NZ228707A

NZ228707A - Small peptide derivatives with the ability to inhibit plasma renin

Info

Publication number: NZ228707A
Application number: NZ228707A
Authority: NZ
Inventors: Peter Raddatz; Joachim Gante; Johannes Sombroek; Claus J Schmitges; Klaus-Otto Minck
Original assignee: Merck Patent Gmbh
Priority date: 1988-04-14
Filing date: 1989-04-12
Publication date: 1992-03-26
Also published as: FI891761A0; KR890016062A; DK177789A; JPH026449A; EP0337334A3; FI891761A; AU3255589A; EP0337334A2; HU206888B; AU618335B2; DK177789D0; ZA892720B; PT90273A; CN1037155A; PT90273B; HUT52786A; DE3812328A1

Description

<div id="description" class="application article clearfix"> New Zealand Paient Spedficaiion for Paient Number £28707 228707 N.Z. No. NEW ZEALAND Patents Act 1953 /* //a; £ N ,7-s'" ^ O COMPLETE SPECIFICATION |'V AMINO ACID DERIVATIVES 12 APR We, MERCK PATENT GESELLSCHAFT mit beschrankter HAFTUNG, a German company of Frankfurter Strasse 250, 61 Darmstadt, Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement - 1 - (Followed by 1A) ZZ8 7 0 7 -1 A- Amino acid derivatives The invention relates to new amino acid derivatives of the formula I ' R1-C H_ -(NH) -CO-NH-CHR2-C0-Z-CHo-C0- ■p 2p y m 2m NH-CHR3-CR4-(CHR5) -CO-E-Q-Y in which 10 R1 is R6R7N-, R6-NH-C(=NH)-NH-, N C-NH -C ( = NH )-NH- , R600C-, R603S- or R6-O-(CH2CH20)r-, Z is -0-, - C H 2 - , -CH = CH-, -C=C-, -NR8-, -CH2-0-, -CH2~NR°- or -CH2-S-, E is 0 to 2 amino acid residues which are linked 15 together in the manner of a peptide and are selected from the group comprising Abu, Ala, Cae, His, lie, Leu, Met, Nle, Nva, Phe, Trp, Tyr and V a I , Q isOorNR^, 20 Y is ~Ct;ri2t~Rl^' _ct^2t_R^ or -CwH2w-(CR 'J)s-CtH2t-R11, R^, R"^ and R ^ ^ are each H, A, A r, Ar-alkyl, Het, Het-alkyl, unsubstituted or singly or multiply, by A, AO and/or Hal, substituted cycloalkyl having 25 3-7 C atoms, cycIoa Iky I a I ky I having 4-11 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, bicycIoa Iky I a Iky I or tricycIoa IkyI a IkyI each having 8-18 C atoms, R^ and R^ are each (H, OH), (H, NH2) or = 0, 30 R^, R^ and R^ are each H or A, R^ and R7 are each H, A or Ar-alkyl, R7 is also R^-0-CxH2x-C0-, R^-CxH2x-0-C0- or Ac, o R is A or Ar-alkyl, 35 R^R^N is also a piperidinyl, morpholinyl, piperazinyl or- pyrrol id i nyl group which is unsubstituted or substituted by A, OH, NH2, NHA, NA2, NHAc, PAT LOG 14 060488 m 12 22 8 7 0 7 NH-CO-CxH2x-O-R9, NH-C0-0-CxH2x-R9, NH-S02~A, hydroxyatkyI, COOH, COOA, C 0 N H 2 , CN, aminoalkyl, HAN-alkyl, A2N-aLkyl, A3N®alkyl An®, NH-CO-NH2, NH-CO-NHA, NH-CO-NA2, guanidinyl or guanidinyl-alkyl, is -SO3H, -so2nh2, -so2nha, -so2na2, -NH2, -NHA, -na2, -NH-C(=NH)-nh2, -NH-C(=NH)-NHCN, -NH-C0-NH2, -NH-CO-NHA, -NH-C0-NA2, -nh-CS-nh2, -nh-CS-nha,-NH-CS-NA2, -COOH, -COOA, -COO-alkyl-Ar, -CONH^, -CONHA or -CONA„, 10 y is O or 1, n and s are each 1 or 2, m , p , t, w and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, r i s 1 , 2 0 r 3, 15 Ar is phenyl which is unsubstituted or singly or multiply substituted by A, OA, Hal, CF3, OH, N 0 2 , hydroxyalkyl, N H 2 , NHA, NA2, N H A c , SA, S 0 -A, S02-A, S02NH2, S02NHA, COOH , COOA, C0NH2, CN, aminoalkyl, HAN-alkyl, A2N-alkyl, f A 20 A 3 N a L k y L An and/or guanidinyl-alkyl, or is unsubstituted naphthyl, Het i0 J saturated or unsaturated 5- or 6-membered heterocyclic radical wnich has 1-4 N, 0 and/or S atoms and can be fused with a benzene ring and/or can 25 be singly or multiply substituted by A, OA, Hal, CF3, OH, N 0 2 , carbonyl oxygen, NH2, NHA, NA2, NHAc, SA, SO-A, SO2-A, S02NH2, S02NHA, COOH, COOA, C0NH2, CN, NH-S02-A, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl and/or aminoalkyl, 30 and/or whose N and/or S hetero atoms can also be oxidized, Hal is F, CI, Br or I, Ac is H-CO-, A-CO-, CF3-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH-CO- An® is an anion, which can also be absent if,in its 35 stead, a carboxyl group contained in the compound of the formula I is in the form of a carboxylate anion, -alkyl- is an alkylene group having 1-8 C atoms, and A is alkyl having 1-8 C atoms, 40 in which, furthermore, it is also possible for one or more PAT LOG 14 060488 22 87 0 7 - 3 - -NH-CO- groups to be replaced by one or more -NA-CO-groups, as well as the salts thereof. Similar compounds are disclosed in EP-A 249096. Indicated therein is a formula "I" which also em-5 braces some of the compounds of the present formula I, especially some of those compounds of the formula I in which R1 is R6R7N-CpH2p-CO-, R6 and R7 are each H or alkyl, and p is 0, 1, 2, 3, 4 or 5. Neither the latter group of compounds nor any individual compound covered 10 thereby is, however, mentioned in EP-A 249096, nor is it possible to deduce from anywhere in this publication that particularly this group of compounds has especially advantageous properties. The invention had the object of finding new com-15 pounds with valuable properties, in particular those which can be used for the preparation of medicaments. It has been found that the compounds of the formula I and the salts thereof have very valuable properties. In particular, they inhibit the activity of human 20 plasma renin. This action can be detected, for example, by the method of F. Fyhrquist et al., Clin. Chem. 2_2, -250-256 (1976). The noteworthy point is that these compounds are very specific inhibitors of renin; as a rule, the concentrations of these compounds necessary for the inhibition 25 of other aspartyl proteinases (for example pepsin and cathepsin D) are about 100 to 1000 times as high as for renin inhibition. The actions of the compounds on the blood pressure and/or on the heart rate, as well as the inhibition of renin activity in blood plasma can further-30 more be determined in conscious monkeys, for example female monkeys (Macaca fascicuLaris); it is possible in this for the blood pressure and heart rate to be measured by a modification of the method of M.J. Wood et al., J. Hypertension 4, 251-254 (1985). In order to stimulate 35 renin activity in this, the animals are preferably pre- treated with a saluretic. Blood samples for the determination of the plasma renin activity can be obtained by puncture of the femoral vein. The compounds can be used as pharmaceuticaLLy PAT LOG 14 060488 10 15 - 4 - 22 8 7 0 7 active substances in human and veterinary medicine, in particular for the prophylaxis and for the treatment of diseases of the heart, circulation and vessels, especially of hypertension, cardiac insufficiency and hyperaLdosteronism. In addition, the compounds can be used for diagnostic purposes in order to