DE3619508A1 - Amino acid derivatives - Google Patents

Abstract

Amino acid derivatives of the formula I X-NR<2>-CHR<3>-CO-Z-(CH2)m-CO-NR<4>-CHR<5>-CR<6>-(CHR<7>)n -CO-E-Q-Y I in which X, Z, E, Q, Y, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, m and n have the meanings stated in Claim 1, and their salts inhibit the activity of human plasma renin.

Description

The invention relates to new amino acid derivatives Formula I.

X-NR ² -CHR ³ -CO-Z- (CH ₂ ) _m -CO-NR ⁴ -CHR ⁵ -CR ⁶ - (CHR ⁷ -) _n -CO-EQY (I)

wherein
X H, R ¹ -OC _m H _{2 m} -CO-, R ¹ -C _m H _{2 m} -O-CO-, R ¹ -C _m H _{2 m} -CO-, R ¹ -SO ₂ -, (R ¹ -C _m H _{2 m} ) -L (R ¹ -C _p H _{2 p} ) -C _r H _{2 r} -CO-, R ¹ - (NHCH ₂ CH ₂ ) _m -NH-CH ₂ CO- or 9-fluorenyl -C _m H _{2 m} -O-CO-,
Z -O-, -CH ₂ -, -CH = CH-, -NR ⁸ -, -CH ₂ -O-, -CH ₂ -NR ⁸ - or -CH ₂ -S-,
E 0 to 2 amino acid residues linked together in peptides selected from the group consisting of Abu, Ala, Cal, His, Ile, Leu, Met, Nle, Phe, Trp, Tyr and Val,
Q O or NH,
Y -C _t H _{2 t} -R ⁹ or -C _w H _{2 w} - (CR ¹¹ ) _s -C _{t -} H _{2 t} - R ⁹ ,
R ¹ , R ³ , R ⁵ and R ^{9 in} each case H, A, Ar, Ar-alkyl, Het, Het-alkyl, unsubstituted or mono- or polysubstituted by A, AO and / or Hal cycloalkyl with 3-7 C- Atoms, cycloalkylalkyl with 4-11 C atoms, bicycloalkyl or tricycloalkyl, each with 7-14 C atoms, bicycloalkylalkyl or tricycloalkylalkyl, each with 8-18 C atoms,
R ² , R ⁴ , R ⁷ , R ⁸ and R ^{10 are} each H or A,
R ⁶ and R ¹¹ each (H, OH), (H, NH ₂ ) or = O,
L CH or N,
m, p, r and t each 0, 1, 2, 3, 4 or 5,
n and s each 1 or 2,
w 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
Ar unsubstituted or mono- or polysubstituted by A, AO, Hal, CF ₃ , HO, hydroxyalkyl with 1-8 C atoms, H ₂ N and / or aminoalkyl with 1-8 C atoms or unsubstituted naphthyl,
Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical with 1-4 N, O and / or S atoms, which condenses with a benzene ring and / or one or more times by A, AO, Hal, CF ₃ , HO, O ₂ N, carbonyl oxygen, H ₂ N, HAN, A ₂ N, AcNH, AS, ASO, ASO ₂ , AOOC, CN, H ₂ NCO, HOOC, H ₂ NSO ₂ , ASO ₂ NH, Ar, Ar alkenyl, hydroxyalkyl and / or aminoalkyl can each be substituted with 1-8 C atoms and / or its N and / or S heteroatoms can also be oxidized,
Hal F, Cl, Br or J,
Ac A-CO-, Ar-CO- or A-NH-CO- and
A is alkyl with 1-8 C atoms,
and their salts.

Similar compounds are known from EP-A-1 63 237.

The object of the invention was to create new connections with valuable properties, especially those used in 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 they all inhibit the activity of human plasma arsenin. This effect can e.g. B. by the method of F. Fyhrquist et. al., Clin. Chem. 22, 250-256 (1976), be detected. It is noteworthy that these connections are very specific inhibitors of renin; For the inhibition of other aspartyl proteinases (e.g. pepsin and cathepsin D) are usually much higher Concentrations of these compounds are necessary.  

The compounds can be used as active pharmaceutical ingredients in human and veterinary medicine are used, in particular for the prophylaxis and treatment of cardiac, Circulatory and vascular diseases, especially hypertension, Heart failure and hyperaldosteronism. Furthermore can use the connections 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 abbreviations of Amino acid residues stand for the residues -NH-CHR-CO- (where R the specific meaning known for each amino acid has) the following amino acids:

Abu2-aminobutyric acid AlaAlanin CalCyclohexylalanin GlyGlycin HisHistidin IleIsoleucin LeuLeucin MetMethionin α Nal α -Naphthylalanin β Nal β -Naphthylalanin NleNorleucin PhePhenylalanin TrpTryptophanVyralinTyrosine.

Furthermore, below means:

BOCtert.-butoxycarbonyl imi-BOMBenzyloxymethyl in the 3-position of the imidazole ring CBZ benzyloxycarbonyl DNP2,4-dinitrophenyl imi-DNP2,4-dinitrophenyl in the 1-position of the imidazole ring FMOC9 fluorenylmethoxycarbonyl IPOC isopropoxycarbonyl OMe methyl ester OEtEthylester POAPhenoxyacetyl DCCIDicyclohexylcarbodiimide HOBt1-hydroxybenzotriazole.

If the above amino acids in several enantiomeric forms can occur, so are pre- and below, e.g. B. as part of the compounds of Formula I, all of these forms and also their mixtures (e.g. the DL forms) included. The L-shapes are preferred. If individual connections are listed below are the abbreviations of these amino acids each on the L-shape, unless expressly something else is specified.

Above and below, the residues or parameters have X, Z, E, Q, Y, R ¹ to R ¹¹ , L, m, n, p, r, s, t , Ar, Het, Hal, A, G ¹ , G ² , W, Z ¹ , E ¹ and E ^{2 have} the meanings given in the formulas I, II or III, unless expressly stated otherwise. If two radicals R ^{1 are present} in a compound of the formula I, they can be identical or different.

In the above formulas, A has 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, 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 preferably means cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl or cycloheptyl, but also e.g. B. 1-, 2- or 3-methylcyclopentyl, 1-, 2-, 3- or 4-methylcyclohexyl.

Accordingly, cycloalkyl-alkyl preferably means Cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 2-cyclopentylethyl, Cyclohexylmethyl, 2-cyclohexylethyl, but also e.g. B. 1-, 2- or 3-methylcyclopentylmethyl, 1-, 2-, 3- or 4-methylcyclohexylmethyl.

Bicycloalkyl preferably means 1- or 2-decalyl, 2-bicyclo [2,2,1] heptyl or 6,6-dimethyl-2-bicyclo- [3.1.1] heptyl.

Tricycloalkyl preferably means 2-adamantyl.

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

Ac preferably means 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- such as N-methyl- or N-ethyl carbamoyl.  

Ar is preferably phenyl, more 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-hydroxymethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, o-, m- or p-aminophenyl, o-, m- or p-aminomethylphenyl, 1- or 2-naphthyl.

Accordingly, Ar-alkyl preferably means 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, o-, m- or p-hydroxymethylbenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, o-, m- or p-aminobenzyl, o-, m- or p-aminomethylbenzyl, 1- or 2-naphthylmethyl.

