaloyl, 3,3-dimethylbutyryl, 4-aminobutyryl, 6-aminohexanoyl, 8-aminooctanoyl, 4-dimethylaminobutyryl, 5-dimethylaminopentanoyl, 2-benzyl-5-dimethylaminopentanoyl, MAC, 2- (2,5-dioxopyrrolidino) -3-phenylpropionyl, 2- (3-benzyl-2,5-dioxopyrrolidino) -3-phenylpropionyl, 4-Amino-piperidinocarbonyl, 4-amino-piperidinoacetyl.

Z is preferably one, but also 0 or 2, furthermore 3 peptigartig with each other or with the groups R¹ and NR² connected amino acid residues, in particular the group Phe, furthermore one of the groups α Nal, β Nal, Trp or Tyr, furthermore preferably one of the groups Abu, Ada, Asn, Bia, Cal, Gln, Gly, His, N (im) -Methyl-His, Leu, Nle, Pia, Pya, Abu-His, Ada-His, Ala-His, Ala-Phe, Asn His, Bia-His, Cal-His, Dab-His, Glu-His, Gly-His, His-His, Ile-His, Leu-His, tert-Leu-His, Lys-His, Met-His, α Nal-His, β Nal-His, Nbg-His, Nle-His (N-Me-His) -His, (N-Me-Phe) -His, Orn-His, Phe-Abu, Phe-Ada, Phe Ala, Phe-Arg, Phe-Asn, Phe-Bia, Phe-Cal, Phe-Dab, Phe-Gln, Phe-Glu, Phe-Gly, Phe- (N-in-methyl-His), Phe-Ile , Phe-Leu, Phe-tert-Leu, Phe-Lys, Phe-Met, Phe-α Nal, Phe-β-Nal, Phe-Nbg, Phe-Nle, Phe (N-Me-His), Phe- (N-Me-Phe), Phe-Orn, Phe-Phe, Phe-Pro, Phe-Ser, Phe-Thr, Phe-Tic, Phe-Trp, Phe-Tyr, Phe-Val, Pro-His, Ser- His, Thr-His, Tic-His, Trp-His, Tyr-His, Val-His, also Ada-Phe-His, Pro-Ala-His, Pro-Ala-Phe, Pro-Phe-Ala, Pro-Phe-Phe, Pro-Abu-His, Pro-Ada-His, Pro-Arg-His, Pro-Asn-His, Pro Bia-His, Pro-Dab-His, Pro-Glu-His, Pro-His-His, Pro-Ile-His, Pro-Leu-His, Pro-Tert-Leu-His, Pro-Lys-His, Pro-Met-His, Pro-Nbg-His, Pro-Nle-His, Pro (N-Me-His) -His, Pro (N-Me-Phe) -His, Pro-Orn-His, Pro Phe-Abu, Pro-Phe-Ada, Pro-Phe-Arg, Pro-Phe-Asn, Pro-Phe-Bia, Pro-Phe-Dab, Pro-Phe-Gln, Pro-Phe-Glu, Pro-Phe- His, Pro-Phe- (N-in-methyl-His), Pro-Phe-Ile, Pro-Phe-Leu, Pro-Phe-tert-Leu, Pro-Phe-Lys, Pro-Phe-Met, Pro -Phe-Nbg, Pro-Phe-Nle, Pro-Phe (N-Me-His), Pro-Phe (N-Me-Phe), Pro-Phe-Orn, Pro-Phe-Pro, Pro-Phe -Ser, Pro-Phe-Thr, Pro-Phe-Tic, Pro-Phe-Trp, Pro-Phe-Tyr, Pro-Phe-Val, Pro-Pro-His, Pro-Ser-His, Pro-Thr-His Pro-Tic-His, Pro-Trp-His, Pro-Tyr-His, Pro-Val-His.

If R¹ is one of the groups R⁰-CH (CH₂C₆H₅) -CO-, where R⁰ = R⁶-C _m H _{2 m} - (T) _x - (G) _y -C _r H _{2 r} , but preferably pyrrolidino, 2- Oxo-pyrrolidino, 2,5-dioxopyrrolidino, 3-benzyl-2,5-dioxopyrrolidino, piperidino, morpholino, alkyl, alkoxy or alkylthio each having 1-9 C-atoms or A₂N-C _r H _{2 r} , Z is preferably absent.

M is preferably Gly, Ala or β furthermore preferably 3-Pya.

E is preferably absent or preferably Ile or Leu, furthermore preferred Abu, Cal, Met, Nle, Phe or Val.

Q is preferably NH.  

R² and R⁵ are preferably H or methyl, furthermore ethyl, propyl, isopropyl, butyl or isobutyl. If n = 2, the two radicals R⁵ may be the same or different; Preferably in this case the one radical R⁵H, the other A, in particular isopropyl.

R³ is preferably cyclohexylmethyl, more preferably A, in particular methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, sec-butyl, pentyl, isopentyl (3-methylbutyl) or 2-methylbutyl, phenyl, benzyl, p-chlorobenzyl, 2-cyclohexylethyl, bicyclo [2,2,1] heptyl-2-methyl or 6,6-dimethylbicyclo [3,1,1] heptyl-2-methyl.

R⁴ is preferably (H, OH).

R⁶ and R⁷ are preferably A, in particular methyl, Ethyl, propyl, isopropyl, butyl, isobutyl or tert. Butyl, furthermore preferably cyclopropyl, cyclopentyl, Cyclohexyl, phenyl, benzyl, pyrrolidino, piperidino or morpholino.

R⁸, R⁹, R¹⁰ are each preferably A; prefers they are the same and are each methyl or ethyl, one of these radicals preferably also higher alkyl with preferably 6-18 C atoms or benzyl, two of these radicals preferably also tetramethylene, pentamethylene, 3-oxapentamethylene or 3-NR 11 -pentamethylene.

R 11 is preferably H, A, phenyl or benzyl.

The group R⁸R⁹R¹⁰N⊕, hereinafter referred to as "Am", Accordingly, preferably denotes trialkylammonium, in particular trimethyl- or triethylammonium, further preferably dimethyl-butyl, pentyl, hexyl, heptyl,  octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl or octadecyl ammonium, N-alkyl pyrrolidinium, N-alkylpiperidinium, N-alkylmorpholinium.

The group Y is preferably -alkylene-Am, in particular -CH₂CH₂-Am or -CH₂CH₂CH₂-Am, furthermore preferably -CH₂-p- C₆H₄-CH₂-Am; -Alkylene- (1-pyridinium), in particular -CH₂CH₂- (1-pyridinium) or -CH₂CH₂CH₂- (1-pyridinium); -Alkylene- (2-, - (3 or - (4-N-alkyl-pyridinium; N, N-dialkyl- 2-, 3- or 4-piperidinium; N-alkyl-N-Ar-alkyl-2-, -2- or 4-piperidinium; Alkylene-2-, -3- or -4-N, N- dialkyl-piperidinium; Alkylene-2-, -3- or -4-N-alkyl- N-Ar-alkyl-piperidinium. Further, the group Y is preferable 1- (or 3-) A-4-amino-2-methylpyrimidinium-5- methyl, 1-A-2,6-dimethylpyridinium-3-methyl, 1-A-2 hydroxy-4,6-dimethyl-pyridinium-3-methyl, 3-A-thiazolium 4- or 5-methyl, 3-A-benzthiazolium-2-methyl.

The group W is preferably -NH-CHR³-CHOH-CH₂-CO-, in particular -NH-CH (cyclohexylmethyl) -CHOH-CH₂-CO- ("AHCP" derived from 4-amino-3-hydroxy-5-cyclohexyl) pentanoic acid), furthermore -NH-CH (CH₂CH₂-cyclohexyl) -CHOH-CH₂-CO- ("AHCH" derived from 4-amino-3-hydroxy-6-cyclohexyl hexanoic acid), -NH-CH (isobutyl) -CHOH-CH₂-CO- ("Sta"; of statin) or -NH-CH (benzyl) -CHOH-CH₂-CO ("AHPP" derived from 4-amino-3-hydroxy-5-phenyl-pentanoic acid). The group W furthermore preferably denotes -NH-CHR³- CH (NH₂) -CH₂-CO-, in particular -NH-CH (cyclohexylmethyl) - CH (NH₂) -CH₂-CO- ("DACP", derived from 3,4-diamino-5- cyclohexylpentanoic acid), -NH-CH (CH₂CH₂-cyclohexyl) -CH (NH₂) - CH₂-CO- ("DACH") derived from 3,4-diamino-6-cyclohexyl hexanoic acid), -NH-CH (isobutyl) -CH (NH₂) -CH₂-CO- ("DAMH"; derived from 3,4-diamino-6-methylheptanoic acid) or -NH-CH (benzyl) -CH (NH₂) -CH₂-CO- ("DAPP"; derived from 3,4-Diamino-5-phenyl-pentanoic acid.  