determine, in patients with hypertension or hyperaLdosteronism, the possible contribution of the renin activity to maintaining the pathological state. The procedure for such diagnostic tests can be similar to that indicated in EP-A 77 028. The abbreviations quoted hereinbefore and hereinafter for amino acid residues represent the radicals -NR'-R"—CO-, as a rule -NH-CHR-CO- (in which R, R' and R" have the specific meaning known for each amino acid), of the following amino acids: Abu 2-Aminobutyric acid AHCH 4S-Amino-3S-hydroxy-6-cyc I ohexyI-hexanoic acid AHCP 4S-Amino-3S-hydroxy-5-cycIohexyI-penta noic acid AHPP 4S-Amino-3S-hydroxy-5-phenyI-penta noic acid 20 Ala Alanine 8Ala B-Alanine Cal 3-CycIohexyI a I anine DACH 3S,4S-0iamino-6-cycIohexyI-hexanoic acid DACP 3S,4S-Diamino-5-cycIohexyI-penta noic acid 25 DAMH 3S,4S-Diamino-6-methyI-heptanoic acid DAPP 3S,4S-Diamino-5-phenyI-penta noic acid Gly Glycine His His.tidine lie Isoleucine 30 Leu Leucine Mai 3-(p-MethoxyphenyI)-a I anine Met Methionine' aNal 3-(a-NaphthyL)-aLanine BNal 3-(8-NaphthyL)-a I anine 35 Nle Norleucine N-Me-His N-Methyl-histidine N-Me-Phe N-MethyL-phenyI aLanine Nva Norvaline Phe Phenylalanine PAT LOG 14 060488 - 5 - 22 8 7 0 7 Pia 3-(PiperidyL)-aLanine [e.g. 2-pia= 3-(2-piperidyl)-alanine] Pya 3-(PyridyI)-aLanine Ce.g. 3-pya = 3-(3-pyr idyl)-alan i n e ] 5 Sta Statine Tia 3-( Th i eny I )-a I an i ne Ce.g. 2-tia 3-(2-th ienyl)-alanine] Trp Tryptophan Tyr Tyrosine 10 Val Valine. Further meanings hereinafter are: ADPA N-2-Amino-5,6-dimethyl-3-pyrazinylmethyl-amide AMPA N-4-Amino-2-methyI-5-pyrimidiny1 methyI-amide 80C tert.-Butoxycarbony I 15 BOM BenzyloxymethyI imi-BOM BenzyIoxymethy I in the 1 position of the imidazole ring CBZ BenzyIoxycarbonyI DCCI DicycIohexyIcarbodiimide 20 DMF 0imethyIformamide DNP 2,4-DinitrophenyI imi-DNP 2,4-Dinitrophenyl in the 1 position of the imidazole ring ETOC Ethoxycarbony I 25 FMOC 9-FIuoreny1 methoxycarbony I HOB t 1-HydroxybenzotriazoIe IPOC Isopropoxycarbony I OMe Methyl ester OEt Ethyl ester 30 POA PhenoxyacetyI THF Tetrahydrofuran. If the abovementioned amino acids can occur in more than one enantiomeric form, then all these forms, as well as mixtures thereof (for example the DL forms), are 35 included hereinbefore and hereinafter, for example as constituent of the compounds of the formula I. The L forms are preferred. Where individual compounds are mentioned hereinafter, then the abbreviations of these amino acids each relate to the L form unless expressly indicated PAT LOG 14 060488 10 . 6 _ 228707 otherwise. The invention furthermore relates to a process for the preparation of an amino acid derivative of the formula I, and of the salts thereof, characterized in that it is liberated from one of its functional derivatives by treatment with a solvolyzing or hydrogenoIyzing agent, or in that a carboxylic acid of the formula II ^"CpH^-fNHJy-CO-G^OH n in which G^ is (a) absent, (b) -NH-CHR2-C0-, (c) -NH-CHR2-C0-Z-CmH2m-C0-, 15 (d) -NH-CHR2-CO-Z-CmH2m-CO-W-, (e) -NH-CHR2-CO-Z-CmH2m-CO-w-E1-, (f) -NH-CHR2-CO-Z-CmH2m-CO-W-E- and W is -NH-CHR3-CR4-(CHR5)n-co- or one of the reactive derivatives thereof, is reacted 20 with an amino compound of the formula III H-G2 III in which G2 is 25 (a) -nh-chr2-co-z "cmh2m-c0-w-e-q-y (b ) -z-c^-co-w- -e-q-y. (c) -w-e-q-y, (d) -e-q-y , (e) -e2-q-y, ( f ) -nr10-y and 29 JANt99^rrj A J E1 and E2 stand for 0 to 1 amino acid residue selected from the group given in the 3 0 definition of E, and in that a functionally modified amino and/or hydroxyl group in a compound of the formula I is liberated where appropriate by treatment with solvolyzing or hydrogenoIyz- ing agents, and/or for the preparation of a compound of the formula I, R^ = (H, OH) or (H, NH2), an amino keto 35 acid derivative of the formula I, R = 0, is reduced or reductively aminated, and/or one radical R1 is converted to another radical R1 and/or a compound of the formula I is converted by treatment with an acid into one of the salts thereof. Hereinbefore and hereinafter the radicals and 22 8 7 0 7 - 7 - 1 13 parameters R to R , Z , E , Q, Y, m, n, p, r, s, t, w, x, y, Ar, Het, HaL, Ac, An, A, G^, G^, E^, E^ and W have the meanings indicated for the formulae I, II or III unless expressly indicated otherwise. 5 A in the formulae mentioned hereinbefore has 1-8, preferably 1, 2, 3 or 4, C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl, as well as pentyl, 1-, 2- or 3-methyIbuty I , 1,1-, 1,2- or 2,2-dimethyIpropy I , 1-ethyl-10 propyl, hexyl, 1-, 2-, 3- or 4-methyIpenty1, 1,1-, 1,2-, 1.3-, 2,2-, 2,3- or 3,3-dimethyIbutyI, 1- or 2-ethyl-butyl, 1-ethyl-l-methylpropyl, 1-ethyI-2-methyIpropy I, 1,1,2- or 1,2,2-trimethylpropyl, heptyl or octyl. Cycloalkyl is preferably cyclopropyl, cyclobutyl, 15 cyclopentyl, cyclohexyl or cycloheptyl, but is also, for example, 1-, 2- or 3-methyIcycI opentyI, or 1-, 2-, 3- or 4-methylcyclohexyl. Correspondingly, cycIoaIkyI a IkyI is preferably cycI opropyI methyI, 2-cycI op ropy IethyI, cyc I obutyI methyI, 20 2-cycIobutyIethyI, cycI opentyI methyI, 2-cycI opentyIethyI, c y c I o h e x y I me t h y I , 2-c y c I ohexy-l e t hy I , but is also, for example, 1-, 2- or 3-methyIcycI opentyI methyI, or 1-, 2-, 3-or 4-methyIcycIohexyI methyI. Bicycloalkyl is preferably 1- or 2-decalyl, 2 — b i — 25 cycIoC2 .2.1]heptyI or 6,6-dimethyI-2-bicycIoL3.1.1]heptyI. Tricycloalkyl is preferably 1-adamantyl. Hal is preferably F, CI or Br, but is also I. Ac is preferably A-C0-, such as acetyl, propionyl or butyryl, Ar-CO- such as benzoyl, o-, m- or p-methoxy-30 benzoyl or 3,4-dimethoxybenzoyI, or A-NH-CO- such as N-methyl- or N-ethy I carbamoyI. Ar is preferably phenyl and is furthermore preferably o-, m- or p-tolyl, o-, m- or p-ethyIphenyI, o-, m- or p-methoxyphenyI, o-, m- or p-f I uorophenyI, o-, m-35 or p-chIorophenyI, o-, m- or p-bromophenyI, o-, m- or p-iodophenyl, o-, m- or p-trifIuoromethyIphenyI, o-, m-or p-hydroxyphenyI, o-, m- or p-suIfamoyIphenyI, 2,3-, 2.4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyI, 3,4,5-trimethoxyphenyI, o-, m- or p-aminophenyI, o-, m- or PAT LOG 14 060488 228707 - 8 - p-aminomethyIphenyI, o-,. m- or p-dimethylaminomethylphenyl, 0-, m- or p-guanidinomethyIphenyI, or 1- or 2-naphthyl. Correspondingly, Ar-alkyl is preferably benzyl, 1-or 2-phenylethyl, o-, m- or p-methylbenzyl, 1- or 2-o-, 5 -m- or -p-to IyIethyI, o-, m- or p-ethyI benzyI, 1- or 2-o-, -m- or -p-ethyIphenyIethy I , o-, m- or p-methoxybenzyI, 1-or 2-o-, -m- or -p-methoxy-phenyIethyI, o-, m- or p-fluoro-benzyl, 1- or 2-o-, -m- or -p-fIuorophenyIethyI, o-, m- or p-chIorobenzyI, 