Het is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrryl, 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-pyrimidyl, further preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,  1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 2,1,5- Thiadiazol-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-benzothienyl, 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-benzothiazolyl, 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-chinnolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolyl. The heterocyclic radicals can also be partially or completely be hydrated. Het can, for. 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, 2,5-dihydro-1-, -2-, -3-, -4- or 5-pyrazolyl, Tetrahydro-1-, -3-, or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetryhydro-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-dioxan-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 can also be as indicated be substituted. Het can also preferably 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 z. 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-pyrryl, 1-methyl-4- or -5-nitro-2-pyrryl, 3,5-dimethyl-4-ethyl-2-pyrryl, 4-methyl-5-pyrazolyl, 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-dichloropyridyl, 2-hydroxy-3-, -4-, -5- or -6-pyridyl (= 1H-2-pyridon-3-, -4-, -5- or -6-yl), 5-phenyl-1H-2-pyridon-3-yl, 5-p-methoxyphenyl-1H-2-pyridon-3-yl, 2-methyl-3-hydroxy- 4-hydroxymethyl-5-pyridyl, 2-hydroxy-4-amino-6-methyl-3- pyridyl, 3-N'-methylureido-1H-4-pyridon-5-yl, 5- or 6-methyl-4-pyrimidyl, 2,6-dihydroxy-4-pyrimidyl, 5-chloro 2-methyl-4-pyrimidyl, 2-methyl-4-amino-5-pyrimidyl, 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.  

R ¹ preferably denotes A, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, further preferably cyclopropyl, cyclopentyl, cyclohexyl, methylcyclohexyl such as trans-4-methylcyclohexyl, tert. Butylcyclohexyl such as trans-4-tert-butylcyclohexyl, phenyl or benzyl.

R ² , R ⁴ , R ⁷ , R ⁸ and R ^{10 are} preferably H or methyl, furthermore ethyl, propyl, isopropyl, butyl or isobutyl.

R ³ and R ^{5 are} preferably cyclohexylmethyl, further preferably A, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl (3-methylbutyl) or 2-methylbutyl, phenyl, benzyl, p- Chlorobenzyl, 1- or 2-naphthylmethyl, 2-phenylethyl, 3-phenylpropyl, 2-cyclohexylethyl, 1- or 2-decalylmethyl, bicyclo [2,2,1] heptyl-2-methyl or 6,6-dimethylbicyclo [3, 1,1] heptyl-2-methyl. In particular, R ^{3 is} preferably benzyl, R ^{5 is} preferably cyclohexylmethyl.

R ⁶ is preferably (H, OH).

R ⁹ is preferably H, A or Het.

R ¹¹ is preferably = O.

L is preferably CH.

Q is preferably NH.

E is preferably absent or preferably means one of the indicated amino acid residues, especially Ile.  

The parameters m, p and r are preferably 0, 1 or 2; n and s are preferably 1. The groups C _t H _{2 t} and C _w H _{2 w} are each preferably -CH ₂ -, - (CH ₂ ) ₂ -, -CH (CH ₃ ) -, -CH (isobutyl) - or -CH (sec-butyl).

X preferably denotes H, POA, alkoxycarbonyl such as IPOC or BOC, CBZ, alkanoyl such as acetyl, propionyl, butyryl or isobutyryl, cycloalkylcarbonyl such as cyclopentylcarbonyl or cyclohexylcarbonyl, aroyl such as benzoyl, Arylalkanoyl such as phenylacetyl, 2- or 3-phenylpropionyl, 4-phenylbutyryl, 2-benzyl-3-phenylpropionyl, 2-benzyl-4- phenylbutyryl, 2- (2-phenylethyl) -4-phenylbutyryl, 2- (2-naphthylmethyl) -4-phenylbutyryl, 2- or 3-o-, -m- or -p-fluorophenylpropionyl, 2- or 3-o-, -m- or p-chlorophenylpropionyl, cycloalkylalkanoyl such as cyclohexylacetyl, 2- or 3-cyclohexylpropionyl, FMOC. Especially preferred radicals X are H and BOC, furthermore POA, 4-phenylbutyryl, 2-benzyl-3-phenylpropionyl, 2-benzyl-4- phenylbutyryl, 2- (2-phenylethyl) -4-phenylbutyryl, 2- (2-naphthylmethyl) -4-phenylbutyryl and CBZ.

The group -NR ² -CHR ³ -CO- preferably means Phe, further preferably Cal, α Nal or β Nal.

Z preferably denotes -NR ⁸ -, in particular NH, further preferably -CH ₂ -, -CH ₂ -O-, -CH ₂ -NR ⁸ - (in particular -CH ₂ -NH-) or -CH ₂ -S-.

Accordingly, the group -Z- (CH ₂ ) _m denotes -CO- preferably Gly, further preferably -CH ₂ CH ₂ CO-, -CH ₂ -O-CH ₂ CO-, -CH ₂ -Gly-, -NH-CO -, -CH ₂ -NH-CO- or -CH ₂ -S-CH ₂ -CO-.
-

The group W preferably denotes -NH-CHR ⁵ -CHOH-CH ₂ -CO-, in particular -NH-CH (cyclohexylmethyl) -CHOH-CH ₂ -CO- ("AHCP", derived from 4-amino-3-hydroxy- 5-cyclohexylpentanoic acid), also -NH-CH (CH ₂ CH ₂ -cyclohexyl) -CHOH-CH ₂ -CO- ("AHCH"; derived from 4-amino-3-hydroxy-6-cyclohexyl-hexanoic acid), -NH -CH (isobutyl) -CHOH-CH ₂ -CO- ("Sta"; derived from statin) or -NH-CH (benzyl) -CHOH-CH ₂ -CO ("AHPP"; derived from 4-amino-3- hydroxy-5-phenylpentanoic acid). The group W also preferably denotes -NH-CHR ⁵ -CH (NH ₂ ) -CH ₂ -CO-, in particular -NH-CH (cyclohexylmethyl) -CH (NH ₂ ) -CH ₂ -CO- ("DACP"; derived of 3,4-diamino-5-cyclohexylpentanoic acid), -NH-CH (CH ₂ CH ₂ -cyclohexyl) -CH (NH ₂ ) -CH ₂ -CO- ("DACH"; derived from 3,4-diamino-6 -cyclohexylhexanoic acid), -NH-CH (isobutyl) -CH (NH ₂ ) -CH ₂ -CO- ("DAMH"; derived from 3,4-diamino-6-methylheptanoic acid) or -NH-CH (benzyl) -CH (NH ₂ ) -CH ₂ -CO- ("DAPP"; derived from 3,4-diamino-5-phenylpentanoic acid).

Group W has at least two chiral centers. The compounds of the formula I can therefore exist in various - optically inactive or optically active - forms. Formula I encompasses all of these forms. If W denotes -NH-CHR ⁵ -CR ⁶ -CH ₂ -CO- and R ⁶ (H, OH) or (H, NH ₂ ), the 3S-hydroxy-4S-amino enantiomers or 3S, 4S- Diamino enantiomers preferred. Unless otherwise stated in the description of individual substances, the abbreviations AHCP, AHCH, Sta, AHPP, DACP, DACH, DAMH and DAPP always refer to these 3S, 4S forms.