The group W has at least one chiral center. In the groups R¹, Z, M, E and Y can be further chiral centers to be available. The compounds of the formula I can therefore in different - optically inactive or optical active - forms occur. Formula I encloses everyone these forms. If W is -NH-CHR³-CR⁴-CH₂-CO- with R⁴ = (H, OH) or (H, NH₂), the 3S-hydroxy-4S-amino Enantiomers or 3S, 4S-diamino enantiomers are preferred. If the designation of individual substances nothing else specified, the abbreviations AHCP, AHCH, Sta, AHPP, DACP, DACH, DAMH and DAPP always on the 3S, 4S-forms.

Accordingly, the subject of the invention in particular those compounds of the formula I in which at least one of the radicals mentioned is one of those indicated above has preferred meanings. Some preferred groups Compounds can be identified by the following subformulae Ia to Ih are expressed, which correspond to the formula I, wherein, however

In Ia R¹ is AO-CO-, A-CO-, A₂N-C _t H _{2 t} -CO- or R⁰-CH (CH₂CH₆H₅) -CO-;
in Ib R¹ is BOC;
in Ic Z means Phe;
in Id M β is Ala, Gly or 3-Pya;
in Ie represents -NR²-CHR³-CR⁴- (CHR⁵) _n -CO- (= W) AHCP;
in If E Ile or Leu means;
in Ig R 1 -Z AO-CO-Phe, A-CO-Phe, -A-CO-CH₂-CH (CH₂-C₆H₅) -CO- or 2,5-dioxopyrrolidino-CH- (CH₂-C₆H₅) -CO- .
M β Ala, Gly or 3-Pya,
W AHCP or 2-isopropyl-3-hydroxy-4-amino-5-cyclohexyl-pentanoyl and
E Ile or Leu mean;
in Ih R¹-Z BOC-Phe,
M β Ala, Gly or 3-Pya,
W AHCP and
E Ile or Leu mean:

In particular, compounds of the subformulae are preferred:

I * and Ia * to Ih *, the formulas I and Ia to Ih correspond, wherein, however

QY is -NH- (CH₂) _z -Am, -NH-CH₂-p-C₆H₄-CH₂Am, -NH- (CH₂) _z - (1-pyridinium) or -NH- (CH₂) _z - (1A-2, -3- or -4-pyridinium),
z is 1, 2, 3, 4 or 5 and
Tris-C _1-18 -alkyl-ammonium, 1-A-pyrrolidinium, 1-A-piperidinium or 1-A-morpholinium;

I 'and Ia' to Ih ', the formulas I and Ia to Ih correspond, wherein, however

QY -NH- (CH₂) _z -NA₃⊕ and
z is 2 or 3;

I "and Ia" to Ih ", the formulas I and Ia to Ih correspond, wherein, however

Q-Y-NH-CH₂- (1- or 3-A-4-amino-2-methyl-5-pyrimidinium), or -NH-CH₂- (1-A-2-, 3- or 4-pyridinium) means.

The compounds of the formula I and also the starting materials for their preparation are otherwise known per se Methods prepared as in the literature (eg in the standard works such as Houben-Weyl, Methoden of organic chemistry, Georg-Thieme-Verlag, Stuttgart;  also EP-A-45 665, EP-A-77 028, EP-A-77 029, EP-A-81 783) are described, under reaction conditions, known and suitable for the reactions mentioned are. You can also of known, here unspecified variants make use.

The starting materials can, if desired, also in situ be formed, so that you from the reaction mixture not isolated, but immediately continue to the connections the formula I implements.

The compounds of the formula I can be obtained by getting them out of their functional derivatives Solvolysis, in particular hydrolysis, or by hydrogenolysis sets in freedom.

Preferred starting materials for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, preferably those which are substituted for an H- Atoms, which is connected to an N-atom, carry an amino protecting group, z. Those which correspond to the formula I but instead of a His group contain an N (im) -R'-His group (in which R 'represents an amino-protecting group, eg BOM or DNP) or those of the formula R¹-ZM-NR²-CHR³-CH (NHR ') - (CHR⁵) _n -CO-EQY.

Furthermore, preference is given to starting materials which, instead of the H atom of a hydroxy group, carry a hydroxyl-protecting group, eg. Those of the formula R¹-ZM-NR²-CHR³-CHOR "- (CHR⁵) _n -CO-EQY wherein R" represents a hydroxy-protecting group.

It can also be several - same or different - protected amino and / or hydroxy groups in the molecule of Starting material be present. If the existing Protective groups are different from each other, they can in many cases selectively split off.

The term "amino protecting group" is well known and refers to groups that are suitable Protect amino group from chemical reactions (zu block), but are easily removable after the desired chemical reaction at another location of the molecule has been carried out. Typical for such Groups are especially unsubstituted or substituted Acyl, aryl (eg DNP), aralkoxymethyl (e.g. BOM) or aralkyl groups (eg, benzyl, 4-nitrobenzyl, Triphenylmethyl). Since the amino protecting groups after the desired reaction (or reaction sequence are removed, By the way, its nature and size are not critical. however, preferred are those with 1-20, in particular 1-8 C atoms. The term "acyl group" is related with the present method in the broadest sense specific. It encloses of aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acid-derived acyl groups, and in particular Alkoxycarbonyl, aryloxycarbonyl and especially Aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl, such as methoxycarbonyl, ETOC, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC. preferred Amino protecting groups are BOC, DNP and BOM, furthermore CBZ, FMOC, benzyl and acetyl.  

The term "hydroxy protecting group" is also generic known and refers to groups that are suitable are, a hydroxy group before chemical reactions too protect, but are easily removable after the desired chemical reaction at another location of the Molecule has been performed. Typical of such groups are the above unsubstituted or substituted Aryl, aralkyl or acyl groups, further also Alkyl groups. The nature and size of the hydroxy protecting groups is not critical, as it is the desired chemical Reaction or reaction sequence removed again become; preferred are groups of 1-20, in particular 1-10 C atoms. Examples of hydroxy protecting groups are u. a. tert-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and Acetyl, with benzyl and acetyl being particularly preferred.

The functional substances to be used as starting materials Derivatives of the compounds of the formula I can according to customary Methods of amino acid and peptide synthesis prepared become, how they z. B. in the said standard works and patent applications are described, for. Belly according to the solid-phase method according to Merrifield.

The in-freedom setting of the compounds of formula I from their functional derivatives succeed - depending on the used ones Protective group - z. B. with strong acids, appropriate with trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids like hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always required. Suitable inert solvents are preferably organic, for example carboxylic acids such as Acetic acid, ethers such as tetrahydrofuran or dioxane, amides  such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, as well as alcohols such as methanol, Ethanol or isopropanol and water. Further come Mixtures of the aforementioned solvents in question. Trifluoroacetic acid is preferably in excess without Addition of another solvent used, perchloric acid in the form of a mixture of acetic acid and 70% Perchloric acid in the ratio 9: 1. The reaction temperatures for the split are appropriate between about 0 and about 50 °, preferably working between 15 and 30 ° (room temperature).

The BOC group can, for. B. preferably with 40% trifluoroacetic acid in methylene chloride or with about 3 to 5 n HCl cleaved in dioxane at 15-30 °, the FMOC group with an approximately 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 °. A spin - off of the DNP group succeeds z. B. also with an about 3-10% solution of 2-mercaptoethanol and DMF / water at 15-30 °.

Hydrogenolytically removable protecting groups (eg BOM, CBZ or benzyl) may e.g. B. by treatment with hydrogen in the presence of a catalyst (eg a noble metal catalyst like palladium, appropriate on a support like coal) are split off. Suitable solvents while the above, in particular z. For example, alcohols such as methanol or ethanol or amides such as DMF. The Hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably carried out at 20-30 ° and 1-10 bar. A Hydrogenolysis of the CBZ group succeeds z. B. good 5-10% Pd-C in methanol at 20-30 °.  

Compounds of formula I can also be obtained by direct peptide synthesis from a carboxylic acid (formula II) and a Amine component (Formula III) can be obtained. As carboxylic acid components are suitable for. B. those of the sub-formulas R¹-Z-OH, R¹-Z-M-OH, R¹-Z-M-W-OH or R¹-Z-M-W-E-OH, as Amine components of the sub-formulas H-M-W-E-Q-Y, H-W-E-Q-Y, H-E-Q-Y or H₂N-Y. But the peptide bond can also within the group Z or E; there is a carboxylic acid of the formula R¹-Z¹-OH or R₁-Z-M- W-E¹-OH with an amino compound of the formula H-Z²-M-W- Converted E-Q-Y or H-E²-Q-Y, where Z¹ + Z² = Z or E¹ + E² = E is. It works expedient according to usual Methods of peptide synthesis, as z. In Houben-Weyl, 1.c., vol. 15 / II, pages 1-806 (1974) are.

The reaction is preferably carried out in the presence of a Dehydrating agent, for. B. a carbodiimide as DCCI or dimethylaminopropylethyl carbodiimide, further Propanephosphonic anhydride (see Angew Chem 92, 129 (1980)), diphenyl phosphoryl azide or 2-ethoxy-N-ethoxycarbonyl 1,2-dihydroquinoline, in an inert solvent, z. As a halogenated hydrocarbon such Dichloromethane, an ether such as tetrahydrofuran or Dioxane, an amide such as DMF or dimethylacetamide, a Nitrile such as acetonitrile, at temperatures between about -10 and 40, preferably between 0 and 30 °.