1- or 2-o-, -m- or -p-chIorophenyIethyI, 10 o -, m- or p-b r omobe n z y I , 1- or 2-o-, -in- or -p-bromo-phenylethyl, o-, m- or p-iodobenzyI, 1- or 2-o-, -m- or -p-iodophenyIethyI, o-, m- or p-1rif I uoromethyI benzyI, o-, m- or p-hydroxybenzyI, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3 , 5-dimethoxybenzyI, 3,4,5-1rimethoxybenzyI, o-, m- or p-15 aminobenzyl, o- m- or p-aminomethylbenzyl, o-, m- or p-dimethyI aminomethyI benzyI, o-, m- or p-guanidinomethyI-benzyl, or 1- or 2-naphthyI methyI. Het is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazoIy I, 1-, 3-, 20 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5- isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazoIyI, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or — 5 — y I , 1,2,4-triazol-1-, -3- or — 5 — y 1, 1- or 5-tetrazolyl, 1,2,3-oxa- 25 diazol-4- or — 5 — yI, 1,2,4-oxadiazoI-3- or — 5-yI , 1,3,4-th iadiazoI-2- or — 5 — yI, 1,2 , 4-1hiadiazol-3- or — 5 -yI, 2 , 1, 5-1hiadiazoI-3- or -4-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyI, 3- or 4-pyrida-zinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryI, 2-, 30 3-, 4-, 5-, 6- or 7-benzothienyI, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindoIyI, 1-, 2-, 4- or 5-benzimidazo I yI, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyI, 3-, 4-, 5-, 6- or 7-benzisox azoIyI, 2-, 4-, 5-, 6- or 7-benzo-35 thiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyI, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyI, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquino IyI, 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-, PAT LOG 14 060488 22 8 7 0 7 - 9 - 4-, 5-, 6-, 7- or 8-quinazo I yL . The heterocyclic radicals can also be partially or completely hydrogenated. Thus, Het can also be, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyL, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetra-5 hydro-2- or -3-furyl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrroIidinyI , tetrahydro-1-, -2- or -4-imidazoIyI, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrazoIyI , tetrahydro- 1 -, -3- or -4-pyra-10 zolyl, 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-piperidinyI, 2-, 3- or 4-morpho IinyI, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4-or 15 — 5 — yI, hexahydro-1-, -3- or -4-pyridazinyI , hexahydro-1 -, -2-, -4- or -5-pyrimidiny I , 1-, 2- or 3-piperaziny I , 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-isoquino IyI. 20 The heterocyclic radicals can also be substituted as indicated. Het can also preferably be, for example, 2-amino-4-1hiazoIyI, 4-carboxy-2-thiazoIyI , 4-carbamoyI-2-thiazolyl, 4-(2-aminoethyI)-2-1hiazoIyI, 4-amino-2-methy I - 5-pyrimidiny I , 2 - amino-5,6-dimethy I-3-pyraziny I , 4-carbamoyl 25 piperidino, furthermore, for example, 3-, 4- or 5-methyl- 2-furyl, 2-, 4- or 5-methy I-3-furyI, 2 , 4-dimethyI-3-furyI, 5-nitro-2-furyI, 5-styryI-2-furyI, 3-, 4- or 5-methyl-2-thienyl, 2-, 4- or 5-methyI-3-1hienyI, 3-methyI -5-tert.-butyI-2-1hienyI, 5-chIoro-2-thienyI, 5-phenyl-2- or -3-30 thienyl, 1-, 3-, 4- or 5-methyI-2-pyrroIyI, 1-methyl-4- or -5-nitro-2-pyrroIyI, 3,5-dimethyI-4-ethyI-2-pyrroIy I , 4-methyI-5-pyrazoIyI, 5-methyI-3-isoxazoIyI, 3,4-dimethyI -5-isoxazolyl, 4- or 5-methyI-2-thiazoIyI, 2- or 5-methyl-4-thiazolyl, 2- or 4-methyl-5-thiazolyl, 2,4-dimethyl-5-35 thiazolyl, 3-, 4-, 5- or 6-methyI-2-pyridyI, 2-, 4-, 5-or 6-methyI-3-pyridyI, 2- or 3-methyI-4-pyridy I , 3-, 4-, 5- or 6-chIoro-2-pyridyI, 2-, 4-, 5- or 6-chIoro-3-pyridyI, 2- or 3-chloro-4-pyridyI, 2,6-dichIoropyridyI, 2-hydroxy- 3-, -4-, -5- or -6-pyridyl (= 1H-2-pyridon-3-, -4-, -5- or PAT LOG 14 060488 228 7 0 7 - 10 - 6-yl), 5-phenyI- 1H-2-pyridon-3-yL, 5-p-methoxyphenyI- 1H-2-pyridon-3-yl, 2-methyL-3-hydroxy-4-hydroxymethyl-5-pyr idyl, 2-hydroxy-4-amino-6-methyl-3-pyridyl, 3-N'-methylureido-1H- 4-pyridon-5-yl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-2-5 pyrimidinyI, 2-, 5- or 6-methyL-4-pyrimidinyI, 2,6-di- methyI-4-pyrimidiny I , 2,6-dihydroxy-4-pyrimidinyL , 5-chLoro-2-methyL-4-pyrimidinyI, 3-methyI-2-benzofury I , 2-ethyI-3-benzofury I, 7-methyL-2-benzothienyI, 1-, 2-, 4-, 5-, 6-. or 7-methyl-3-indolyl, 1-metHyl-5- or -6-benzimida-10 zolyl, 1-ethyL-5- or -6-benzimidazolyI, 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2-quino IyL, 2-oxo-pyrroIidino, 2-oxo-piperi-dino, 2,5-dioxopyrroIidino or 3-benzyL-2,5-dioxopyrroIidino. is preferably R^R^N or R^OOC. O Z is preferably -NR in particular -NH- or 15 -N(CH3)-, furthermore preferably -CH2-, -CH2-0-, -CH2-NR8-(in particular -CH2-NH-) or -CH2-S-. Correspondingly, -Z-CmH2m~C0- is preferably Gly or BAla, furthermore preferably -CH2CH2~C0-, -CH2CH2CH2~C0- or -CH2-S-CH2_C0-. The parameter y is prefrably 0; n and s are pre-20 ferably each 1; m is preferably 1 or 2, furthermore preferably 0; p is preferably 1, 2, 3, 4 or 5, furthermore 6 or 7; r is preferably 1 or 2. The groups CmH2m and CpH2p are preferably particular -CH2~r or in particular -CH2~, -(CH2)2~r -(CH2)4~ or ~(CH2)5~. The 25 groups CtH2t and CWH2W are preferably each -CH2-, -(ch2)2-/ —chcch3)—, -CH ( isobutyI ) - or -CH(sec .-butyI)-; it is also possible and preferable for the group C t H 21 to be absent (t = 0). The parameter x is preferably 1, furthermore 0 or 2. 2 • 30 R is preferably Ar-alkyl, in particular benzyl, 1- or 2-naphthyI methyI, furthermore preferably cycloalkyl- alkyl, in particular cyc I ohexyI methyI, as well as Het-alkyl, in particular 2-, 3- or 4-piperidyI methyI, 2-, 3- or 4- pyridylmethyl, 2- or 3-thienylmethyl. Accordingly, the 35 group -NH-CHR^-C0- is preferably Phe, and is furthermore preferably Mai, aNal, BNal, Cal, Pia, Pya or Tia. R3 is preferably cyclohexylmethyl, furthermore preferably A, in particular methyl, ethyl, propyl, iso- propyl, butyl, isobutyl, sec.-butyl, pentyl, isopentyl, PAT LOG 14 060488 228707 (3-methyIbuty I) or 2-methyIbutyI, phenyl, benzyl, p-chloro-benzyl, 2-cycI ohexyIethyI, bicycIo[2.2.1]heptyI-2-methyI or 6,6-dimethylbicycloC3.1. 1]heptyl-2-methyl . R4 and R^3 are each preferably (H, OH). 