A particularly preferred meaning of the group X-NR ² -CHR ³ -CH-Z- (CH ₂ ) _m -CO-W- is BOC-Phe-Gly-AHCP.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Io, which correspond to formula I, but in which
in Ia X denotes BOC;
in Ib represents -NR ² -CHR ³ -CO- Phe;
in Ic represents -Z- (CH ₂ ) _m -CO- Gly;
in Id X-NR ² -CHR ³ -CO- Boc-Phe-;
in Ie denotes -NR ² -CHR ³ -CO-Z- (CH ₂ ) _m -CO- Phe-Gly-;
in If X is-NR ² -CHR ³ -CO-Z- (CH ₂ ) _m -CO- BOC-Phe-Gly-;
in Ig W means AHCP;
in Ih X-NR ² -CHR ³ -CO-Z- (CH ₂ ) _m -CO-W- BOC-Phe-Gly-AHCP-;
missing in Ij E or means Ile;
in Ik means EQ NH or Ile-NH;
in Il Y is H, 3-pyridylmethyl or 2-amino-5,6-dimethyl-3-pyrazinylmethyl;
in Im
XBOC or benzoyl, -NR ² -CHR ³ -CO-Phe, Z-NH-, -CH ₂ - or -CH ₂ -S-, m and n each 1, R ⁴ and R ⁷ each H R ⁵ A or cycloalkyl 6-10 C atoms, R ⁶ OH, missing, Ile or Ile-Phe, YH, A, C _t H _{2 t} Het or C _w H _{2 w} -CO-C _t H _{2 t} Het, t 1, 2, 3, 4 or 5, w 5 and HetPyridyl, 2-amino-5,6-dimethyl-3-pyrazinyl, 2-amino-4-thiazolyl, 4- (2-aminoethyl) -2-thiazolyl or 4-carbamoylpiperidino; in In
X-NR ² -CHR ³ -CO-Z- (CH ₂ ) _m -CO-WE-
WE-BOC-Phe-Gly-AHCP- or
BOC-Phe-Gly-AHCP-Ile means; in Io
X-NR ² -CHR ³ -CO-Z- (CH ₂ ) _m -CO-W-
W-BOC-Phe-Gly-AHCP-, Missing or Ile Q-YOH, OMe, NH ₂ , 3-pyridylmethylamino or 2-amino-5,6-dimethyl-3-pyrazinylmethylamino mean.

The invention further relates to a process for the preparation of an amino acid derivative of the formula I and of its salts, characterized in that it is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent
or that a carboxylic acid of formula II

X-NR ² -CHR ³ -G ¹ -OH (II)

where G ¹

• (a) -CO-,
• (b) -CO-Z- (CH ₂ ) _m -CO-,
• (c) -CO-Z- (CH ₂ ) _m -CO-W-,
• (d) -CO-Z- (CH ₂ ) _m -CO-WE ¹ -.
• (e) -CO-Z- (CH ₂ ) _m -CO-WE- and

W -NR ⁴ -CHR ⁵ -CR ⁶ - (CHR ⁷ ) _n -CO- mean
or one of their reactive derivatives
with a compound of formula III

HG ² (III)

where G ²

• (a) -Z ¹ - (CH ₂ ) _m -CO-WEQY,
• (b) -W-E-Q-Y,
• (c) -E-Q-Y,
• (d) -E ² -QY,
• (e) -Q-Y,

Z ¹ -O- or -NR ⁸ - and
E ¹ + E ² together mean E.
or one of their reactive derivatives,
and / or that a functionally modified amino and / or hydroxyl group is optionally liberated in a compound of the formula I by treatment with solvolysing or hydrogenolysing agents and / or a keto group is reduced to a CHOH group or to a CH (NH ₂ ) Group reductively aminated and / or a compound of formula I converted into one of its salts by treatment with an acid.

The compounds of formula I and also the starting materials for their manufacture are otherwise known per se Methods produced as described in the literature (e.g. in the standard works such as Houben-Weyl, methods 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 that are known and suitable for the above-mentioned implementations. It is also possible to do this from known ones, not here make use of the variants mentioned in more detail.

The starting materials can, if desired, also in situ are formed so that they can be removed from the reaction mixture not isolated, but immediately to the connections Formula I implemented.

The compounds of the formula I can thus be obtained by removing them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis sets you free.

Preferred starting materials for solvolysis or hydrogenolysis are those which, instead of one or more free amino and / or hydroxyl groups, contain corresponding protected amino and / or hydroxyl groups, preferably those which instead of an H atom which is linked to an N- Atom is attached, carry an amino protecting group, e.g. B. those which correspond to the formula I, but instead of a His group contain an N (im) -R ¹² -His group (in which R ^{12 is} an amino protecting group, for example BOM or DNP), or those of Formula X-NR ² -CHR ³ -CO-Z- (CH ₂ ) _m -CO-NR ⁴ -CHR ⁵ -CH (NHR ^-12 ) - (CHR ⁷ ) _n -CO-EQY.

Furthermore, starting materials are preferred which carry a hydroxyl protective group instead of the H atom of a hydroxyl group, e.g. B. those of the formula X-NR ² -CHR ³ -CO-Z- (CH ₂ ) _m - CO-NR ⁴ -CHR ⁵ -CHOR ¹³ - (CHR ⁷ ) _n -CO-EQY, wherein R ^{13 is} a hydroxy protecting group .

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

The term "amino protecting group" is well known and refers to groups that are suitable an amino group protect against chemical reactions (block), which are easily removable after the desired one chemical reaction elsewhere in the molecule has been carried out. Typical for such groups are in particular unsubstituted or substituted acyl, Aryl- (e.g. 2,4-dinitrophenyl), aralkoxymethyl- (e.g. Benzyloxymethyl) or aralkyl groups (e.g. benzyl, 4-nitrobenzyl, Triphenylmethyl). Since the amino protecting groups after the desired reaction (or reaction sequence) are removed, their type and size is otherwise not critical; prefers However, those with 1-20, in particular 1-8 C atoms. The term "acyl group" is related to the present To understand procedures in the broadest sense. It encloses of aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids Acyl groups and especially 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 phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC. Preferred amino protecting groups are DNP, BOM, CBZ, FMOC, benzyl and acetyl.  

The term "hydroxy protecting group" is also general known and refers to groups that are suitable are, a hydroxyl group before chemical reactions too protect, but are easily removable after the desired chemical reaction at other points in the molecule has been carried out. Typical for such groups are the above unsubstituted or substituted Aryl, aralkyl or acyl groups, and also alkyl groups. The nature and size of the hydroxy protecting groups is not critical since it is chemical-based Reaction or sequence of reactions are removed again; prefers are groups with 1-20, especially 1-10 carbon atoms. Examples of hydroxy protecting groups include a. Benzyl,  p-nitrobenzoyl, p-toluenesulfonyl and acetyl, with benzyl and acetyl are particularly preferred.

The functional derivatives to be used as starting materials of the compounds of the formula I can be prepared according to conventional Methods of amino acid and peptide synthesis be how they z. B. in the mentioned standard works and Patent applications are described.

The liberation of the compounds of formula I. their functional derivatives succeed - depending on the one used Protecting group - e.g. B. with strong acids, useful with trifluoroacetic acid or perchloric acid, however also with other strong inorganic acids such as 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 necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, Ethers such as tetrahydrofuran (THF) or dioxane, amides such as  Dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, also alcohols such as methanol, Ethanol or isopropanol and water. Mixtures also come of the aforementioned solvents in question. Trifluoroacetic acid is preferably in excess without addition another solvent used, perchloric acid in Form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the splits are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (Room temperature).