In place of II or III also suitable reactive Derivatives of these substances used in the reaction be, for. For example, those in which reactive groups intermediar are blocked by protecting groups. The  Amino acid derivatives III can, for. B. in the form of their activated Esters are used, which are useful in situ are formed, for. B. by adding HOBt or N-hydroxysuccinimide.

The starting materials of formulas II and III are largely known. Unless they are known, they can according to known methods, for. As the methods given above the peptide synthesis and the deprotection getting produced.

The compounds of the formula I are furthermore obtainable by a tertiary amine, which otherwise corresponds to the formula I, treated with a quaternizing agent.

Suitable tertiary amines z. B. (a) compounds, which correspond to the formula I, but instead of the radical Y. contain an alkylene chain, wherein also a CH₂ group replaced by an aryl group or het-ylene group can be, with a total of 1-20 C-atoms, which by a R⁹R¹⁰N group or an unsubstituted or an on or multiply substituted by A, AO and / or Hal pyridyl group is substituted. Also suitable are (b) pyridine or amines of the formula R⁸R⁹R¹⁰N. As a quaternizing agent in the case (a) halides of the formula R⁸X (X = Cl, Br or J), z. B. alkyl halides such as methyl iodide or Ethyl bromide, or aralkyl halides such as benzyl chloride, in case (b) against z. B. halides of the formula R¹-Z-M-W E-Q-alkylene-X, e.g. BOC-Phe-Gly-AHCP-Ile-N- (2-bromoethyl) - amide or 2- (2,5-dioxopyrrolidino) -3-phenylpropionyl-gly- AHCP-Ile-N- (3-chloropropyl) amide.  

It is advisable to quaternize in the presence of one of the above specified inert solvent, for. As acetonitrile, at Temperatures between about -10 and + 40 °.

If desired, in a compound of formula I a functionally modified amino and / or hydroxy group by solvolysis or hydrogenolysis according to one of above described methods are set free.

Thus, in particular a compound of formula I, wherein R¹ is other than H, in a compound of formula I. (R¹ = H) are converted, suitably by hydrogenolysis, if R1 = CBZ, otherwise by selective solvolysis. If R¹ = BOC, z. B. with HCl in dioxane at Room temperature, split off the BOC group.

Furthermore z. B. keto compounds of the formula I (R⁴ = O) reduced to compounds of formula I (R⁴ = (H, OH)) be, for example with a complex metal hydride such as NaBH₄, which does not simultaneously contain the peptide carbonyl groups reduced, in an inert solvent such as Methanol at temperatures between about -10 and + 30 °.

Keto compounds of the formula I (R⁴ = O) may also be reductive amination in compounds of the formula I (R⁴ = H, NH₂) are transferred. One can one or more stages aminate reductively. So you can z. B. the keto compound with ammonium salts, eg. As ammonium acetate, and treat NaCNBH₃, preferably in an inert solvent, e.g. B. an alcohol such as methanol, at temperatures between about 0 and 50 °, in particular between 15 and 30 °. Furthermore is it is possible, the keto compound first with hydroxylamine in the usual way to convert into the oxime and this, z. B. by catalytic hydrogenation of Raney nickel, for To reduce amine.  

A base of formula I can with an acid in the associated Acid addition salt to be converted. For this In particular acids come into question, the physiological provide harmless salts, so can inorganic Acids are used, for. For example sulfuric acid, Nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as Orthophosphoric acid, sulfamic acid, furthermore organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic Carboxylic, sulfonic or sulfuric acids, e.g. Formic acid, Acetic acid, propionic acid, pivalic acid, diethylacetic acid, Malonic acid, succinic acid, pimelic acid, fumaric acid, Maleic acid, lactic acid, tartaric acid, malic acid, Citric acid, gluconic acid, ascorbic acid, nicotinic acid, Isonicotinic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and di-sulfonic acids, Lauryl sulfuric acid. Salts with physiologically harmless Acids, e.g. As picrates, can be used for isolation and / or purification of the compounds of formula I used become.

It is also possible in a compound of formula I exchange an anion An⊖ for another anion An⊖. Anions An⊖ are the anions of the above acids mentioned; preferred are the chlorides, bromides, Methanesulfonates, acetates, citrates, fumarates, maleates and Succinate. For anion exchange can be z. B. the starting material subjected to gel chromatography, wherein one uses as eluent a solvent mixture, the contains the desired anion in excess. As a carrier is preferably a crosslinked polydextran. Want to obtain an acetate, it works z. With acetic acid / Water or methanol / acetic acid / water as eluant.  

The new compounds of formula I and their physiological harmless salts may be used for the preparation of pharmaceutical Preparations can be used by putting them together with at least one carrier or excipient and, if desired, together with one or more others Substance (s) brings in a suitable dosage form. The preparations thus obtained may be used as medicaments used in human or veterinary medicine. Suitable carrier substances are organic or inorganic Substances in question that are suitable for enteral (eg oral or rectal) or parenteral application or for a Application in the form of an inhalable spray are suitable and Do not react with the new connections, for example Water, vegetable oils, benzyl alcohols, polyethylene glycols, Glycerol triacetate and other fatty acid glycerides, Gelatin, soy lecithin, carbohydrates like lactose or starch, magnesium stearate, talc, cellulose. to In particular, tablets, dragees, Capsules, syrups, juices or drops; are of interest especially coated tablets and capsules with enteric coating Coatings or capsule shells. For rectal use serve suppositories, for parenteral administration solutions, preferably oily or aqueous solutions, further Suspensions, emulsions or implants. For the application sprays can be used as inhalation spray which either dissolves or suspends the active ingredient in a propellant gas mixture (eg chlorofluorocarbons) contain. Appropriately used the active ingredient in micronized form, with one or more additional physiologically acceptable solvents may be present, for. For example, ethanol. inhalation solutions can be administered using standard inhalers. The new compounds can also be lyophilized and the obtained lyophilisates z. B. for the preparation of injection preparations  be used. The specified preparations may be sterilized and / or adjuvants such as preservatives, stabilizers and / or wetting agents, Emulsifiers, salts for influencing the osmotic Printing, buffer substances, colorants and / or flavorings contain. You can, if desired, also one or contain several other active ingredients, for. B. one or several vitamins.

The substances of the invention are usually in Analogous to other known, commercially available Peptides, but in particular in analogy to those in the EP-A-16 32 27, EP-A-17 34 81 and EP-A-20 98 97 described Administered compounds, preferably in Dosages between about 100 mg and 30 g, in particular between 500 mg and 5 g per dosage unit. The daily Dosage is preferably between about 2 and 600 mg / kg body weight. The special dose for everyone However, certain patients depend on the most diverse Factors, such as the effectiveness of used special compound, from age, body weight, general health, sex, from the diet, from the time and way of the intake, from the Excretion rate, drug combination and Severity of the particular condition, which the therapy applies. Parenteral administration is preferred.

Above and below, all temperatures are given in ° C. In the following examples, "common Work-up ": Water is added, if necessary, depends on the constitution of the end product for pH Values between 2 and 8, extracted with ethyl acetate or Dichloromethane, separates, the organic phase is dried over sodium sulfate, filtered, evaporated, subjecting the  usually oily crude product of a gel filtration on cross-linked Polydextran with methanol / water or acetic acid / Water as eluent, evaporated again and purified by Chromatography on silica gel and / or crystallization. When in gel filtration, the eluent contains acetic acid, the quaternary acetates of the formula I, An = are obtained CH₃COO. The Rf values are thin-layer chromatographic obtained on silica gel; Eluent methanol / acetic acid / water 7: 2: 1, unless stated otherwise.

Example 1

A mixture of 1.079 g of N-2- [3S-hydroxy-4S- (N-tert-butoxycarbonyl- L-phenylalanyl-N (imi) - (2,4-dinitrophenyl) - L-histidyl-glycyl-amino) -5-cyclohexyl-pentanoyl-L-isoleucyl amino] -ethyl-N, N, N-trimethyl-ammonium acetate ["N-2 (BOC-Phe- (imi-DNP-His) -Gly-AHCP-Ile-amino) ethyl-N, N, N- trimethylammonium acetate "obtainable by reaction of BOC-Ile-N-2-dimethylaminoethyl-amide (mp. 100-105 °) with CH₃I to N-2- (BOC-Ile-amino) -ethyl-N, N, N-trimethylammonium iodide (Oil, Rf 0.45, trichloroethane / methanol / acetic acid 6: 3: 1), cleavage of the BOC group with HCl / dioxane to N-2- (H-Ile-amino) -ethyl-N, N, N-trimethylammoniumchloride hydrochloride (F. 89-120 °) and condensation with BOC Phe- (imi-DNP-His) -Gly-AHCP-OH], 2 g of 2-mercaptoethanol, 20 ml of DMF and 20 ml of water with stirring at 20 ° with aqueous Na₂CO₃ solution adjusted to pH 8 and 2 hrs. stirred at 20 °. After usual work-up one receives N-2- [3S-Hydroxy-4S- (N-tert-butoxycarbonyl-L-phenylalanyl L-histidyl-glycyl-amino) -5-cyclohexyl-pentanoyl-L- isoleucyl-amino] ethyl-N, N, N-trimethylammonium [ "N-2- (BOC-Phe-His-Gly-Ile-AHCP-amino) ethyl-N, N, N-trimethylammonium acetate"].  

example 2

Dissolve 1 g of N-2- [BOC-Phe (CBZ-3-Pia) -AHCP-Ile-amino] - ethyl-N, N, N-triethylammonium acetate [available from Hydrogenation of BOC-Phe-3-Pya-ACHP-OH to BOC-3-Pia-AHCP OH, reaction with CBZ-Cl to BOC- (CBZ-3-Pia) -AHCP-OH, condensation with N- (2-H-Ile-aminoethyl) -N, N, N-trimethylammonium chloride hydrochloride and HPLC with ammonium acetate] in 15 ml of ethanol, hydrogenated for 3 hours on 0.5 g of 10%. Pd-C at 20 ° and 1 bar, filtered, evaporated and receives after chromatographic purification N-2 (BOC-Phe-3-Pia) AHCP-Ile-amino) ethyl-N, N, N-trimethylammonium.