5 R^, R^, R7, R® and R ^ are each preferably H or methyl, furthermore ethyl, propyl, isopropyl, butyl or isobutyl, and R is also preferably benzyl, a Ikoxycarbony I such as ETQC, IPOC or BOC or Ar-a Ikoxycarbony I such as CBZ, and R ^ R 7 N is also preferably pyrrolidino, piperidino 10 or 4-methyIpiperidino. i Accordingly, the group R -CpH2p-(NH)y-C0- is preferably R^-CpH2p-C0~, in particular R^(CH2)p-CO-, specifically and in particular R^R7N-CpH2p-C0-, preferably R^R7N-(CH2)p-C0~, especially H2N-CpH2p-C0-, such as aminocar-15 bonyl, aminoacetyl (H-Gly-), 3-aminopropionyI (H-BAla-), 4-amino-butyryI, 5-aminopentanoyI, 6-aminohexa noyI, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10- aminodecanoyI, 11-aminoundecanoyI, but also, for example, 2-amino-propionyI (Ala), 2 - amino-2-methyIpropionyI; ANH-20 CpH2p-C0- such as methy I aminocarbonyI, methyI amino acety I (sarcosyl), 3-methyI aminopropionyI, 4-methyI aminobutyry I , 5-methyI aminopentanoyI, 6-methyI aminohex a noyI, 6-ethyl- aminohexanoyI, 7-methy I aminoheptanoyI, 8-methyI aminooctanoyI, 9-methyI aminononanoyI, 10-methyI aminodecanoyI, 11-methyl-25 aminoundecanoyI; A2N-CpH2p-C0- such as dimethyI amino- carbonyl, dimethyI aminoacetyI, 3-dimethyI aminopropiony I , 4-dimethyI aminobutyryI, 5-dimethyI aminopentanoyI, 6-dimethyI aminohexanoyI, 6-diethyI aminohexanoyI, 7-dimethyl-aminoheptanoyI, 8-dimethyI aminooctanoyI, 9-dimethyI amino-30 nonanoyl, 10-dimethyI aminodecanoyI, 11-dimethyI aminounde-canoyl; A-0-C0-NH-CpH2p-C0- such as BOC-Gly, ETOC-Gly-, IPOC-Gly, BOC-BAla, ETOC-BAla, IPOC-BAla-, 4-BOC-amino-butyryl, 5-BOC-amino-pentanoy I , 6-BOC-amino-hexanoyI, 7-BOC-amino-heptanoyI, 8-BOC-amino-octanoyI, 9-BOC-amino-35 nonanoyl, 10-BOC-amino-decanoyI, 11-BOC-amino-undecanoy I ; ArCH2"0-CO-NH-CpH2p-CO- such as CBZ-Gly-, CBZ-BAla, 4-CBZ-amino-butyryI, 5-CBZ-amino-hexanoyI, 7-CBZ-amino-heptanoy I , 8-CBZ-amino-octanoyI, 9-CBZ-amino-nonanoyI, 10-CBZ-amino-decanoyl, 11-CBZ-amino-undecanoyI; PyrroIidino-CpH2p~C0-PAT LOG 14 060488 22 8 7 0 7 such as pyrroLidinocarbonyI, pyrroLidino-acetyI , 3-pyrro-lidino-propionyl, 4-pyrrolidino-butyryl, 5-pyrrolidino-pentanoyl, 6-pyrrolidino-hexanoyl, 4-pyrrolidino-heptanoyl, 8-pyrroIidino-octanoyL, 9-pyrroLidino-nonanoyL , 5 10-pyrroLidino-decanoyI; piperidino-CpH2p-C0- such as piperidinocarbony I , piperidinoacetyL, 3-piperidino-propionyl, 4-piperidino-butyryI, 5-piperidino-pentanoy I , 6-piperidino-hexanoyL, 7-piperidinoheptanoyI, 8-piperidino-octanoyl, 9-piperidino-nonanoyI, 1 0-piperidino-decanoyI ; 10 morphoLino-CpH2p-C0- such as morpho Iinocarbony I, morphoIinoacetyI, 3-morphol ino-propionyl, 4-morphoLino-butyryl, 5-morphoLino-pentanoyL, 6-morphoIino-hexanoyL, 7-morpholino-heptanoyL, 8-morpho Iino-octanoyI, 9-morpho- l ino-nonanoyL, 10-morphoLino-decanoyL; 4-amino-piperidino-15 CpH2p-C0- such as 4-amino-piperidino-carbonyl, 4-amino- piperidino-acetyt, 3-(4-amino-piperidino)-propionyl, 4-(4-amino-piperidino)-butyryl, 5-(4-amino-piperidino)-pentanoyl, 6-(4-amino-piperidino)-hexanoyL, 7-(4-amino-piperidino)-heptanoyl, 8-(4-amino-piperidino)-octanoyl, 20 9-(4-amino-piperidino)-nonanoyL, 1 0-(4-amino-piperidino ) -decanoyl; 4-diaLkyI amino-piperidino-CpH2p-C0- such as 4-dimethylamino-piperidinocarbonyl, 4-dirnethylaminopiperi-dino-acetyl; 4-guanidino-piperidino-CpH2p-C0- such as 4-guanidino-piperidino-carbonyL, 4-guanidino-piperidino-25 acetyl; 4-carboxy-piperidino-CpH2p-C0- such as 4-carboxy-piperidino-carbonyl, 4-carboxy-piperidino-acetyl; 4-aLkoxycarbony I-piperidino-CpH2p-C0- such as 4-methoxycar-bonyl-piperidino-carbonyl, 4-ethoxycarbonyl-piperidino-carbonyl, 4-methoxycarbonyL-piperidino-acetyL, 4-ethoxy-30 carbonyIpiperidino-acetyL; 4-AcNH-piperidino-CpH2p~C0-such as 4-acetamido-piperidino-carbonyl, 4-acetamido-piperidino-acetyL; H2N-C(=NH )-NH-CpH2p~C0- such as guani-dinoacetyl, 3-guanidinopropionyL, 4-guanidino-butyryl, 5-guanidino-pentanoyI, 6-guanidino-hexanoyL, 7-guanidino-35 heptanoyl, 8-guanidino-octanoyL; NC-NH-C(=NH)-NH-CpH2p-C0-such as N1-cyanoguan id ino-acetyl, 3-(N1 -cyanoguanidino)-propionyl, 4-(N1-cyanoguanidino)-butyryI; 5-(N'-cyano-guanidino)-pentanoyl, 6-(N'-cyanoguanidino)-hexanoyl, 7-(N'-cyanoguanidino)-heptanoyl, 8-(N'-cyanoguanidino)-PAT LOG 14 060488 22 8 7 0 7 octanoyl; H00C-CpH2p~C0- such as mal.onyl, succinyl, glutaryl, adipyl, 6-carboxyhexanoyI, 7-carboxyheptanoyI, 8-carboxyoctanoyI, 9-carboxynonanoyL, 10-carboxy-decanoyI, 11-carboxyundecanoyl; A00C-CpH2p-C0- such as methoxycar-5 bonyL-acetyL, 3-methoxycarbonyI-propionyI, 4-methoxy- carbonyL-butyryI, 5-methoxycarbony I-pentanoyL, 6-methoxy-carbonyI-hexanoyL, 7-methoxycarbonyI-heptanoyI, 8-methoxy-carbonyI-octanoyI, 9-methoxycarbonyI-nonanoyL, 10-methoxy-carbony I-decanoyI, ethoxycarbonyl-acetyL, 3-ethoxycarbonyI -10 propionyl, 4-ethoxycarbonyI-butyryL, 5-ethoxycarbony I-pentanoyl, 6-ethoxycarbonyL-hexanoyL, 7-ethoxycarbony I-heptanoyl, 8-ethoxycarbony I-octanoyI, 9-ethoxycarbonyL-nonanoyl, 10-ethoxycarbonyL-decanoyI; H-S03-CpH2p-C0- such as su I fo-acety I , 3-suIfo-propionyI, 4-suLfo-butyryL, 15 5-sulfo-pentanoyI, 6-suIfo-hexanoy I , 7-sulfo-heptanoyI, 8-suIfo-octanoyI, 9-suIfo-nonanoyI, 10-suLfo-decanoyL; A-S03-CpH2p-C0- such as methoxysuIfonyl-acetyI, 3-methoxy-su I fonyI-propionyI, 4-methoxysuIfonyI-butyryL, 5-methoxysulfonyl-pentanoyl, 6-methoxysulfonyl-hexanoyl, 20 7-methoxysuIfonyI-heptanoyI, 8-methoxysuLfonyI-octa noyI, 9-methoxysulfonyl-nonanoyl, 10-methoxysulfonyl-decanoyL, ethoxysuLfonyL-acetyL, 3-ethoxysuLfonyL-propionyL , 4- ethoxysuLfonyI-butyryL , 5-ethoxysuLfonyL-pentanoyL, o-ethoxysuLfonyL-hexanoyL, 7-ethoxysuLfonyI-heptanoyL, 8-25 ethoxysuLfonyI-octanoyI, 9-ethoxysuIfonyt-nonanoyI, 10- e t ho x y s u L f ony L-de c anoy L ; A-0-( CH2CH2O ) r_(-p^2p-(-0~ such as 3.6-di0xa-heptanoy I , 3,6- or 4 , 7-dioxa-octanoyL, 3,6-, 4.7- or 5,8-dioxa-nonanoyL> 3 , 6 , 9-1ri0xa-decanoyL, 3,6,9-or 4,7,10-trioxa-undecanoyL, 3,6,9-, 4,7,10- or 5,8,11— 30 tri0xa-dodecanoyL. If n is 2, the two radicals can be identical to or different from one another; in the latter case, preferably one radical R^ is H and the other is A, in particular isopropyl, and the group —(CHR^)n— is pre-35 ferably -CH2-CHA-, in particular -CH2-CH(isopropyI)-. R is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl or benzyl. The group W is preferably -NH-C4R3-CHOH-CH2~CO-, in particular AHCP, AHCH, Sta or AHPP. The group W is PAT LOG 14 060488 - 14 - 22 8 7 0 7 furthermore preferably -NH-CHR3-CH(NH2)-CH2-C0-, in particular DACP, DACH, DAMH or DAPP. The group W has at least one chiral centre. -] Further chiral centres may be present in the groups R to 5 R , cp^2p' cm^2m' z Q anc^ Y- compounds of the formula I can therefore occur in various, optically inactive or optically active, forms. The formula I embraces all these forms. If W is -NH-CHR3-CR^-CH2-CO- with R4 being (H, OH) or (H, NH2), the 3S-hydroxy-4S-amino 10 enantiomers and 3S,4S-diamino enantiomers are preferred. The abbreviations AHCP, AHCH, Sta, AHPP, DACP, DACH, DAMH and DAPP always relate to the 3S,4S forms. The abovementioned cycloalkyl and phenyl groups are preferably unsubstituted or preferably have 1 to 3, in 15 particular 1 or 2, substituents . E is preferably one of the said amino acid residues, t in particular lie or Leu; furthermore, E is preferably absent or is preferably Abu, Cal, Met, Nle, Nva, Phe or Val. 1 n Q is preferably NR , in particular NH or N(CH-j). 