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

Hydrogenolytically removable protective groups (e.g. BOM, CBZ or benzyl) z. B. by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst like palladium, suitably on a support like Coal) can be split off. Are suitable as solvents the above, especially z. B. alcohols such as methanol or ethanol or amides such as DMF. Hydrogenolysis is usually 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 e.g. B. good at 5- up to 10% Pd-C in methanol at 20-30 °.  

Compounds of formula I can also be obtained from a carboxylic acid and an amine component by direct peptide synthesis. As carboxylic acid components are, for. B. those of the sub-formulas (a) X-NR ² -CHR ³ -COOH, (b) X-NR ² -CHR ³ -CO-Z- (CH ₂ ) _m -COOH, (c) X-NR ² -CHR ³ -CO-Z- (CH ₂ ) _m -CO-W-OH, (d) X-NR ² -CHR ³ -CO-Z- (CH ₂ ) _m -CO - WE ¹ -OH or (e) X-NR ² -CHR ³ -CO-Z- (CH ₂ ) _m -CO-WE-OH, as amine components those of the partial formulas (a) Z ¹ - (CH ₂ ) _m -CO-WE- QY, (b) HWEQY, (c) HEQY, (d) HE ² -QY or (e) HQY. In case (d) the peptide bond can be linked within group E if E consists of two of the amino acid residues indicated; a carboxylic acid is reacted with an amine of the formulas given under (d), E ¹ and E ² each representing one of the amino acid residues given in the definition of E and E ¹ + E ² = E. It is convenient to work according to conventional methods of peptide synthesis, such as. B. in Houben-Weyl, 1.c., volume, volume 15 / II, pages 1 to 806 (1974) are described.

The reaction is preferably carried out in the presence of a Dehydrating agent, e.g. B. a carbodiimide such as DCCI or dimethylaminopropylethyl carbodiimide, further Propanephosphonic acid hydride (cf. Angew. Chem. 92, 129 (1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl- 1,2-dihydroquinoline, in an inert solvent, e.g. B. a halogenated hydrocarbon such as  Dichloromethane, an ether such as THF or dioxane, one Amide such as DMF or dimethylacetamide, a nitrile like Acetonitrile, at temperatures between about -10 and 40, preferably between 0 and 30 °.

Instead of II or III, suitable reactive ones can also be used Derivatives of these substances in the reaction are used, e.g. B. those in which reactive Groups are temporarily blocked by protective groups. The amino acid derivatives III can e.g. B. in the form of their activated esters are used, which are conveniently in situ be formed, e.g. B. by adding 1-hydroxybenzotriazole or N-hydroxysuccinimide.

Urea derivatives of the formula I [-Z- (CH ₂ ) _m - = -CH ₂ -NH-] are obtainable from the corresponding cyanates of the formulas X-NR ² -CHR ³ -CO-CH ₂ -NCO, which consist of the corresponding bromides and KNCO can be prepared (preferably in situ), and the amino compounds of the formula HWEQY.

Most of the starting materials of formulas II and III are known. If they are not known, they can go to known methods, e.g. B. the methods given above peptide synthesis and deprotection, getting produced.

If desired, in a compound of formula I a functionally modified amino and / or hydroxy group by solvolysis or hydrogenolysis after one released from the methods described above will.  

In particular, a compound of the formula I in which X is different from H, into a compound of formula I. (X = H) are converted, advantageously by hydrogenolysis, if X = CBZ, otherwise by selective solvolysis. If X = BOC, one can e.g. B. with HCl in dioxane Split off the BOC group at room temperature.

In a compound of formula I, a keto group can also be reduced to a CHOH group, for example with a complex metal hydride such as NaBH ₄ , which does not simultaneously reduce the peptide carbonyl groups, in an inert solvent such as methanol at temperatures between about -10 and + 30 °.

A keto group in a compound of formula I can also be converted to a CH (NH ₂ ) group by reductive amination. One can reductively amine in one or more stages. So you can z. B. the keto compound with ammonium salts, e.g. B. treat ammonium acetate and NaCNBH ₃ , 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, it is possible to convert the keto compound with hydroxylamine in the usual way into the oxime and this, z. B. by catalytic hydrogenation on Raney nickel to reduce the amine.

A base of formula I can with an acid in the associated Acid addition salt can be transferred. For this conversion is particularly suitable for acids, which provide physiologically acceptable salts. So can inorganic acids are used, e.g. B. sulfuric acid, Nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids  such as orthophosphoric acid, sulfamic acid, also organic Acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic one or polybasic carboxylic, sulfonic or sulfuric acids, e.g. B. Formic acid, acetic acid, propionic acid, pivalic acid, Diethyl acetic acid, malonic acid, succinic acid, pimelic acid, Fumaric acid, maleic acid, lactic acid, tartaric acid, Malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic 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 disulfonic acids, lauryl sulfuric acid. Salts with physiological not harmless acids, e.g. B. picrates for the isolation and / or purification of the compounds of the Formula I can be used.

The new compounds of formula I and their physiological harmless salts can be used to manufacture pharmaceutical preparations can be used by one with at least one carrier or Excipient and, if desired, together with a or more other active ingredient (s) in a suitable Dosage form brings. The preparations thus obtained can be used as a medicine in human or veterinary medicine be used. As carriers are organic or inorganic substances in question, which are suitable for enteral (e.g. oral or rectal) or parenteral application or for an application in the form of an inhalation spray and with the new ones Compounds do not react, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, Glycerol triacetate and other fatty acid glycerides, gelatin, Soy lecithin, carbohydrates such as lactose or starch,  Magnesium stearate, talc, cellulose. For oral use serve in particular tablets, coated tablets, capsules, syrups, Juices or drops; coated tablets are of particular interest and capsules with enteric coatings or capsule shells. Serve for rectal use Suppositories, for parenteral application solutions, preferably oily or aqueous solutions, furthermore Suspensions, emulsions or implants. For the application sprays can be used as an inhalation spray be either the active ingredient dissolved or suspended in a propellant gas mixture (e.g. fluorochlorine hydrocarbons). Used appropriately the active ingredient in micronized form, where one or more additional physiologically acceptable Solvents may be present, e.g. B. ethanol. Inhalation solutions can be made using standard inhalers be administered. The new connections can also be lyophilized and the lyophilizates obtained e.g. B. for the preparation of injectables be used. The specified preparations can be sterilized and / or auxiliary substances such as preservatives, Stabilizing and / or wetting agents, emulsifiers, Salts to influence the osmotic pressure, Contain buffer substances, colors and / or flavorings. If you want, you can also choose one or more contain other active ingredients, e.g. B. one or more Vitamins.

The substances according to the invention are usually in analogy to other known, commercially available Peptides, but especially in analogy to those in the Compounds described in EP-A-1 63 237, preferably in doses 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 one However, dose for each particular patient depends on various factors, for example the Effectiveness of the special connection used, from Age, body weight, general health, Gender, diet, timing and -away, from the rate of excretion, drug combination and severity of the disease, which the therapy applies. The parenteral application is prefers.