Analog is obtained by hydrogenolysis of the corresponding CBZ derivatives:

N-2- (BOC-Phe-2-Pia-AHCP-Ile-amino) ethyl-N, N-trimethylammoniumacet-at N
N-2- (BOC-Phe-4-Pia-AHCP-Ile-amino) ethyl-N, N-trimethylammoniumacet-at N
N-3- (BOC-Phe-2-Pia-AHCP-Ile-amino) propyl-N, N, N-trimethylammoniumace-tat
N-3- (BOC-Phe-3-Pia-AHCP-Ile-amino) propyl-N, N, N-trimethylammoniumace-tat
N-3- (BOC-Phe-4-Pia-AHCP-Ile-amino) propyl-N, N, N-trimethylammoniumace-tat
N-2- (BOC-Phe-Gly-Leu-DACP-amino) ethyl-N, N, N-trimethylammoniumacetat-
N-2- (BOC-Phe-Gly-Leu-DACH-amino) ethyl-N, N, N-trimethylammoniumacetat-
N-2- (BOC-Phe-Gly-Leu-DAMH-amino) ethyl-N, N, N-trimethylammoniumacetat-
N-2- (BOC-Phe-Gly-Leu-DAPP-amino) ethyl-N, N, N-trimethylammoniumacetat-.

example 3

A solution of 2.88 g of N-2- (H-Ile-amino) -ethyl-N, N, N-trimethylammonium chloride hydrochloride [F. 89-120 °, obtainable by reaction of BOC-Ile-N-2-dimethylaminoethylamide (mp. 100-105 °) with CH₃I to give N- (2-BOC-1-aminoethyl) -N, N, N-trimethylammonium iodide (oil ) and cleavage of the BOC group with HCl in dioxane] in 160 ml of DMF is treated with 1.01 g of N-methylmorpholine. While stirring, 5.19 g of BOC-Phe-Gly-AHCP-OH, 1.35 g HOBt and a solution of 2.06 g DCCI in 50 ml CH₂Cl₂ added, stirred for 14 hrs. At 4 °, filtered the precipitated dicyclohexylurea and evaporated the filtrate. After usual workup, N-2- (BOC-Phe-Gly-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate ("A"), m.p. 55-67 °, Rf 0, 68th
Analogously you get:

N-2- (BOC-Phe-β-Ala-Ile AHCP-amino) ethyl-N, N, N-trimethylammonium
N-2- (BOC-Phe-2-Pya-AHCP-Ile-amino) ethyl-N, N-trimethylammoniumacet-at N
N-2- (BOC-Phe-3-Pya-AHCP-Ile-amino) ethyl-N, N-trimethylammoniumacet-at N
N-2- (BOC-Phe-4-Pya-AHCP-Ile-amino) ethyl-N, N-trimethylammoniumacet-at N

N-3- (BOC-Phe-Gly-AHCP-Ile-amino) -propyl-N, N, N-trimethylammoniumaceta-t, m.p. 61-72 °, Rf 0.63
N-3- (BOC-Phe-β-Ala-Ile AHCP-amino) propyl-N, N, N-trimethylammonium
N-3- (BOC-Phe-2-Pya-AHCP-Ile-amino) propyl-N, N, N-trimethylammoniumace-tat
N-3- (BOC-Phe-3-Pya-AHCP-Ile-amino) propyl-N, N, N-trimethylammoniumace-tat
N-3- (BOC-Phe-4-Pya-AHCP-Ile-amino) propyl-N, N, N-trimethylammoniumace-tat

N-4- (BOC-Phe-Gly-Ile-AHCP-amino) butyl-N, N, N-trimethylammoniumacetat-
N-4- (BOC-Phe-β-Ala-Ile AHCP-amino) butyl-N, N, N-trimethylammonium
(BOC-Phe-3-Pya-AHCP-Ile-amino), N-trimethylammoniumacet-at N-4-butyl-N, N

N-5- (BOC-Phe-Gly-Ile-AHCP-amino) -pentyl-N, N, N-t-trimethylammoniumaceta
N-5- (BOC-Phe-β-Ala-Ile AHCP-amino) -pentyl-N, N, N-trimethylammonium
N-5- (BOC-Phe-3-Pya-AHCP-Ile-amino) -pentyl-N, N, N-trimethylammoniumace-tat.

example 4

Analogously to Example 3, BOC-Pro-OH and N-2- (H-) are obtained. Phe-Gly-Ile-AHCP-amino) ethyl-N, N, N-triethylammonium chloride the N-2- (BOC-Pro-Phe-Gly-AHCP-Ile-amino) -ethyl-N, N, N-triethylammonium chloride.

example 5

Analogously to Example 3 is obtained from BOC-Phe-OH and N-2- (H-Gly-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium chloride "A", mp 55-67 °.
Analogously you get:

N-2- (BOC- α- Nal-Gly-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate
N-2- (BOC-β Nal-Gly-Ile-AHCP-amino) ethyl-N, N, N-trimethylammonium
N-2- (BOC-Trp-Gly-Ile-AHCP-amino) ethyl-N, N, N-trimethylammoniumacetat-
N-2- (BOC-Tyr-Gly-Ile-AHCP-amino) ethyl-N, N, N-trimethylammoniumacetat-

N-2- (pivaloyl-Phe-Gly-Ile-AHCP-amino) ethyl-N, N, N-trimethylammoniuma-acetate

N-2- (3,3-dimethylbutyryl-Phe-Gly-AHCP-Ile-amino) -ethyl- N, N, N-trimethylammonium acetate, Rf 0.70
N-2- (3,3-dimethylbutyryl-Phe-β-Ala-Ile-AHCP amino) ethyl N, N, N-trimethylammonium
N-2- (3,3-dimethylbutyryl-Phe-3-Pya-AHCP-Ile-amino) -ethyl- N, N, N-trimethylammonium acetate
N-3- (3,3-dimethylbutyryl-Phe-Gly-AHCP-Ile-amino) -propyl-N, N, N-trimethylammonium acetate
N-3- (3,3-dimethylbutyryl-Phe-β-Ala-Ile-AHCP amino) propyl N, N, N-trimethylammonium
N-3- (3,3-dimethylbutyryl-Phe-3-Pya-AHCP-Ile-amino) -propyl-N, N, N-trimethyl-ammonium acetate

N-2- (MAC-Phe-Gly-Ile-AHCP-amino) ethyl-N, N, N-trimethylammoniumacetat-
N-2- (MAC-Phe-β-Ala-Ile AHCP-amino) ethyl-N, N, N-trimethylammonium
N-2- (MAC-Phe-3-Pya-AHCP-Ile-amino) ethyl-N, N-trimethylammoniumacet-at N

N-3- (MAC-Phe-Gly-Ile-AHCP-amino) propyl-N, N, N-t-trimethylammoniumaceta
N-3- (MAC-Phe-β-Ala-Ile AHCP-amino) propyl-N, N, N-trimethylammonium
N-3- (MAC-Phe-3-Pya-AHCP-Ile-amino) propyl-N, N, N-trimethylammoniumace-tat

N-2- (MAC-Phe-Gly-Leu-AHCP-amino) ethyl-N, N, N-trimethylammoniumacetat-
N-2- (MAC-Phe-β Ala-AHCP-Leu-amino) ethyl-N, N, N-trimethylammonium
N-2- (MAC-Phe-3-Pya-AHCP-Leu-amino) ethyl-N, N-trimethylammoniumacet-at N

N-2- (3-dimethylaminopropionyl-Phe-Gly-AHCP-Ile-amino) - ethyl-N, N, N-trimethylammonium acetate
N-2- (3-dimethylaminopropionyl-Phe-β-Ala-Ile AHCP-amino) - ethyl-N, N, N-trimethylammonium
N-2- (3-Dimethylaminopropionyl-Phe-3-Pya-AHCP-Ile-amino) - ethyl-N, N, N-trimethylammonium acetate