11 12 20 Y is preferably -Cj-H^-R or -ct^2t-(^ ' ^n Par~ ticular -CH2R11, -CH2R12 or -CH2CH2R12. In these, R11 is preferably H, A, Ar or Het, specifically and preferably H, alkyl having 3-5 C atoms, phenyl, o-, m- or p-amino- methy I phenyI, o-, m- or p-guanidinomethyIphenyI, o-, m- or 25 p-dia IkyI aminomethyIphenyI, such as o-, m- or p-dimethyl- aminomethyIphenyI, 2-, 3- or 4-pyridyl, 2-hydroxy-4,6- dimethyI-3-pyridyI, 4-amino-2-methyI -5-pyrimidinyI or 2- 12 amino-5,6-dimethyI-3-pyrazinyI. R is preferably -SO3H, -S02NH2, -NA2, -NA3+An", -NH-C(=NH)-NH2, -NH-CO-NHA or -NH-30 CS-NHA, wherein A is preferably CH3. Some particularly preferred meanings of the group Q-Y are -NH-CH2-(4-amino-2-methyI-5-pyrimidinyI) ("AMPA"), -NH-CH2-(2-amin0-5,6-dimethyI-3-pyrazinyI) ("ADPA") and -NH-CH2-(3-pyridyI), furthermore -NH-A. 35 Accordingly, the invention particularly relates to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated hereinbefore. Some preferred groups of compounds can be represented by the following part-formulae la to PAT LOG 14 060488 10 15 20 25 30 35 - 15 - Ii, which correspond to the formula I but in which 22 8 7 0 7 i n I a r 1 i s r6r7n- / i n lb r 1 i s r6-nh- c(=nh)-nh or nc-nh- i n Ic r 1 i s r6ooc- / i n Id r i s r6o3s- i n Ie r 1 i s r-0-(ch2ch20)r-; i n If r 1 i s r°r'n- / r6 i s H 0 r A / r7 i s h, A, boc or cbz, r6r7n i s also 4 -aminopiperidino. y i s 0 and p i s 0, 1, 2, 3, 4, 5, 6 or 7; i n ig r 1 i s r6ooc, r6 i s H 0 r A and y i s 0; i n Ih r 1 i s r6o3s, r6 i s H 0 r A and y i s 0; in I i ,6n7. R^R'N is 4-aminopiperidino and y and p are each 0. Particularly preferred compounds are those of the part-formulae: (a) Iaa to Iia, which correspond to the formulae la to Ii but in which additionally R 2 is phenyl or p-methoxyphenyl; (b) lab to lib as well as Iaab to Iiab, which correspond to the formulae la to Ii and Iaa to Iia but in which additionally -Z-CmH2m~ is -NH-CH2- or -nh-ch2ch2-; (c) lac to lie, Iaac to Iiac, Iabc to Iibc and Iaabc to Iiabc, which correspond to the formulae la to Ii, Iaa to Iia, lab to lib and Iaab to Iiab but in which additionally -NH-CHR3-CR4-( CHR5 ) n-C0- ( = VI) is AHCP; (d) lad to lid, Iaad to Iiad, Iabd to Iibd, Iacd to lied, Iaabd to Iiabd, Iaacd to Iiacd, Iabcd to Iibcd and Iaabcd to Iiabcd, which correspond to the formulae la to Ii, Iaa to Iia, lab to lib, lac to lie, Iaab to Iiab, Iaac to Iiac, Iabc to Iibc and Iaabc to Iiabc but in which additionally PAT LOG 14 060488 22 8 7 0 7 - 16 - E is lie or Leu; Particularly preferred compounds are those of the part-formulae: I* and la* to Ii*, which correspond to the formulae I and 5 la to Ii, as well as those compounds which correspond to the other abovementioned part-formulae but in which additionally Q is NH, Y i s H, A or -CH2R 11 and 1 1 10 R is o-, m- or p-aminomethyI benzyI, o-, m- or p-guan- idinomethyI benzyI, 3-pyridyl, 4-amino-2-methyI-5 -pyrimidinyl or 2-amino-5,6-dimethyI-3-pyrazinyI; I' and la' to Ii', which correspond to the formulae I and la to Ii, as well as those compounds which correspond to 15 the other abovementioned part-formuIae but in which additionally Q i s NH and Y is H, A, 4-amino-2-methyI-5-pyrimidinyI methy I or 2-amino-5,6-dimethyl-3-pyraz inylmethyl. 20 The compounds of the formula I, as well as the starting materials for the preparation thereof, are furthermore prepared by methods which are known per se and as are described in the literature (for example in the standard works such as Houben-Weyl), Methoden der organischen Chemie, 25 (Methods of Organic Chemistry), published by Georg Thieme, Stuttgart; as well as EP-A 45665, EP-A 77028, EP-A 77029, EP-A 81783, EP-A 249096) specifically under reaction conditions which are known and suitable for the said reactions. In this connection it is also possible to make use of 30 variants which are known per se and which are not mentioned in detail herein. It is also possible, if desired, to form the starting materials in situ so that they are not isolated from the reaction mixture but are immediately reacted further 35 to give the compounds of the formula I. The compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenoIysis . Preferred starting materials for the solvolysis PAT LOG 14 060488 ZZ 8 7 0 7 - 17 - or hydrogenoLysis are those which correspond to the formula I apart from containing, in place of one or more free amino and/or hydroxyl groups, corresponding protected amino and/or hydroxyl groups, preferably those which carry 5 an amino protective group in place of an H atom bonded to an N atom, for example those which correspond to the formula I but contain in place of a His group an N(im)-R'-His group (in which R' is an amino protective group, for i example BOM or DNP), or those of the formula R ~CpH2p-10 (NH)y-CO-NH-CHR2-CO-Z-CmH2ni-CO-NH-CHR3-CH(NHR,)-(CHR5)n-CO-E-Q-Y. Further preferred starting materials are those which carry, in place of the H atom of a hydroxyl group, a hydroxyl protective group, for example those of the 15 formula R 1 - C pH2 p" ( NH ) y-C0-NH-CHR2-C0-Z-C mH2n,-C0-NH-C HR3-CH0R"-(CHR5)n-C0-E-Q-Y, in which R" is a hydroxyl protective group. It is also possible for more than one - identical or different - protected amino and/or hydroxyl groups to 20 be present in the molecule of the starting material. It the protective groups which are present differ from one another it is possible in many cases to eliminate them selectively. The term "amino protective group" is generally 25 known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted 30 or substituted acyl, aryl (for example DNP), aralkoxy-methyl (for example BOM) or aralkyl groups (for example benzyl, 4-nitrobenzyI, triphenyI methyI). Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size are not 35 otherwise critical; however, those which are preferred have 1-20, in particular 1-8, C atoms. The term "acyl group" in connection with the present process is to be interpreted in the widest sense. It embraces acyl groups derived from aliphatic, araliphatic, aromatic or PAT LOG 14 060488 22 8 7 0 7 - 18 - heterocyclic carboxylic acids or sulfonic acids, as well as, in particular, a Ikoxycarbony I, aryIoxycarbony I and, especially, ara Ikoxycarbony I groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, 5 butyryl; aralkanoyl such as phenyI acetyI; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxy-carbonyl such as methoxycarbony I, ETOC, 2,2,2-trichIoro-ethoxycarbonyI, IPOC, BOC, 2-iodoethoxycarbony I ; aralkyl-oxycarbonyl such as CBZ, 4-methoxybenzyIoxycarbony I , 10 FMOC. Preferred amino protective groups are BOC, DNP and BOM, as well as CBZ, FMOC, benzyl and acetyl. The term "hydroxyl protective group" is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions 15 but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryI, aralkyl or acyl groups, as well as alkyl groups. The nature and size of the hydroxyl pro-20 tective groups are not critical because they are removed again after the desired chemical reaction or reaction sequence; preferred groups have 1-20, in particular 1-10, C atoms. Examples of hydroxyl protective groups are, inter alia, tert.-butyl, benzyl, p-nitrobenzoy I , p-toluene-25 sulphonyl and acetyl, with benzyl and acetyl being particularly preferred. The functional derivatives of the compounds of the formula I which are to be used as starting materials can be prepared by customary methods of amino acid and peptide 30 synthesis as are described, for example, in the said standard works and patent applications, for example also by the solid-phase method of Merrifield. The liberation of the compounds of the formula I from their functional derivatives is effected - depending 35 on the protective group used - for example with strong acids, preferably with trifIuoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic PAT LOG 14 060488 228 7 0 7 - 19 - acids such as benzene- or p-toLuenesuLfonic acid. The presence of an additional inert solvent is possible but not always necessary. Suitable and preferred inert solvents are organic, for example carboxylic acids such as 5 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. Furthermore suitable are mixtures of the abovementioned solvents. 10 TrifLuoroacetic acid is preferably used in excess without the addition of another solvent, and 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 cleavage are preferably between about 0 and about 50°, 15 preferably between 15 and 30° (room temperature). The BOC group can be eliminated, for example, preferably with 40 % trifLuoroacetic acid in dichloro-methane or with about 3 to 5 N HCl in dioxane at 15-30°, and the FMOC group with an approximately 5-20 % solution 20 of dimethyI amine, diethylamine or piperidine in DMF at 15-30°. Elimination of the DNP group is effected, for example, also with an approximately 3-10 % solution of 2-mercaptoethanoI in DMF/water at 15-30°. Protective groups which can be removed by hydrogen-25 olysis (for example BOM, CBZ or benzyl) can be eliminated, for example by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst such as palladium, preferably on a support such as carbon). Solvents suitable for this are those mentioned above, in par-30 ticular, for example, alcohols such as methanol or ethanol or amides such as DMF. Hydrogenolysis is, as a rule, carried out at temperatures between about 0 and 100° under pressures between about 1 and 200 bar, preferably at 20-30° and under 1-10 bar. HydrogenoIysis of the CBZ group 35 is effected satisfactorily, for example, on 5-10 % Pd-C in methanol at 20-30°. Compounds of the formula I can also be obtained by direct peptide synthesis from a carboxylic acid component (formula II) and an amine component (formula III). PAT LOG 14 060488 228 7 0 7 - 20 Examples of suitable carboxylic acid components are those of the part-formulae (a) R 1 -CpH2p~(NH)y-C00H, (b) R1-CpH2p-(NH)y-C0-NH-CHR2-C00H, (c) R 1 -CpH2p-(NH)y-C0-NH-CHR2-C0-Z-Cm-H2m-C00H, (d) R 1 -CpH2p-(NH)y-C0-NH-CHR2-C0-Z-5 CmH2m-C0-W-0H or (f) R 1-CpH2p-(NH)y-C0-NH-CHR2-C0-Z-CmH2m-CO-W-E-OH, and of amine components are those of the part-formulae (a) H2N-CHR2-CO-Z-CmH2m-CO-W-E-Q-Y, (b) H-Z- cmH2m~co"w"E-Q~Y' (c) H-W-E-Q-Y, (d) H-E-Q-Y or (f) H- 1 0 NR -Y. The peptide linkage can, however, also be formed 10 within the group E; this entails a carboxylic acid of the formula (e) R1-CpH2p-(NH)y-C0-NH-CHR2-C0-Z-CniH2m-C0-W-E1- OH being reacted with an amino compound of the formula H- 2 12 E -Q-Y, where E + E = E. The methods preferably used for this are those customary in peptide synthesis, as are 15 described, for example, in Houben-Weyl, I. c., Volume 15/11, pages 1-806 (1974). The reaction is preferably effected in the presence of a dehydrating agent, for example a carbodiimide such as DCCI or dimethyI aminopropyIethyI-carbodiimide, or 20 else propanephosphonic anhydride (compare Angew. Chem. 92, 129 ( 1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon such as dichloro-methane, an ether such as tetrahydrofuran or dioxane, an 25 amide such as DMF or dimethyLacetamide, or a nitrile such as acetonitrile, at temperatures between about -10 and 40, preferably between 0 and 30°. It is also possible, in place of II or III, to use suitable reactive derivatives of these substances in 30 the reaction, for example those in which reactive groups have undergone intermediate blocking with protective groups. The acid derivatives II can be used, for example, in the form of their activated esters which are preferably formed in situ, for example by addition of.HOBt or N-35 hydroxysuccinimide. Urea derivatives of the formula I (y = 1) can be obtained, for example, by reacting an isocyanate of the formula R^-CpH2p-NC0 (can be prepared from an amine of the formula R^-CpH2p-NH2 and phosgene) with an amine of the PAT LOG 14 060488 - 21 - 22 8 7 0 7 formula H2N-CHR2-CO-Z-CmH2m-CO-W-E-Q-Y (Iia), preferably in an inert solvent such as THF, at temperatures between about -10 and 40°, preferably between 10 and 30°. The starting materials of formulae II and III are 5 mostly known. Those which are unknown can be prepared by known methods, for example the abovementioned methods of peptide synthesis and of elimination of protective groups. If desired, it is possible for a functionally 10 modified amino and/or hydroxyl group in a compound of the formula I to be liberated by solvolysis or hydrogenolysis by one of the methods described above. Thus, for example, a compound of the formula I o which contains an R -CXH2x-0-C0-NH-, an AcNH-, an ArCH2-15 so3- or an AOOC-group can be converted into the corresponding compound of the formula I which contains in its stead an H2N-, an hso3- or an H00C- group, preferably by selective solvolysis by one of the methods indicated above. AOOC-groups can, for example, be hydrolyzed with 20 NaOH or KOH in water/dioxane at temperatures between 0 and 40°, preferably 10 and 30°. Furthermore, for example, keto