All temperatures above and below are given in ° C. In the examples below, "means usual Work up ": if necessary, water is added, neutralized, extracted with ether or dichloromethane, separates, the organic phase dries over Sodium sulfate, filtered, evaporated and cleaned through Chromatography on silica gel and / or crystallization.

example 1

A mixture of 934 mg [3S-hydroxy-4S- (N-tert-butoxycarbonyl-L-phenylalanyl-glycyl-amino) -5-cyclohexylpentanoyl] - L-isoleucyl-N (imi) - (2,4-dinitrophenyl) -L- histidyl amide ["BOC-Phe-Gly-AHCP-Ile- (imi-DNP) -His-NH ₂ "; obtainable by splitting off the BOC group from BOC-Ile- (imi-DNP) -His-NH ₂ with 4 n HCl in dioxane, reaction with BOC-AHCP-OH / DCCI / HOBt to BOC-AHCP-Ile- (imi- DNP) -His-NH ₂ , renewed cleavage of the BOC group, reaction with BOC-Gly-OH to BOC-Gly-AHCP-Ile- (imi-DNP) -His-NH ₂ , cleavage of the BOC group and reaction with BOC-Phe-OH], 860 mg of 2-mercaptoethanol, 10 ml of DMF and 10 ml of water are adjusted to pH 8 with stirring at 20 ° with aqueous Na ₂ CO ₃ solution and stirred at 20 ° for 2 hours. After customary working up, [3S-hydroxy-4S- (N-tert-butoxycarbonyl-L-phenylalanylglycylamino) -5-cyclohexylpentanoyl] -L-isoleucyl-L-histidyl-amide ("BOC-Phe-Gly-AHCP -Ile-His-NH ₂ ").

Analogously one obtains by splitting the corresponding one (imi-DNP) -His derivatives:

BOC-Phe-Gly-AHCP-His-NH ₂
BOC-Phe-Gly-AHCP-His-Ile-NH ₂ .

Example 2

1 g of BOC-Phe-Gly-AHCP-Ile- (imi-BOM-His) -NH ₂ [obtainable from BOC-Phe-OH and H-Gly-AHCP-Ile- (imi-BOM-His) -NH ₂ in the presence of N-methylmorpholine / HOBt / DCCI] in 10 ml of methanol, hydrogenated at 0.5%. Pd-C at 20 ° and 1 bar for 3 hours, filtered, evaporated and, after customary working up, obtained BOC-Phe-Gly-AHCP-Ile-His-NH ₂ .

Example 3

A solution of 5.19 g of 1-amino-2- (H-Gly-AHCP-Ile-aminomethyl) - 4,5-dimethylpyrazine [obtainable by hydrolysis from BOC-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl- amide) (mp 174 °, dec.) with 4 N HCl in dioxane to give H-Ile (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide), condensation with BOC-AHCP-OH to BOC-AHCP-Ile- (N-2-amino-5,6- dimethyl-3-pyrazinylmethyl amide) (mp 175 °, dec.), cleavage the BOC group and condensation with BOC-Gly-OH BOC-Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl- amide) (F. 140 °, decomp.) and cleavage of the BOC Group] in 60 ml dichloromethane with 1.01 g of N-methylmorpholine transferred. While stirring, 2.17 g of BOC  Phe-OH, 1.35 g HOBt and a solution of 2.06 g DCCI in Add 50 ml dichloromethane, stir for 14 hours at 2-6 °, filter the excreted dicyclohexylurea and evaporates the filtrate. You work on and as usual receives BOC-Phe-Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl- 3-pyrazinylmethyl amide), mp 164 ° (dec.).

Analogously, the BOC-Phe-Gly-AHCP-Ile-NH ₂ , F. 124 is obtained from BOC-Gly-AHCP-Ile-NH ₂ (F. 160-164 °) via H-Gly-AHCP-Ile-NH ₂ -126 ° C.

You get analog
IPOC-Phe-Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
CBZ-Phe-Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
POA-Phe-Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
Acetyl-Phe-Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl-amide)
Propionyl-Phe-Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl-amide)
Isovaleryl-Phe-Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl-amide)
Benzoyl-Phe-Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl-amide)

BOC-Phe-Gly-AHCP-Abu-NH ₂
BOC-Phe-Gly-AHCP-Ala-NH ₂
BOC-Phe-Gly-AHCP-Cal-NH ₂
BOC-Phe-Gly-AHCP-Leu-NH ₂
BOC-Phe-Gly-AHCP-Met-NH ₂
BOC-Phe-Gly-AHCP-Nle-NH ₂
BOC-Phe-Gly-AHCP-Phe-NH ₂
BOC-Phe-Gly-AHCP-Trp-NH ₂
BOC-Phe-Gly-AHCP-Tyr-NH ₂
BOC-Phe-Gly-AHCP-Val-NH ₂

BOC-Phe-Gly-AHCH-Ile-NH ₂
BOC-Phe-Gly-Sta-Ile-NH ₂
BOC-Phe-Gly-AHPP-Ile-NH ₂

BOC-Phe-Gly-AHCP- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-AHCP-Abu- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-AHCP-Ala- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-AHCP-Cal- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-AHCP-Leu- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-AHCP-Met- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-AHCP-Nle- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-AHCP-Phe- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-AHCP-Trp- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-AHCP-Tyr- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-AHCP-Val- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-AHCP-Ile- (N-3-pyridylmethyl amide), mp 132-134 °
BOC-Cal-Gly-AHCP-Ile- (N-3-pyridylmethyl-amide)
BOC- α -Nal-Gly-AHCP-Ile- (N-3-pyridylmethyl-amide)
BOC- β -Nal-Gly-AHCP-Ile- (N-3-pyridylmethyl amide)
BOC-L- (2-amino-4-phenylbutyryl) -Gly-AHCP-Ile- (N-3-pyridylmethyl amide)
BOC-L- (2-amino-5-phenylvaleryl) -Gly-AHCP-Ile- (N-3-pyridylmethyl amide)
BOC-L- [2-amino-3- (2-decalyl) propionyl] -Gly-AHCP-Ile- (N-3-pyridylmethyl amide)

N-isobutylcarbamoyl-Phe-Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl-amide)
N-Morpholine carbonyl-Phe-Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl-amide).

Example 4

• a) Analogously to Example 3, BOC-Phe-Gly-OH and AHCP-OMe the BOC-Phe-Gly-AHCP-OMe, mp 73-76 °.
• You get analog
  BOC-Phe-Gly-AHCP-Abu-OMe
  BOC-Phe-Gly-AHCP-Ala-OMe
  BOC-Phe-Gly-AHCP-Cal-OMe
  BOC-Phe-Gly-AHCP-Ile-OMe, mp 87-90 °
  BOC-Phe-Gly-AHCP-Leu-OMe
  BOC-Phe-Gly-AHCP-Met-OMe
  BOC-Phe-Gly-AHCP-Nle-OMe
  BOC-Phe-Gly-AHCP-Phe-OMe
  BOC-Phe-Gly-AHCP-Trp-OMe
  BOC-Phe-Gly-AHCP-Tyr-OMe
  BOC-Phe-Gly-AHCP-Val-OMe.
• b) A mixture of 1 g BOC-Phe-Gly-AHCP-OMe, 50 ml Dioxane and 20 ml of 2N NaOH (aqueous) is 3 hours. stirred at 20 °. After usual work-up BOC-Phe-Gly-AHCP-OH, mp 104 ° (dec.).
• You get analog
  BOC-Phe-Gly-AHCP-Abu-OH
  BOC-Phe-Gly-AHCP-Ala-OH
  BOC-Phe-Gly-AHCP-Cal-OH
  BOC-Phe-Gly-AHCP-Ile-OH, mp 143 ° (dec.)
  BOC-Phe-Gly-AHCP-Leu-OH
  BOC-Phe-Gly-AHCP-Met-OH
  BOC-Phe-Gly-AHCP-Nle-OH
  BOC-Phe-Gly-AHCP-Phe-OH
  BOC-Phe-Gly-AHCP-Trp-OH
  BOC-Phe-Gly-AHCP-Tyr-OH
  BOC-Phe-Gly-AHCP-Val-OH.