N-2- (4-dimethylaminobutyryl-Phe-Gly-Ile-AHCP-amino) - ethyl-N, N, N-trimethylammonium

N-2- (5-dimethylaminopentanoyl-Phe-Gly-AHCP-Ile-amino) - ethyl-N, N, N-trimethylammonium acetate
N-2- (5-Dimethylaminopentanoyl-Phe-β-Ala-Ile AHCP-amino) - ethyl-N, N, N-trimethylammonium
N-2- (5-dimethylaminopentanoyl-Phe-3-Pya-AHCP-Ile-amino) - ethyl-N, N, N-trimethylammonium acetate

N-2- (2-Benzyl-3-dimethylaminopropionyl-Phe-Gly-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate
N-2- (2-Benzyl-3-dimethylaminopropionyl-Phe- β Ala-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate
N-2- (2-Benzyl-3-dimethylaminopropionyl-Phe-3-Pya-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate

N-2- (2-Benzyl-5-dimethylaminopentanoyl-Gly-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate
N-2- (2-benzyl-5-dimethylaminopentanoyl- β-Ala-Ile-AHCP amino) ethyl-N, N, N-trimethylammonium
N-2- (2-Benzyl-5-dimethylaminopentanoyl-3-Pya-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate

N-2- [2- (2,5-dioxopyrrolidino) -3-phenylpropionyl-Gly-AHCP-Ile-amino] -ethyl-N, N, N-trimethylammonium acetate
N-2- [2- (2,5-dioxopyrrolidino) -3-phenylpropionyl- β- Ala-AHCP-Ile-amino] -ethyl-N, N, N-trimethylammonium acetate
N-2- [2- (2,5-dioxopyrrolidino) -3-phenylpropionyl-3-pya-AHCP-Ile-amino] -ethyl-N, N, N-trimethylammonium acetate

N-2- [2- (2,5-dioxopyrrolidino) -3-phenylpropionyl-Gly-AHCP-leu-amino] -ethyl-N, N, N-trimethylammonium acetate
N-2- [2- (2,5-dioxopyrrolidino) -3-phenylpropionyl- β- Ala-AHCP-leu-amino] -ethyl-N, N, N-trimethylammonium acetate
N-2- [2- (2,5-dioxopyrrolidino) -3-phenylpropionyl-3-pya-AHCP-leu-amino] -ethyl-N, N, N-trimethylammonium acetate

N-2- [2- (3-benzyl-2,5-dioxopyrrolidino) -3-phenylpropionyl- Gly-AHCP-Ile-amino] ethyl-N, N, N-trimethylammonium

N-3- [2- (2,5-dioxopyrrolidino) -3-phenylpropionyl-Gly-AHCP-Ile-amino] -propyl-N, N, N-trimethylammonium acetate, Rf 0.55
N-3- [2- (2,5-dioxopyrrolidino) -3-phenylpropionyl- β- Ala-AHCP-Ile-amino] -propyl-N, N, N-trimethylammonium acetate
N-3- [2- (2,5-Dioxopyrrolidino) -3-phenylpropionyl-3-Pya-AHCP-Ile-amino] -propyl-N, N, N-trimethylammonium acetate

N-2- (CBZ-Phe-Gly-Ile-AHCP-amino) ethyl-N, N, N-trimethyl- ammonium acetate.

example 6

Analogously to Example 3 is obtained from BOC-Phe-3-Pya-OH and N-2- (H-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium chloride, the N-2- (BOC-Phe-3 -Pya-AHCP-Ile-amino) -ethyl- N, N, N-trimethylammonium chloride, mp 225-230 °.
Analogously you get:

N-2- (BOC-Phe-Gly-AHCP-Leu-amino) -ethyl-N, N, N-trimethylammoniumchloride, m.p. 141-142 °
N-2- (BOC-Phe-β Ala-AHCP-Leu-amino) ethyl-N, N, N-trimethylammonium chloride
N-2- (BOC-Phe-2-Pya-AHCP-Leu-amino) ethyl-N, N, N-trimethylammoniumchlo user_rid
N-2- (BOC-Phe-3-Pya-AHCP-Leu-amino) ethyl-N, N, N-trimethylammoniumchlo user_rid
N-2- (BOC-Phe-4-Pya-AHCP-Leu-amino) ethyl-N, N, N-trimethylammoniumchlo user_rid

N-3- (BOC-Phe-Gly-Leu-AHCP-amino) propyl-N, N, N-trimethylammoniumchlor-id
N-3- (BOC-Phe-β Ala-AHCP-Leu-amino) propyl-N, N, N-trimethylammonium chloride
N-3- (BOC-Phe-2-Pya-AHCP-Leu-amino) propyl-N, N, N-trimethylammoniumchl-ORID
N-3- (BOC-Phe-3-Pya-AHCP-Leu-amino) propyl-N, N, N-trimethylammoniumchl-ORID
N-3- (BOC-Phe-4-Pya-AHCP-Leu-amino) propyl-N, N, N-trimethylammoniumchl-ORID

N-2- (BOC-Phe-Gly-AHCP-Nle-amino) ethyl-N, N, N-trimethylammoniumchlori-d
N-2- (BOC-Phe-β Ala-AHCP-Nle-amino) ethyl-N, N, N-trimethylammonium chloride
N-2- (BOC-Phe-3-Pya-AHCP-Nle-amino) ethyl-N, N, N-trimethylammoniumchlo user_rid

N-2- (BOC-Phe-Gly-Phe-AHCP-amino) ethyl-N, N, N-trimethylammoniumchlori-d
N-2- (BOC-Phe-β Ala-AHCP-Phe-amino) ethyl-N, N, N-trimethylammonium chloride
N-2- (BOC-Phe-3-Pya-AHCP-Phe-amino) ethyl-N, N, N-trimethylammoniumchlo user_rid

N-2- (BOC-Phe-Gly-Val-AHCP-amino) ethyl-N, N, N-trimethylammoniumchlori-d
N-2- (BOC-Phe-β-Ala-Val AHCP-amino) ethyl-N, N, N-trimethylammonium chloride
N-2- (BOC-Phe-3-Pya-AHCP-Val-amino) ethyl-N, N, N-trimethylammoniumchlo user_rid

N-2- (BOC-Phe-Gly-Ile-Sta-amino) ethyl-N, N, N-trimethylammonium chloride
N-2- (BOC-Phe-Gly-Ile-AHCH-amino) ethyl-N, N, N-trimethylammoniumchlori-d
N-2- (BOC-Phe-Gly-Ile-AHPP-amino) ethyl-N, N, N-trimethylammoniumchlori-d

N-2- (2-benzyl-4-oxo-5,5-dimethyl-hexanoyl-Gly-Ile-AHCP amino) -ethyl-N, N, N-trimethylammonium acetate, Rf 0.68

N-2- (2-isopropyl-4S-hydroxy-5S-BOC-Phe- β- Ala-amino-6-cyclohexyl-hexanoyl-amino) -ethyl-N, N, N-trimethyl-ammonium chloride, m.p. 129-130 °

N-2- (N-benzoyl-N-benzyl-Gly-Ile-AHCP-amino) ethyl-pyridinium bromide

N-2- [2- (2,5-dioxopyrrolidino) -3- (p-hydroxyphenyl) -propionyl-Gly-AHCP-Ile-amino] -ethyl-N, N, N-trimethylammonium methanesulfonate
N-2- [2- (2,5-dioxopyrrolidino) -3- (3-indolyl) -propionyl-Gly-AHCP-Ile-amino] -ethyl-N, N, N-tripropylammonium chloride
N-2- [2- (2,5-dioxopyrrolidino) -3- (1-naphthyl) -propionyl-Gly-AHCP-Ile-amino] -ethyl-N, N, N-tributylammonium chloride
N-2- [2- (2,5-dioxopyrrolidino) -3- (2-naphthyl) -propionyl-Gly-AHCP-Ile-amino] -ethyl-N-2-phenylethyl-morpholinium chloride

N-2 - [(3-Benzyl-2,5-dioxopyrrolidino) -acetyl-AHCP-Ile-amino] -ethyl-N, N, N-trimethylammonium acetate
N-2- [2- (3-benzyl-2,5-dioxopyrrolidino) -propionyl-AHCP-Ile-amino] -ethyl-N, N, N-trimethylammonium acetate
N-2- [2- (3-Benzyl-2,5-dioxopyrrolidino) -3- (4-imidazolyl) -propionyl-ACHP-Ile-amino] -ethyl-N, N, N-trimethylammonium acetate

N-2- (2-Benzyl-4-dimethylamino-4-oxobutyryl-Gly-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate
N-2- (2-benzyl-4-dimethylamino-4-oxobutyryl- β-Ala-Ile-AHCP amino) ethyl-N, N, N-trimethylammonium
N-2- (2-Benzyl-4-dimethylamino-4-oxo-butyryl-3-phenyl-AHCP-Ile-amino) -ethyl-N, N, N-trimethyl-ammonium acetate