compounds of the 4 formula I (R =0) can be reduced to compounds of the formula I (R4 = (H, OH)), for example with a complex metal 25 hydride such as NaBH^ which does not simultaneously reduce the peptide carbonyl groups, in an inert solvent such as methanol at temperatures between about -10 and +30°. Keto compounds of the formula I (R4 = 0) can also be converted into compounds of the formula I (R4 = H, NH2) 30 by reductive amination. The reductive aminat ion can be carried out in one or more stages. Thus, for example, the keto compound can be treated with ammonium salts, for example ammonium acetate and NaCNBHj, preferably in an inert solvent, for example an alcohol such as methanol, 35 at temperatures between about 0 and 50°, in particular between 15 and 30°. It is furthermore possible initially to convert the keto compound into the oxime, using hydroxyl-amine in a customary manner, and to reduce the oxime to the amine, for example by catalytic hydrogenation on Raney PAT LOG 14 060488 22 87 0 7 - 22 - nickel. A base of the formula I can be converted into the relevant acid addition salt using an acid. Particularly suitable acids for this reaction are those which provide 5 physiologically accetable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydro-bromic acid, phosphoric acids such as orthop hosphoric acid, sulfamic acid, as well as organic acids, in particular 10 aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, 15 lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or 'ethanesuIfonic acid, ethanedisuLfonic acid, 2-hydroxyethanesuIfonic acid, benzenesulfonic acid, p-toIuenesuIfonic acid, naphthalene-mono- and 20 -disulfonic acids and lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds of the formula I. The new compounds of the formula I and the physio-25 logically acceptable salts thereof can be used to prepare pharmaceutical products by converting them, together with at least one vehicle or auxiliary and, if desired, together with one or more other active substance(s), into a suitable dosage form. The compositions obtained in this 30 way can be used as medicaments in human or veterinary medicine. Suitable vehicles are organic or inorganic substances which are suitable for enteral (for example oral or rectal) or parenteral administration or for administration in the form of a spray for inhalation and which do 35 not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc and cellulose. Used orally are, in PAT LOG 14 060488 22 87 0 7 particular, tablets, coated tablets, capsules, syrups, elixirs or drops; specifically of interest are lacquered tablets and capsules with enteric coatings or capsule shells. Used rectally are suppositories, and for parent-5 eral administration are solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants. For administration by spray for inhalation, it is possible to use sprays which contain the active substance either dissolved or suspended in a propellant gas 10 mixture (for example f I uorochIorohydrocarbons). The active substance is preferably used for this in micronized form, with one or more additional physiologically tolerated solvents possibly being present, for example ethanol. Solutions for inhalation can be administered with the aid 15 of customary inhalers. The new compounds can also be freeze-dried and the resulting Iyophi I isates used, for example, to prepare products for injection. The stated compositions can be sterilized and/or contain auxiliaries such as preservatives, stabilizers and/or wetting agents, 20 emulsifiers, salts to influence the osmotic pressure, buffer substances, colorants and/or flavourings. They can, if desired, also contain one or more other active substances, for example one or more vitamins. The substances according to the invention are, 25 as a rule, administered in analogy to other known, commercially available peptides, but especially in analogy to the compounds described in EP-A 249096, preferably in dosages between about 10 mg and 1 g, in particular between 50 mg and 500 mg, per dosage unit. The daily dosage is 30 preferably between about 0.2 and 20 mg/kg, in particular 1 and 10 mg/kg, of bodyweight. The specific dose for each particular patient depends, however, on a wide variety of factors, for example on the activity of the specific compound used, on the age, body weight, general state of 35 health and sex, on the diet, on the time and route of administration and on the rate of excretion, medicinal substance combination and severity of the particular disease for which the therapy is applied. Parenteral administration is preferred. PAT LOG 14 060488 22 8 7 0 7 - 24 - Renin-dependent hypertension and hyperaLdosteronism can be effectively treated by administration of dosages between, in particular, about 1 and 300, preferably between 5 and 50, mg/kg of body weight. For diagnostic purposes, 5 it is possible and preferable for the new compounds to be administered in single doses, particularly in about 0.1 and 10 mg/kg of body weight. All temperatures stated hereinbefore and hereinafter are in °C. In the examples which follow, "usual 10 working up" means: if necessary, water is added, the pH is adjusted to betwen 2 and 8, depending on the constitution of the final product, extraction is carried out with ethyl acetate or dichIoromethane, the organic phase is separated off, dried over sodium sulfate, filtered and concentrated, 15 and purification is carried out by chromatography on silica gel and/or crystallization. Example 1 A mixture of 890 mg of 3S-hydroxy-4S-(4-dimethy I -aminobutyryl-L-phenylalanyl-glycyl-amino)-5-cyclohexyl-20 pentanoyl-N-imi-(2,4-dinitrophenyl)-L-histidine N-butyl-amide C"4-dimethylaminobutyryl-Phe-Gly-AHCP-(imi-DNP-His) N-butyI amide" ; obtainable by reaction of 4-dimethyI amino-butyric acid with H-Phe-Gly-AHCP-(imi-DNP-His) N-butylamide], 2 g of 2-mercaptoethanoI, 20 ml of DMF and 20 ml of water 25 is adjusted to pH 8 with aqueous Na2C03 solution while stirring at 20° and is stirred at 20° for 2 hours. The usual working up results in 4-dimethyI aminobutyryI-Phe-Gly-AHCP-His N-butylamide. Example 2 30 10 g of 3S-CBZ-amino-4S-(4-dimethyI amino-butyryI- Phe-GIy-amino)-5-cycIohexyI-pentanoyI-IIe AMPA (obtainable by reaction of 4-dimethyI aminobutyryI-Phe-0H with 3S-CBZ-amino-4S-Gly-amino-5-cyclohexyl-pentanoyl-Ile AMPA) are dissolved in 150 ml of ethanol and hydrogenated on 5 g of 35 10 % Pd-C at 20° and under 1 bar until H£ uptake ceases, the mixture is filtered, the filtrate is evaporated, and purification by chromatography results in 