Example 5

Analogously to Example 3, BOC-Phe-Gly-OH and H-AHCP-Ile- (N-3-pyridylmethyl amide) the BOC-Phe-Gly-AHCP- Ile- (N-3-pyridylmethyl amide), mp 132-134 °.

You get analog
IPOC-Phe-Gly-AHCP-Ile- (N-3-pyridylmethyl-amide)
CBZ-Phe-Gly-AHCP-Ile- (N-3-pyridylmethyl-amide)
POA-Phe-Gly-AHCP-Ile- (N-3-pyridylmethyl amide)
Acetyl-Phe-Gly-AHCP-Ile- (N-3-pyridylmethyl-amide)
Propionyl-Phe-Gly-AHCP-Ile- (N-3-pyridylmethyl amide)
Isovaleryl-Phe-Gly-AHCP-Ile- (N-3-pyridylmethyl-amide)
Benzoyl-Phe-Gly-AHCP-Ile- (N-3-pyridylmethyl-amide)
N- [3- (BOC-Phe) propionyl] -AHCP- (N-isobutylamide) [with 3- (BOC-Phe) propionic acid]
N- [3- (BOC-Phe) propionyl] AHCP- (N-isopentylamide)
N- [3- (BOC-Phe) propionyl] AHCP-Ile- (N-isobutylamide)
N- [3- (BOC-Phe) propionyl] AHCP-Ile- (N-isopentylamide)

N- [3- (BOC-Phe) propionyl] AHCP-Ile- (N-3-pyridylmethyl amide)
N- [3- (Benzoyl-Phe) propionyl] -AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl-amide), mp 182-184 °
N- [4- (BOC-Phe) -3-thiabutyryl] -AHCP-Ile- (N-3-pyridylmethyl amide) [F. 118-120 °; with 4- (BOC-Phe) -3-thiabutyric acid, mp 110-111 °, obtainable from BOC-Phe-CH ₂ Br and HS-CH ₂ COOH in THF in the presence of NaOCH ₃ ]
N- [4- (BOC-Phe) -3-thiabutyryl] -AHCP- (N-isobutylamide)
N- [4- (BOC-Phe) -3-thiabutyryl] -AHCP- (N-isopentylamide)
N- [4- (BOC-Phe) -3-thiabutyryl] -AHCP-Ile- (N-isobutylamide)
N- [4- (BOC-Phe) -3-thiabutyryl] -AHCP-Ile- (N-isopentylamide)
N- [4- (BOC-Phe) -3-thiabutyryl] -AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl-amide), m.p. 153-155 °.
N- [N- (BOC-Phe-methyl) carbamoyl] -AHCP-Ile- (N-3-pyridylmethyl amide)
N- (BOC-Phe-methoxyacetyl) -AHCP-Ile- (N-3-pyridylmethyl amide)
N- [4- (Morpholinocarbonyl-Phe) -3-thiabutyryl] -AHCP- (N-isopentylamide)

BOC-Phe-Gly-AHCH-Ile- (N-3-pyridylmethyl-amide)
BOC-Phe-Gly-Sta-Ile- (N-3-pyridylmethyl amide)
BOC-Phe-Gly-AHPP-Ile- (N-3-pyridylmethyl-amide)

N- [3S-Hydroxy-4S- (BOC-Phe-Gly-amino) -octanoyl] -Ile- (N-3-pyridylmethyl-amide)
N- [3S-Hydroxy-4S- (BOC-Phe-Gly-amino) -5- (trans-4-methylcyclohexyl) pentanoyl] -Ile- (N-3-pyridylmethyl amide), mp 97-99 °
N- [3S-Hydroxy-4S- (BOC-Phe-Gly-amino) -5- (trans-4-tert-butylcyclohexyl) pentanoyl] -le- (N-3-pyridylmethyl amide), m.p. 122 -125 °

BOC-Phe-Gly-AHCH-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-Sta-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-AHPP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)

N- [3S-hydroxy-4S- (BOC-Phe-Gly-amino) octanoyl] -Ile- (N-2- amino-5,6-dimethyl-3-pyrazinylmethyl amide), mp 183-185 °

N- [3- (BOC-Phe) propionyl] AHCP-Ile- (N-2-amino-5,6- dimethyl-3-pyrazinylmethyl amide), mp 167-169 °

[N- (4- (BOC-Phe) -3-thiabutyryl) -AHCP-Ile- (N-2-amino-5,6- dimethyl-3-pyrazinylmethyl amide), mp 153-155 °.

With H-AHCP-Ile-NH ₂ one obtains analogously:
IPOC-Phe-Gly-AHCP-Ile-NH ₂
BOC-Phe-Gly-AHCP-Ile-NH ₂ , mp 124-126 °
CBZ-Phe-Gly-AHCP-Ile-NH ₂
POA-Phe-Gly-AHCP-Ile-NH ₂
Acetyl-Phe-Gly-AHCP-Ile-NH ₂
Propionyl-Phe-Gly-AHCP-Ile-NH ₂
Isovaleryl-Phe-Gly-AHCP-Ile-NH ₂
Benzoyl-Phe-Gly-AHCP-Ile-NH ₂

N- [3- (BOC-Phe) propionyl] AHCP-Ile-NH ₂
N- [4- (BOC-Phe) -3-thiabutyryl] -AHCP-Ile-NH ₂ , m.p. 125-128 °
N- (BOC-Phe-methoxyacetyl) -AHCP-Ile-NH ₂ .

Example 6

Analogously to Example 3, BOC-Phe-Gly-AHCP-OH and Isoleucine (N-3-pyridylmethyl amide) of BOC-Phe-Gly-AHCP- Ile- (N-3-pyridylmethyl amide), mp 132-134 °.

The following is obtained analogously with the corresponding amino compounds:
BOC-Phe-Gly-AHCP- (N-isobutylamide)
BOC-Phe-Gly-AHCP- (N-isopentylamide)

BOC-Phe-Gly-AHCP- [N-1- (2-amino-4-thiazolyl) -2-methylbutylamide], mp 138-140 °
BOC-Phe-Gly-AHCP- [N-1- (4- (2-aminoethyl) -2-thiazolyl) -2-methyl-butyl-amide], mp 78-80 °
BOC-Phe-Gly-AHCP- [N-1- (4-carbamoyl-2-thiazolyl) -2-methyl-butyl-amide]
BOC-Phe-Gly-AHCP- [N-1- (4-carboxy-2-thiazolyl) -2-methylbutyl amide]
BOC-Phe-Gly-AHCP- [N-1- (4-ethoxycarbonyl-2-thiazolyl) -2-methyl-butyl-amide], mp 84-88 °
BOC-Phe-Gly-AHCP- [N-1- (5-tetrazolyl) -2-methyl-butyl-amide]
BOC-Phe-Gly-AHCP- [N-1- (5-tetrazolyl) -3-methyl-butyl-amide]
BOC-Phe-Gly-AHCP- [N-1- (4-carbamoylpiperidinoacetyl) -2-methyl-butyl-amide], mp 100-102 °.