N-2- (2-Benzyl-4- (3-dimethylaminopropyl) -4-oxobutyryl-Gly-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate
N-2- (2-Benzyl-4- (3-dimethylaminopropyl) -4-oxobutyryl- b Ala-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate
N-2- (2-Benzyl-4- (3-dimethylaminopropyl) -4-oxobutyryl-3-pya-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate

N-2- (2-Benzyl-4-oxo-5,5-dimethyl-hexanoyl-Gly-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate
N-2- (2-Benzyl-4-oxo-5,5-dimethyl-hexanoyl- β- Ala-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate
N-2- (2-Benzyl-4-oxo-5,5-dimethyl-hexanoyl-3-phenyl-AHCP-Ile-amino) -ethyl-N, N, N-trimethyl-ammonium acetate

N-2- (2-dimethylamino-3-phenyl-propionyl-Gly-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate
N-2- (2-dimethylamino-3-phenylpropionyl- b Ala-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate
N-2- (2-dimethylamino-3-phenylpropionyl-3-phenyl-AHCP-1-amino) -ethyl-N, N, N-trimethylammonium acetate.

example 7

Analogously to Example 3 is obtained from BOC-Phe-Gly-AHCP-Ile-OH and N-2-aminoethyl-N, N, N-trimethylammonium chloride "A", mp 55-67 °.
Analogously you get:

N-4- (BOC-Phe-Gly-Ile-AHCP-amino) butyl-N, N, N-trimethylammoniumacetat-
N-5- (BOC-Phe-Gly-Ile-AHCP-amino) -pentyl-N, N, N-t-trimethylammoniumaceta
N-6- (BOC-Phe-Gly-Ile-AHCP-amino) hexyl-N, N, N-trimethylammoniumacetat-
N-7- (BOC-Phe-Gly-Ile-AHCP-amino) heptyl-N, N, N-t-trimethylammoniumaceta
N-8- (BOC-Phe-Gly-Ile-AHCP-amino) -octyl-N, N, N-trimethylammoniumacetat-
N-9- (BOC-Phe-Gly-Ile-AHCP-amino) nonyl-N, N, N-trimethylammoniumacetat-
N-10- (BOC-Phe-Gly-Ile-AHCP-amino) decyl-N, N, N-t-trimethylammoniumaceta

N-p- (BOC-Phe-Gly-Ile-aminomethyl AHCP-) benzyl-N, N, N-trimethylammoniu-macetat

N-2- (BOC-Phe-Gly-AHCP-Ile-amino) -ethyl-N, N-dimethyl-N-octyl-ammonium acetate
N-2- (BOC-Phe-β-Ala-Ile AHCP-amino) ethyl-N, N-dimethyl-N-octyl-ammonium acetate
N-2- (BOC-Phe-3-Pya-AHCP-Ile-amino) -ethyl-N, N-dimethyl-N-octyl-ammonium acetate
N-3- (BOC-Phe-Gly-AHCP-Ile-amino) -propyl-N, N-dimethyl-N-octyl-ammonium acetate
N-3- (BOC-Phe-β-Ala-Ile AHCP-amino) propyl-N, N-dimethyl-N-octyl-ammonium acetate
N-3- (BOC-Phe-3-Pya-AHCP-Ile-amino) -propyl-N, N-dimethyl-N-octyl-ammonium acetate
N-5- (BOC-Phe-Gly-AHCP-Ile-amino) -pentyl-N, N-dimethyl-N-octyl-ammonium acetate
N-5- (BOC-Phe-β-Ala-Ile AHCP-amino) -pentyl-N, N-dimethyl-N-octyl-ammonium acetate
N-5- (BOC-Phe-3-Pya-AHCP-Ile-amino) -pentyl-N, N-dimethyl-N-octyl-ammonium acetate
N-2- (BOC-Phe-Gly-AHCP-Ile-amino) -ethyl-N, N-dimethyl-N-decyl-ammonium acetate

N-2- (BOC-Phe-Gly-Ile-AHCP-amino) ethyl-N-methyl-pyrrolidiniumacetat
N-3- (BOC-Phe-Gly-Ile-AHCP-amino) propyl-N-methyl-pyrrolidiniumacetat-
N-2- (BOC-Phe-Gly-Ile-AHCP-amino) ethyl-N-methyl-piperidinium acetate
N-3- (BOC-Phe-Gly-Ile-AHCP-amino) propyl-N-methyl-piperidinium acetate
N-2- (BOC-Phe-Gly-Ile-AHCP-amino) ethyl-N-methyl-morpholiniumacetat
N-3- (BOC-Phe-Gly-Ile-AHCP-amino) propyl-N-methyl-morpholiniumacetat

N-Benzyl-4- (BOC-Phe-Gly-Ile-AHCP-amino) -N-methyl-piperidinium acetate

3- (BOC-Phe-Gly-AHCP-Ile-aminomethyl) -N-methyl-pyridinium chloride, F. 138 °

N-2- (BOC-Phe-Gly-Ile-AHCP-amino) ethyl-pyridinium.

example 8

Analogously to Example 3 is obtained from BOC-Phe-Gly-AHCP-Ala-OH and N-2- (H-leu-amino) -ethyl-N, N, N-trimethylammonium chloride the N-2- (BOC-Phe-Gly-AHCP-Ala-Leu-amino) -ethyl-N, N, N- trimethyl ammonium chloride.

example 9

To a suspension of 1 g BOC-Phe-Gly-AHCP-Ile-N- (2- Dimethylaminoethyl) -amide in 12 ml of acetonitrile is added dropwise at 0 ° with stirring, a solution of 0.4 g of CH₃I in 2 ml Acetonitrile, stirred for 4 more hours at 20 °, evaporated, washes the crude product several times with ether, works as usual on and receives "A", f. 55-67 °.

The same product is analogous from equimolar amounts BOC-Phe-Gly-AHCP-Ile-N- (2-chloroethyl) -amide and trimethylamine receive.

Analogously, IPOC-Phe-Gly-AHCP-Ile- (3-bromopropyl ester) is obtained. and N-methylmorpholine the N-3- (IPOC-Phe-Gly-AHCP- Ile-oxy) -propyl-N-methyl-morpholiniumbromid.  

example 10

A solution of 1 g of N-2- (BOC-Phe-Gly-AHCP-Ile-amino) - ethyl-N, N, N-trimethylammonium acetate in 20 ml of 4N HCl in Dioxane is stirred for 30 min. At 20 ° and then evaporated. N-2- (H-Phe-Gly-AHCP-Ile-amino) -ethyl-N, N, N- trimethylammonium chloride hydrochloride.

example 11

Analogously to Example 2, from N-2 (CBZ-Phe-Gly-AHCP- Ile-amino) -ethyl-N, N, N-trimethylammonium acetate Hydrogenolysis the N-2- (H-Phe-Gly-AHCP-Ile-amino) -ethyl- N, N, N-trimethylammonium.

example 12

A solution of 751 mg of N-2- [N- (3-oxo-4S-BOC-Phe-Gly-amino- 5-cyclohexylpentanoyl) -Ile-amino] ethyl-N, N, N-trimethylammoniumchlor-id and 1.43 g Na₂CO₃ · 10 H₂O in 5 ml of methanol and 5 ml of water and is combined with 70 mg of hydroxylamine hydrochloride mixed and stirred for 14 hrs. At 20 °. The failed one Oxime is filtered off, dried, in 10 ml of methanol dissolved and hydrogenated at 0.5 g Raney Ni at 20 ° and 5 bar. The catalyst is filtered off, the filtrate is evaporated, separates the resulting mixture on silica gel and obtains N-2 [N- (3S-amino-4S-BOC-Phe-Gly-amino-5-cyclohexylpentanoyl) - Ile-amino] -ethyl-N, N, N-trimethyl-ammonium chloride ["N-2 (BOC-Phe-Gly-Ile-DACP-amino) ethyl-N, N, N-trimethylammonium chloride "]; - besides, one obtains the 3R amino epimer.

Analogously, one obtains from the corresponding oxo compounds:

N-2- (BOC-Phe-Gly-Ile-DACH-amino) ethyl-N, N, N-trimethylammoniumchlori-d,
N-2- (BOC-Phe-Gly-Ile-DAMH-amino) ethyl-N, N, N-trimethylammoniumchlori-d,
N-2- (BOC-Phe-Gly-Ile-DAPP-amino) ethyl-N, N, N-trimethylammoniumchlori-d.

example 13

Analogously to Example 2, but in acetic acid instead of ethanol, obtained by hydrogenolysis of BOC-Phe-imi-BOM- His-AHCP-Ile-AMPA-methoiodide the BOC-Phe-His-AHCP-Ile- AMPA methoacetate, mp 121 °.