Example 7

Analogously to Example 3, the BOC-Phe-Gly-AHCP-Ile-Phe-NH ₂ , mp 188 ° (dec.) Is obtained from BOC-Phe-Gly-AHCP-Ile-OH and H-Phe-NH ₂ .

The corresponding amino acid amides are obtained analogously;
BOC-Phe-Gly-AHCP-Ile-Abu-NH ₂
BOC-Phe-Gly-AHCP-Ile-Ala-NH ₂
BOC-Phe-Gly-AHCP-Ile-Cal-NH ₂
BOC-Phe-Gly-AHCP-Ile-Ile-NH ₂
BOC-Phe-Gly-AHCP-Ile-Leu-NH ₂
BOC-Phe-Gly-AHCP-Ile-Met-NH ₂
BOC-Phe-Gly-AHCP-Ile-Nle-NH ₂
BOC-Phe-Gly-AHCP-Ile-Trp-NH ₂
BOC-Phe-Gly-AHCP-Ile-Tyr-NH ₂
BOC-Phe-Gly-AHCP-Ile-Val-NH ₂ .

Example 8

Analogously to Example 3, BOC-Phe-Gly-AHCP-Ile-OH is obtained and 2-amino-3-aminomethyl-5,6-dimethylpyrazine the BOC-Phe- Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl- amide), mp 164 ° (dec.).

Similarly, with the corresponding amines:
BOC-Phe-Gly-AHCP-Ile- (N-2-pyridylmethyl amide)
BOC-Phe-Gly-AHCP-Ile- (N-3-pyridylmethyl amide), mp 132-134 °
BOC-Phe-Gly-AHCP-Ile- (N-4-pyridylmethyl-amide)

BOC-Phe-Gly-AHCP-Ile- (Nm-aminomethylbenzyl-amide)
BOC-Phe-Gly-AHCP-Ile- (N-5-p-methoxyphenyl-1H-2-pyridon-3-yl-methyl-amide)
BOC-Phe-Gly-AHCP-Ile- [N-2- (2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl) ethyl amide]
BOC-Phe-Gly-AHCP-Ile- (N-2-methyl-4-amino-5-pyrimidylmethyl amide), mp 129-131 °
BOC-Phe-Gly-AHCP-Ile- (N-2-hydroxy-4-amino-6-methyl-3-pyridyl-methyl-amide), mp 173-175 °
BOC-Phe-Gly-AHCP-Ile- [N-2- (4-methyl-5-thiazolyl) ethyl amide]
BOC-Phe-Gly-AHCP-Ile (N-5-tetrazolyl-methyl-amide), mp 155 ° (dec.)
BOC-Phe-Gly-AHCP-Ile- (N-2-morpholinoethyl-amide)
BOC-Phe-GLy-AHCP-Ile- [N-2- (4-pyridyl) ethyl amide], mp 106-108 °
BOC-Phe-Gly-AHCP-Ile- (N-2-dimethylaminoethyl amide), mp 102-105 °
BOC-Phe-Gly-AHCP-Ile- (N-3-N'-methylureido-1H-4-pyridon-5-yl-amide)
BOC-Phe-Gly-AHCP-Leu- (Nm-aminomethylbenzyl-amide).

Example 9

Analogously to Example 3, BOC-Phe-Gly-AHCP-Ile-OH is obtained and 3-pyridine methanol the BOC-Phe-Gly-AHCP-Ile- (3-pyridyl methyl ester).

Example 10

A suspension of 3.42 g of N-tert-butoxycarbonyl-L-phenylalanyl-methyl bromide (L-1-bromo-3-tert-butoxycarbonyl-4-phenyl-2-butanone; BOC-Phe-CH ₂ Br) and 0.81 g of KOCN in 45 ml of benzene and 5 ml of DMF is stirred at 20 ° for 5 hours. BOC-Phe-CH ₂ -NCO is formed as an intermediate. 3.64 g of H-AHCP-Ile-NH ₂ and 1 g of N-methylmorpholine are added, the mixture is stirred at 20 ° for 16 hours, worked up as usual (pH 3) and N- [N- (BOC-Phe- methyl) carbamoyl] - AHCP-Ile-NH ₂ .

You get analog
N- [N- (BOC-Phe-methyl) carbamoyl] -AHCP-Ile- (N-3-pyridylmethyl amide)
N- [N- (BOC-Phe-methyl) carbamoyl] AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl-amide).

Example 11

• a) Analogously to Example 3, BOC-Phe-Gly-OH and [3-oxo-4S-amino-5-cyclohexylpentanoyl] -Ile-NH ₂ [obtainable by reaction of 2S-BOC-amino-3-cyclohexylpropionic acid with carbonyldiimidazole to imidazolide, conversion with malonic acid monomethyl ester to 3-oxo-4S-BOC-amino-5-cyclohexylpentanoic acid methyl ester, saponification, condensation with H-Ile-NH ₂ to (3-oxo-4S-BOC-amino-5-cyclohexylpentanoyl) - Ile-NH ₂ and cleavage of the BOC group] the [3-oxo-4S- (BOC-Phe-Gly-amino) -5-cyclohexylpentanoyl] -Ile-NH ₂ .
• b) A solution of 10 g of the above amide in 250 ml of CH ₃ OH is 10% in 1 g. Pd-C hydrogenated at 20 ° C and 1 bar to a standstill. After filtering and evaporating, a mixture of [3R- and [3S-hydroxy-4S- (BOC-Phe-Gly-amino) -5-cyclohexylpentanoyl] -Ile-NH _{2 is obtained} , which can be separated by chromatography.

Example 12

A solution of 601 mg [3-oxo-4S- (BOC-Phe-Gly-amino) -5-cyclohexylpentanoyl] -Ile-NH ₂ and 1.43 g Na ₂ CO ₃ · 10 H ₂ O in 5 ml methanol and 5 ml of water are mixed with 70 mg of hydroxylamine hydrochloride and stirred at 20 ° for 14 hours. The precipitated oxime is filtered off, dried, dissolved in 10 ml of methanol and hydrogenated on 0.5 g of Raney Ni at 20 ° and 5 bar. It is filtered, the filtrate is evaporated and, after customary working up, BOC-Phe-Gly-DACP-Ile-NH _{2 is obtained} as a mixture of diastereomers, which can be separated by chromatography.

Example 13

A solution of 1 g of BOC-Phe-Gly-AHCP-Ile-NH ₂ in 20 ml of 4N HCl in dioxane is stirred at 20 ° for 30 minutes and then evaporated. H-Phe-Gly-AHCP-Ile-NH _{2 is obtained} .

Analogously one obtains from the corresponding BOC derivatives:
H-Phe-Gly-AHCP-Ile- (N-3-pyridylmethyl amide)
H-Phe-Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide).

Example 14

1 g of CBZ-Phe-Gly-AHCP-Ile-NH _{2 is dissolved} in 10 ml of ethanol, hydrogenated on 0.5 g of 10% Pd-C at 20 ° and 1 bar until standstill, filtered, evaporated and obtained chromatographic purification H-Phe-Gly-AHCP-Ile-NH ₂ .