Analogously obtained by hydrogenolysis of the Methoiodide the corresponding imi-BOM derivatives are the methoacetates following connections:

6-aminohexanoyl-Phe-His-Ile-AMPA AHCP-
6-aminohexanoyl-Phe-His-Leu-AMPA AHCP-
6-Dimethylaminohexanoyl-Phe-His-Ile-AMPA AHCP-
6-Dimethylaminohexanoyl-Phe-His-Leu-AMPA AHCP-
6-aminohexanoyl-Phe-His-AHCP-Ile (N-2-pyridylmethylamide)
6-aminohexanoyl-Phe-His-Leu-AHCP (N-2-pyridylmethylamide)
6-aminohexanoyl-Phe-His-AHCP-Ile (N-3-pyridylmethylamide)
6-aminohexanoyl-Phe-His-Leu-AHCP (N-3-pyridylmethylamide)
6-aminohexanoyl-Phe-His-AHCP-Ile (N-4-pyridylmethylamide)
6-aminohexanoyl-Phe-His-Leu-AHCP (N-4-pyridylmethylamide)
6-Aminohexanoyl-Phe-His-AHCP-Ile- (N-2-hydroxy-4,6-dimethyl-3-pyridylmethylamide)
6-Aminohexanoyl-Phe-His-AHCP-leu- (N-2-hydroxy-4,6-dimethyl-3-pyridylmethylamide).

example 14

Analogously to Example 3, 4-dimethylaminobutyryl-Phe-Gly-AHCP-Ile-AMPA-methoiodide is obtained from 4-dimethylaminobutyric acid and H-Phe-Gly-AHCP-Ile-AMPA-methiodide.
Analogously you get:

4-dimethylaminobutyryl-Phe-Gly-AHCP-Ile-ADPA-methoiodide
4-dimethylaminobutyryl-Phe-Gly-Leu-AHCP-AMPA-methoiodide
4-dimethylaminobutyryl-Phe-Gly-Leu-AHCP-ADPA-methoiodide
4-Dimethylaminobutyryl-Phe- β Ala-AHCP-Ile-AMPA-methoiodide
4-Dimethylaminobutyryl-Phe- β Ala-AHCP-Ile-ADPA-methoiodide
4-Dimethylaminobutyryl-Phe- β Ala-AHCP-leu-AMPA-methoiodide
4-Dimethylaminobutyryl-Phe- β Ala-AHCP-Leu-ADPA-methoiodide
6-Dimethylaminohexanoyl-Phe-Gly-AHCP-Ile-AMPA-methoiodide
6-Dimethylaminohexanoyl-Phe-Gly-Leu-AHCP-AMPA-methoiodide
6-Dimethylaminohexanoyl-Phe- β Ala-AHCP-Ile-AMPA-methoiodide
6-Dimethylaminohexanoyl-Phe- β Ala-AHCP-leu-AMPA-methoiodide.

example 15

Analogously to Example 9 is obtained from 6-BOC-aminohexanoyl-Phe-Gly-AHCP-Ile- (N-3-pyridylmethylamide) and CH₃I the corresponding methoiodide, Zers. at 96 °.
Analog obtained

BOC-Phe-Gly-AHCP-Ile-AMPA-methochloride, mp 150 °
4-BOC-aminobutyryl-Phe-Gly-AHCP-Ile-AMPA-methoiodide
4-BOC-aminobutyryl-Phe-Gly-AHCP-Ile-ADPA-methoiodide
4-BOC-aminobutyryl-Phe-Gly-Leu-AHCP-AMPA-methoiodide
4-BOC-aminobutyryl-Phe-Gly-Leu-AHCP-ADPA-methoiodide
6-BOC-aminohexanoyl-Phe-Gly-AHCP-Ile-AMPA-methoiodide, m.p. 111 °
6-BOC-aminohexanoyl-Gly-Phe-AHCP-Ile-ADPA-methoiodide
6-BOC-aminohexanoyl-Phe-Gly-AHCP-Ile- (N-2-pyridylmethylamide) -methoiodide
6-BOC-aminohexanoyl-Phe-Gly-AHCP-Ile- (N-4-pyridylmethyl-amide) -methoiodide
6-BOC-aminohexanoyl-Phe-Gly-AHCP-Ile- (N-2-hydroxy-4,6-dimethyl-3-pyridylmethylamide) -methoiodide
6-BOC-aminohexanoyl-Gly-Phe-Leu-AHCP-AMPA-methoiodide
6-BOC-aminohexanoyl-Gly-Phe-Leu-AHCP-ADPA-methoiodide
6-BOC-aminohexanoyl-Phe-Gly-AHCP-leu- (N-2-pyridylmethylamide) -methoiodide
6-BOC-aminohexanoyl-Phe-Gly-AHCP-leu- (N-3-pyridylmethylamide) -methoiodide
6-BOC-aminohexanoyl-Phe-Gly-AHCP-leu- (N-4-pyridylmethylamide) -methoiodide
6-BOC-aminohexanoyl-Phe-Gly-AHCP-leu- (N-2-hydroxy-4,6-dimethyl-3-pyridylmethylamide) -methoiodide
6-BOC-aminohexanoyl-Phe- β Ala-AHCP-Ile-AMPA-methoiodide
6-BOC-aminohexanoyl-Phe- β Ala-AHCP-Ile-ADPA-methoiodide
6-BOC-aminohexanoyl-Phe- β Ala-AHCP-Ile- (N-2-pyridylmethylamide) -methoiodide
6-BOC-aminohexanoyl-Phe- β Ala-AHCP-Ile- (N-3-pyridylmethylamide) -methoiodide
6-BOC-aminohexanoyl-Phe- β Ala-AHCP-Ile- (N-4-pyridylmethylamide) -methoiodide
6-BOC-aminohexanoyl-Phe- β Ala-AHCP-Ile- (N-2-hydroxy-4,6-dimethyl-3-pyridylmethyl-amide) -methoiodide
6-BOC-aminohexanoyl-Phe- β Ala-AHCP-leu-AMPA-methoiodide
6-BOC-aminohexanoyl-Phe- β Ala-AHCP-Leu-ADPA-methoiodide
6-BOC-aminohexanoyl-Phe- β Ala-AHCP-leu- (N-2-pyridylmethylamide) -methoiodide
6-BOC-aminohexanoyl-Phe- β Ala-AHCP-leu- (N-3-pyridylmethylamide) -methoiodide
6-BOC-aminohexanoyl-Phe- β Ala-AHCP-leu- (N-4-pyridylmethylamide) methoiodide
6-BOC-aminohexanoyl-Phe- β Ala-AHCP-leu- (N-2-hydroxy-4,6-dimethyl-3-pyridylmethylamide) -methoiodide
8-BOC-aminooctanoyl-Phe-Gly-AHCP-Ile-AMPA-methoiodide
8-BOC-aminooctanoyl-Phe-Gly-AHCP-Ile-ADPA-methoiodide
8-BOC-aminooctanoyl-Phe-Gly-Leu-AHCP-AMPA-methoiodide
8-BOC-aminooctanoyl-Phe-Gly-Leu-AHCP-ADPA-methoiodide.

example 16

By standing for one week an ethanolic solution of 2-tert-butylamino-3-phenylpropionyl-Gly-AHCP Ile-AMPA with excess CH₃I gives the corresponding (Mono) -methiodide, mp 180 °.

example 17

A solution of 1 g (2-benzyl-4-oxo-5,5, -dimethyl-hexanoyl) - imi-tert-butoxy-methyl-His-AHCP-Ile-AMPA-methoiodide [available by condensation of 2-benzyl-4-oxo-5,5-dimethyl hexanoic acid with H- (imi-tert-butoxymethyl-His) -AHCP-Ile- AMPA and subsequent reaction with CH₃I] in 20 ml of 4N HCl in dioxane is stirred for 30 min. At 20 ° and then evaporated. 2-Benzyl-4-oxo-5,5-dimethyl-hexanoyl-His-AHCP- Ile-AMPA methochloride hydrochloride, Zers. at 102 °.

Analogously, by cleavage of the methoiodides of the corresponding BOC-amino derivatives:

4-aminobutyryl-Phe-Gly-AHCP-Ile-AMPA methochloride
4-aminobutyryl-Phe-Gly-AHCP-Ile-ADPA methochloride
4-aminobutyryl-Phe-Gly-Leu-AHCP-AMPA methochloride
4-aminobutyryl-Phe-Gly-Leu-AHCP-ADPA methochloride
6-aminohexanoyl-Phe-Gly-AHCP-Ile-AMPA-methochloride, dihydrochloride, dec. at 102 °
6-aminohexanoyl-Gly-Phe-AHCP-Ile-ADPA methochloride
6-Aminohexanoyl-Phe-Gly-AHCP-Ile- (N-2-pyridylmethylamide) -methochloride
6-Aminohexanoyl-Phe-Gly-AHCP-Ile- (N-3-pyridylmethyl-amide) -methochloride, dihydrochloride, dec. at 105 °
6-Aminohexanoyl-Phe-Gly-AHCP-Ile- (N-4-pyridylmethyl-amide) -methochloride
6-Aminohexanoyl-Phe-Gly-AHCP-Ile- (N-2-hydroxy-4,6-dimethyl-3-pyridylmethyl-amide) -methochloride
6-aminohexanoyl-Gly-Phe-Leu-AHCP-AMPA methochloride
6-aminohexanoyl-Gly-Phe-Leu-AHCP-ADPA methochloride
6-aminohexanoyl-Phe-Gly-AHCP-leu- (N-2-pyridylmethylamide) methochloride
6-Aminohexanoyl-Phe-Gly-AHCP-leu- (N-3-pyridylmethylamide) methochloride
6-Aminohexanoyl-Phe-Gly-AHCP-leu- (N-4-pyridylmethylamide) methochloride
6-aminohexanoyl-Phe-Gly-AHCP-leu- (N-2-hydroxy-4,6-dimethyl-3-pyridylmethyl-amide) -methochloride
8-Aminooctanoyl-Phe-Gly-AHCP-Ile-AMPA methochloride
8-Aminooctanoyl-Phe-Gly-AHCP-Ile-ADPA methochloride
8-Aminooctanoyl-Phe-Gly-Leu-AHCP-AMPA methochloride
8-Aminooctanoyl-Phe-Gly-Leu-AHCP-ADPA methochloride.

The following examples relate to pharmaceutical Preparations.  

Example A: Injection glasses

A solution of 100 g of N-2- (BOC-Phe-Gly-AHCP-Ile-amino) - ethyl-N, N, N-trimethylammonium acetate and 5 g disodium hydrogen phosphate in 4 liters of double-distilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered and filled into injection jars. It is lyophilized under sterile conditions and occludes sterile. Each injection jar contains 500 mg active substance.

Example B: Suppositories

A mixture of 50 g of N-2 (BOC-Phe-Gly-ACHP) is melted. Ile-amino) -ethyl-N, N, N-trimethylammonium chloride with 10 g Soya lecithin and 140 g of cocoa butter, pour into molds and lets cool. Each suppository contains 250 mg of active ingredient.

Example C: Tablets

A mixture of 1 kg of 6-aminohexanoyl-Phe-Gly-AHCP-Ile- AMPA methochloride dihydrochloride, 4 kg lactose, 1.2 kg Corn starch, 200 g of talc and 100 g of magnesium stearate compressed in the usual way to tablets, such that Each tablet contains 100 mg of active ingredient.

Example D: dragees

Tablets are pressed analogously to Example A, which are subsequently in the usual way with a coating of sucrose, Corn starch, talc, tragacanth and dye are coated.  

Example E: Capsules

500 g of 6-aminohexanoyl-Phe-Gly-AHCP-Ile- (N-3-pyridyl- methylamide) -methochloride dihydrochloride are in common Way filled in hard gelatin capsules, so that Each capsule contains 500 mg of active ingredient.

Claims (7)

1. Amino acid derivatives of the formula I R¹-ZM-NR²-CHR³-CR⁴- (CHR⁵) _n -CO-EQY An⊖ (I) wherein
R¹ R⁶, R⁶-OC _m H _{2 m} -CO-, R⁶-C _m H _{2 m} -O-CO-, R⁶-C _m H _{2 m} -CO-, R⁶-SO₂-, (R⁶-C _m H _{2 m} - (T) _x - (G) _y --C _r H _{2 r} ) -L (R⁷-C _p H _{2 p} ) -C _t H _{2 t} -CO-, R⁶- (NHCH₂CH₂) _m - NHCH₂CO-, or 9-fluorenyl-C _m H _{2 m} -O-CO-,
Z 0 to 3 peptide-like interconnected amino acid residues selected from the group consisting of Abu, Ada, Ala, Ala, Arg, Asn, Asp, Bia, Cal, Dab, Gln, Glu, Gly, His, N β (im) -A- His, Ile, Leu, tert.-Leu, Lys, Met, α Nal, β-Nal, Nbg, Nle, Orn, Phe, Pia, Pro, Pya, Ser, Thr, Tic, Trp, Tyr and Val,
M β Ala, Gly, Pia or Pya, or, if Y in the radical Y is an R⁸N⊕ group instead of an N atom of a het-ylene group, also His,
E 0 to 2 peptide-like linked amino acid residues selected from the group consisting of Abu, Ala, Cal, His, Ile, Leu, Met, Nle, Nva, Phe, Trp, Tyr and Val,
Q is O or NH,
Y is an alkylene chain in which also a CH₂ group can be replaced by an arylene group or hetylene group, having a total of 1-20 C atoms, which by a R⁸R⁹R¹⁰N⊕ group or an unsubstituted or one or more times by A , AO and / or Hal substituted pyridinium group is substituted, and / or in which instead of an N atom of a het- ylengruppen a R⁸N⊕ group,
An⊖ an anion, which may also be absent, if, instead, a carboxy group present in the compound of formula I carboxy is present,
R³, R⁶ and R⁷ are each H, A, Ar, Aralkyl, Het, Het-alkyl, unsubstituted or mono- or polysubstituted by A, AO and / or Hal, cycloalkyl having 3-7 C atoms, cycloalkylalkyl having 4- 11 C atoms, bicycloalkyl or tricycloalkyl having in each case 7-14 C atoms, bicycloalkylalkyl or tricycloalkylalkyl having in each case 8-18 C atoms,
R² and R⁵ are each H or A,
R⁴ (H, OH), (H, NH₂) or = O,
R⁸, R⁹ and R¹⁰ are each alkyl having 1-18 C atoms or Ar-alkyl, two of the radicals R⁸, R⁹ and R¹⁰ together also an alkylene group having 2-8 C-atoms, which by an O atom or by a NR¹- Group can be interrupted,
R¹¹ is H, A, Ar or Aralkyl,
L is CH or N,
T O, S, NH or NA,
G is CO, S, SO or SO₂,
n 1 or 2,
m, p, r and t are each 0, 1, 2, 3, 4 or 5,
x and y are each 0 or 1,
Ar unsubstituted or mono- or polysubstituted by A, AO, Hal, CF₃, OH, H₂NSO₂ and / or NH₂ substituted phenyl or unsubstituted naphthyl,
Het a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N-, O- and / or S-atoms, which condenses with a benzene ring and / or one or more times by A, AO, Hal, CF₃, HO, O₂N, carbonyl oxygen, H₂N, HAN, A₂N, AcNH, AS, ASO, ASO₂, HOOC, AOOC, CN, H₂NCO, H₂NSO₂, ASO₂NH, Ar, Ar-alkyl, ar-alkenyl, hydroxyalkyl and / or aminoalkyl, each with 1 -8 carbon atoms may be substituted and / or its N and / or S heteroatoms may also be oxidized,
Hal F, Cl, Br or J,
Ac A-CO, Ar-CO or A-NH-CO-,
alkyl- an alkylene group having 1-4 C atoms and
A is alkyl having 1-8 C atoms,
in which, instead of one or more -NH-CO groups, one or more NA-CO groups may also be present,
and their salts. Second

• a) Salts of N-2- (BOC-Phe-Gly-AHCP-Ile-amino) - ethyl-N, N, N-trimethylammonium hydroxide.
• b) Salts of N-3- (BOC-Phe-Gly-AHCP-Ile-amino) -propyl-N, N, N-trimethylammonium hydroxide.
• c) Salts of N-2- (BOC-Phe-3-Pya-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium hydroxide.
• d) Salts of N-methyl-3- (6-aminohexanoyl-Phe-Gly-AHCP-Ile-aminomethyl) pyridinium hydroxide.
• e) Salts of 1,2- (or 2,3-) dimethyl-4-amino-5- (6-aminohexanoyl-Phe-Gly-AHCP-Ile-amino-methyl) -pyrimidinium hydroxide.

3. A process for the preparation of an amino acid derivative of the formula I and of its salts, characterized in that it sets free from one of its functional derivatives by treatment with a solvolysierenden or hydrogenolyzing agent or that a carboxylic acid of formula II R¹-G¹-OH (II) wherein
G¹ (a) Z¹,
(b) Z,
(c) ZM,
(d) ZMW,
(e) ZMW-E¹,
(f) ZMWE and
W-NR²-CHR³-CR⁴- (CHR⁵) _n -CO- mean
with an amino compound of the formula IIIH-G² (III) in which
G² (a) -Z²-MWEQY,
(b) -MWEQY,
(c) -WEQY,
(d) -EQY,
(e) -E 2 -QY,
(f) -NH-Y,
E¹ + E² together E and
Z¹ + Z² together Z mean
implements,
or treating a tertiary amine otherwise of formula I with a quaternizing agent,
and optionally optionally freezing a functionally modified amino and / or hydroxy group in a compound of the formula I by treatment with solvolysing or hydrogenolysing agents and / or for preparing a compound of the formula I, R⁴ = (H, OH) or (H , NH₂) a Aminoketosäurederivat of formula I, R⁴ = O, reduced or reductively aminated and / or converted a compound of formula I by treatment with an acid in one of its salts and / or in a compound of formula I an anion An⊖ against a other anion exchanges. 4. Process for the preparation of pharmaceutical preparations, characterized in that one has a compound of the formula I and / or one of their physiological harmless salt together with at least a solid, liquid or semi-liquid carrier or excipient and optionally in combination with one or more other active substance (s) in brings a suitable dosage form.   5. Pharmaceutical preparation, characterized by a content of at least one compound of Formula I and / or one of its physiologically harmless Salts. 6. Use of compounds of the formula I or of their physiologically acceptable salts for the production of a medicine. 7. Use of compounds of the formula I or of their physiologically harmless salts in the Combat renin-dependent hypertension or of hyperaldosteronism.