Example 15

Analogously to Example 14, from N- [3S-benzyloxycarbonylamino-4S- (BOC-Phe-Gly-amino) -5-cyclohexyl-pentanoyl] -Ile-NH _2, the BOC-Phe-Gly-DACP-Ile-NH _2.

Analogously, the corresponding CBZ derivatives are obtained by hydrogenolysis
BOC-Phe-Gly-DACH-Ile-NH ₂
BOC-Phe-Gly-DAMH-Ile-NH ₂
BOC-Phe-Gly-DAPP-Ile-NH ₂
BOC-Phe-Gly-DACP-Ile (N-3-pyridylmethyl amide)
BOC-Phe-Gly-DACH-Ile (N-3-pyridylmethyl amide)
BOC-Phe-Gly-DAMH-Ile (N-3-pyridylmethyl amide)
BOC-Phe-Gly-DAPP-Ile (N-3-pyridylmethyl amide)
BOC-Phe-Gly-DACP-Ile- (N-2-amino-5,6-dimetyhl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-DACH-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-DAMH-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide)
BOC-Phe-Gly-DAPP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinylmethyl amide).

The following examples relate to pharmaceutical preparations.

Example A: Injection glasses

A solution of 100 g BOC-Phe-Gly-AHCP-Ile- (N-3-pyridylmethyl- amide and 5 g disodium hydrogen phosphate in 3 l twice distilled water is mixed with 2N hydrochloric acid Adjusted to pH 6.5, sterile filtered, in injection glasses filled, lyophilized under sterile conditions and sterile closed. Each injection jar contains 500 mg Active ingredient.

Example B: Suppositories

A mixture of 500 g of BOC-Phe-Gly-AHCP-Ile-NH _{2 is} melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 500 mg of active ingredient.

Claims (9)

1. Amino acid derivatives of the formula I X-NR ² -CHR ³ -CO-Z- (CH ₂ ) _m -CO-NR ⁴ -CHR ⁵ -CR ⁶ - (CHR ⁷ -) _n -CO-EQY, 6 (I) wherein
X H, R ¹ -OC _m H _{2 m} -CO-, R ¹ -C _m H _{2 m} -O-CO-, R ¹ -C _m H _{2 m} -CO-, R ¹ -SO ₂ -, (R ¹ -C _m H _{2 m} ) -L (R ¹ -C _p H _{2 p} ) -C _r H _{2 r} -CO-, R ¹ - (NHCH ₂ CH ₂ ) _m -NH-CH ₂ CO- or 9-fluorenyl -C _m H _{2 m} -O-CO-,
Z -O-, -CH ₂ -, -CH = CH-, -NR ⁸ -, -CH ₂ -O-, -CH ₂ -NR ⁸ - or -CH ₂ -S-,
E 0 to 2 amino acid residues linked together in peptides selected from the group consisting of Abu, Ala, Cal, His, Ile, Leu, Met, Nle, Phe, Trp, Tyr and Val,
Q O or NH,
Y -C _t H _{2 t} -R ⁹ or -C _w H _{2 w} - (CR ¹¹ ) _s -C _{t -} H _{2 t} - R ⁹ ,
R ¹ , R ³ , R ⁵ and R ^{9 in} each case H, A, Ar, Ar-alkyl, Het, Het-alkyl, unsubstituted or mono- or polysubstituted by A, AO and / or Hal cycloalkyl with 3-7 C- Atoms, cycloalkylalkyl with 4-11 C atoms, bicycloalkyl or tricycloalkyl, each with 7-14 C atoms, bicycloalkylalkyl or tricycloalkylalkyl, each with 8-18 C atoms,
R ² , R ⁴ , R ⁷ , R ⁸ and R ^{10 are} each H or A,
R ⁶ and R ¹¹ each (H, OH), (H, NH ₂ ) or = O,
L CH or N,
m, p, r and t each 0, 1, 2, 3, 4 or 5,
n and s each 1 or 2,
w 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
Ar unsubstituted or mono- or polysubstituted by A, AO, Hal, CF ₃ , HO, hydroxyalkyl with 1-8 C atoms, H ₂ N and / or aminoalkyl with 1-8 C atoms or unsubstituted naphthyl,
Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical with 1-4 N, O and / or S atoms, which condenses with a benzene ring and / or one or more times by A, AO, Hal, CF ₃ , HO, O ₂ N, carbonyl oxygen, H ₂ N, HAN, A ₂ N, AcNH, AS, ASO, ASO ₂ , AOOC, CN, H ₂ NCO, HOOC, H ₂ NSO ₂ , ASO ₂ NH, Ar, Ar alkenyl, hydroxyalkyl and / or aminoalkyl can each be substituted with 1-8 C atoms and / or its N and / or S heteroatoms can also be oxidized,
Hal F, Cl, Br or J,
Ac A-CO-, Ar-CO- or A-NH-CO- and
A is alkyl with 1-8 C atoms,
and their salts. 2nd

• a) BOC-Phe-Gly-AHCP-Ile- (N-3-pyridylmethyl amide);
• b) BOC-Phe-Gly-AHCP-Ile-NH ₂ ;
• c) BOC-Phe-Gly-AHCP-Ile- (N-2-amino-5,6-dimethyl-3-pyrazinyl-methyl-amide).

3. A process for the preparation of an amino acid derivative of the formula I and of its salts, characterized in that it is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent
or that a carboxylic acid of the formula II X-NR ² -CHR ³ -G ¹ -OH, 6 (II) wherein G ¹

• (a) -CO-,
• (b) -CO-Z- (CH ₂ ) _m -CO-,
• (c) -CO-Z- (CH ₂ ) _m -CO-W-,
• (d) -CO-Z- (CH ₂ ) _m -CO-WE ¹ -.
• (e) -CO-Z- (CH ₂ ) _m -CO-WE- and

W -NR ⁴ -CHR ⁵ -CR ⁶ - (CHR ⁷ ) _n -CO- mean
or one of its reactive derivatives with a compound of the formula III HG ² , 6 (III) in which G ²

• (a) -Z ¹ - (CH ₂ ) _m -CO-WEQY,
• (b) -WEQY,
• (c) -EQY,
• (d) -E ² -QY,
• (e) -QY,

Z ¹ -O- or NR ⁸ - and
E ¹ + E ² together mean E.
or one of their reactive derivatives,
and / or that a functionally modified amino and / or hydroxy group in a compound of the formula I is optionally liberated by treatment with solvolysing or hydrogenolysing agents and / or a keto group is reduced to a CHOH group or to a CH (NH ₂ ) Group reductively aminated and / or a compound of formula I converted into one of its salts by treatment with an acid. 4. Process for the preparation of pharmaceutical preparations, characterized in that one Compound of formula I and / or one of their physiologically acceptable salts together with at least one solid, liquid or semi-liquid Carrier or auxiliary and optionally in combination with one or more further active ingredient (s) in a suitable dosage form brings. 5. Pharmaceutical preparation, characterized by contains at least one compound of Formula I and / or one of its physiologically acceptable Salts. 6. Use of compounds of the formula I or of whose physiologically acceptable salts in the Combat renal hypertension or of hyperaldosteronism. 7. Use of compounds of the formula I or of their physiologically acceptable salts for the production a medicine to fight the renin-dependent hypertension or hyperaldosteronism.