3S-amino-4S-(4-dimethylamino-butyryl-Phe-Gly-amino)-5-cyclohexyl-penta-noyl-Ile AMPA ("4-dimethyI aminobutyryI-Phe-GIy-DA CP-11e PAT LOG 14 060488 22 8 7 0 7 - 25 - AMPA" ) . The following are obtained analogously from the corresponding CBZ derivatives: 5 4-Morpholino-butyryl-Phe-Gly-DACH-Ile-OMe 4-Pyrrolidino-butyryl-Phe-Gly-DAMH-Ile-NH2 4-Piperidino-butyryl-Phe-Gly-DAPP-Ile-OEt. 4-B0C-amino-piperidinocarbonyl-Phe-Gly-AHCP-His-NH2 10 is obtained analogously by hydrogenolysis of 4-BOC-amino-piperidinocarbonyl-Phe-Gly-AHCP-(imi-BOM-His) amide. E x amp Ie 3 A solution of 1 g of the di-BOC derivative of 4-guanidino-piperidinocarbony I-Phe-0AI a-AHCP-11 e AMPA Cob-15 tainable by reaction of N,N'-di-BOC-S-methyI-isothiourea (m.p. 121°) with 4-aminopiperidinocarbony I-Phe benzyl ester to give 4-(N,N1-di-BOC-guanidino)-piperidinocarbony I -Phe benzyl ester, hydrogenolysis to give 4-(N , N 1-di-BOC-guanidino)-piperidinocarbony I-Phe-OH and condensation with 20 H-0AI a-AHCP-11e AMPA3 in 20 ml of 4 N HCl in dioxane is stirred at 20° for 30 min and then evaporated. 4-Guani-dino-piperidinocarbonyI-Phe~8AI a-AHCP-11e AMPA is obtained in the form of the dihydrochIoride. The following are obtained analogously from the 25 corresponding di-BOC or tri-BOC derivatives: 4-Guanidino-piperidinocarbonyl-Phe-Gly-AHCP-I le AMPA 4-Guanidino-piper 4-Guanidino-piper 30 4-Guanidino-piper 4-Guanidino-piper dinocarbonyl-Phe-Gly-AHCP-Ile ADPA dinocarbonyl-Phe-Gly-AHCP-Leu AMPA dinocarbonyl-Phe-Gly-AHCP-Leu ADPA dinocarbonyl-Phe-8Ala-AHCP-Ile ADPA 4-Guadidino-piperidinocarbonyl-Phe-BAla-AHCP-Leu AMPA 4-Guanidino-piperidinocarbonyl-Phe-BAla-AHCP-Leu ADPA 35 6-Guanidino-hexanoyI-Phe-GIy-AHCP-11e AMPA 6-Guanidino-hexanoyl-Phe-Gly-AHCP-Ile ADPA 6-Guanidino-hexanoyl-Phe-Gly-AHCP-Leu AMPA 6-Guanidino-hexanoyl-Phe-Gly-AHCP-Leu ADPA 6-Guanidino-hexanoyl-Phe-BAla-AHCP-Ile AMPA PAT LOG 14 060488 22 8 7 0 7 - 26 - 6-Guanidino-hexanoyl-Phe-BAla-AHCP-Ile ADPA 6-Guanidino-hexanoyl-Phe-BAla-AHCP-Leu AMPA 6-Guanidino-hexanoyl-Phe-BAla-AHCP-Leu ADPA 6-Guanidino-hexanoyl-Mal-Gly-AHCP-Ile AMPA 5 6-Guanidino-hexanoyI-Ma I-GIy-AH CP-1Ie ADPA 6-Guanidino-hexanoyl-Mal-BAla-AHCP-Ile AMPA 6-Guanidino-hexanoyl-Mal-BAla-AHCP-Ile ADPA. 6-Amino-hexanoyl-Phe-Gty-AHCP-Ile N-6-aminohexyl-amide 10 6-Amino-hexanoyl-Phe-8Ala-AHCP-Ile N-6-amino.hexyl-amide 6-Amino-hexanoyl-Phe-Gly-AHCP-Ile N-6-guanidinohexyl-amide 6-Amino-hexanoyl-Phe-BAla-AHCP-Ile N-6-guanidinohexyl-amide, Example 4 15 1.01 g of N-methyI morphoLine are added to a solu tion of 6.52 g of H-Phe-GIy-AHCP-11e AMPA (obtainable by condensation of BOC-Phe-GIy-AHCP-11e-OH with 4-amino-5-aminomethyI-2-methyI-pyrimidine to give BOC-Phe-GIy-AHCP-Ile AMPA and subsequent elimination of the BOC group) in 20 160 ml of DMF. While stirring, 2.31 g of 6-BOC-amino-hexanoic acid, 1.35 g of HOBt and a solution of 2.06 g of DCCI in 50 ml of CH2CI2 are added, the mixture is stirred at 4° for 12 hours, the precipitated dicyclo-hexylurea is filtered off, and the filtrate is evaporated. 25 The usual working up results in 6-BOC-aminohexanoyI-Phe-Gly-AHCP-Ile AMPA, m.p. 114°. The following are obtained analogously: BOC-BAla-Phe-Gly-AHCP-Ile-NH2 30 BOC-BAla-Phe-Gly-AHCP-I le N-butylamide BOC-BAla-Phe-Gly-AHCP-Ile N-pentylamide BOC-BAIa-Phe-GIy-AHCP-11e N,N-diethyI amide BOC-BAla-Phe-Gly-AHCP-Ile AMPA 35 BOC-BAla-Phe-Gly-AHCP-Ile ADPA BOC-BAla-Phe-Gly-AHCP-Leu AMPA BOC-BAla-Phe-Gly-AHCP-Leu ADPA BOC-BAla-Phe-BAla-AHCP-Ile AMPA PAT LOG 14 060488 BOC-BAla-Phe-BAl BOC-BAL a-Phe-8Al BOC-BAla-Phe-BAI - 27 -a-AHCP-II e ADPA a-AHCP-Leu AMPA a-AHCP-Leu ADPA 2Z87 0 7 5 4-BOC-aminobutyryI-Phe-GIy-AH CP-11e AMPA 4-BOC-aminobutyryl-Phe-Gly-AHCP-Ile ADPA 4-BOC-aminobutyryl-Phe-GLy-AHCP-Leu AMPA 4-BOC-aminobutyryl-Phe-Gly-AHCP-Leu ADPA 4-BOC-aminobutyryl-Phe-BAla-AHCP-Ile AMPA 10 4-BOC-aminobutyryI-Phe-BALa-AHCP-ILe ADPA 4-BOC-aminobutyryl-Phe-BAla-AHCP-Leu AMPA 4-BOC-aminobutyryl-Phe-BAla-AHCP-Leu ADPA 4-BOC-aminobutyryl-Mal-Gly-AHCP-Ile AMPA 15 4-BOC-aminobutyryl-MaL-GLy-AHCP-ILe ADPA 4-BOC-aminobutyryl-Mai-BALa-AHCP-ILe AMPA 4-BOC-aminobutyryl-Mal-BAla-AHCP-Ile ADPA 5-BOC-aminopentanoyl-Phe-Gly-AHCP-Ile AMPA 20 5-BOC-aminopentanoyI-Phe-GIy-AHCP-11e ADPA 5-BOC-aminopentanoyl-Phe-BAla-AHCP-Ile AMPA 5-BOC-aminopentanoyl-Phe-BAla-AHCP-ILe ADPA 6-BOC-aminohexanoyl-Phe-Gly-AHCP-Ile amide 25 6-BOC-aminohexanoyI-BA Ia-GIy-AHCP-11e amide 6-BOC-aminohexanoyI-Phe-GIy-AHCP-11e ADPA, m.p. 170-171° 6-BOC-aminohexanoyl-Phe-Gly-AHCP-Leu AMPA 6-BOC-aminohexanoyl-Phe-GLy-AHCP-Leu ADPA 6-BOC-aminohexanoyl-Phe-BAla-AHCP-Ile AMPA 30 6-BOC-aminohexa noyI-Phe-BAI a-AH CP-11e ADPA 6-BOC-aminohexanoyl-Phe-BAla-AHCP-Leu AMPA 6-BOC-aminohexanoyl-Phe-8Ala-AHCP-Leu ADPA 6-BOC-aminohexa noyI-Ma I-GIy-AHCP-11e AMPA 35 6-BOC-aminohexanoyl-Mal-Gly-AHCP-Ile ADPA 6-BOC-aminohexanoyl-Mal-BAla-AHCP-Ile AMPA 6-BOC-aminohexa noyI-Ma I-BAI a-AH CP-11e ADPA 6-BOC-aminohexanoyl-Phe-Gly-AHCP-Ile N-3-pyridylmethyl-amide^ m.p. 167 - 168° PAT LOG 14 060488 22 8 7 0 7 - 28 - 6-BOC-aminohexanoyL-Phe-BALa-AHCP-ILe N-3-pyridylmethylamide 6-BOC-aminohexanoyl-Phe-Gly-AHCP-Ile N-m-aminomethyL-benzylamide 6-B0C-aminohexanoyL-Phe-8ALa-AHCP-ILe N-m-aminomethyL-5 benz y L am i de 6-BOC-aminohexanoyl-Phe-GLy-AHCP-ILe N-p-dimethylamino-methyl-benzylamide 6-B0C-aminohexanoyL-Phe-8ALa-AHCP-ILe N-p-dimethyLamino-methyl-benzylamide 10 6-BOC-aminohexanoyL-Phe-GLy-AHCP-ILe N-5-tetrazoLyL-me thy L am i de 6-B0C-aminohexanoyl-Phe-8Ala-AHCP-ILe N-5-tetrazoLyl-methylamide 6-BOC-aminohexanoyL-Phe-GLy-AHCP-ILe N-3-dimethylamino-15 propyLamide 6-BOC-aminohexanoyl-Phe-BAla-AHCP-Ile N-3-dimethyLamino-propyLamide 6-BOC-aminohexanoyL-Phe-GLy-AHCP-ILe N-2-suLfoethyLamide 6-BOC-aminohexanoyL-Phe-BALa-AHCP-ILe N-2-suLfoethyLamide 20 3-C6-.B0C-aminohexanoyL-Phe]-propionyL-AHCP-ILe AMPA 3-C6-B0C-aminohexanoyL-Phe]-prop ionyl-AHCP-lLe ADPA 4-C6-B0C-aminohexanoyL-Phe]-3-th iabutyryl-AHCP-Ile AMPA 4-C6-B0C-aminohexanoyL-Phe]-3-th iabutyryL-AHCP-ILe ADPA 25 7-BOC-aminoheptanoyL-Phe-GLy-AHCP-ILe AMPA 7-BOC-aminoheptanoyL-Phe-GLy-AHCP-ILe ADPA 7-BOC-aminoheptanoyL-Phe-GLy-AHCP-ILe AMPA 7-BOC-aminoheptanoyL-Phe-GLy-AHCP-ILe ADPA 30 8-BOC-aminooctanoyL-Phe-GLy-AHCP-ILe AMPA, m.p- 162° 8-BOC-aminooctanoyL-Phe-GLy-AHCP-ILe ADPA 8-BOC-aminooctanoyL-Phe-BALa-AHCP-ILe AMPA, m.p. 203° (dec.) 8-BOC-aminooctanoyL-Phe-BALa-AHCP-ILe ADPA 35 DimethyLaminoacetyl-Phe-Gly-AHCP-ILe AMPA 3-Dimethylamino-propionyL-Phe-GLy-AHCP-ILe AMPA 4-Dimethylamino-butyryL-Phe-GLy-AHCP-ILe AMPA, PAT LOG 14 060488 10 15 20 25 - 29 - 22 87 0 7 m.p. 198-199 ; dihydroch I oride m.p. 131 (decomposition) 4-Dimethylamino-butyryL-Phe-Gly-AHCP-Ile ADPA, d i h y dro c h (. o r i de m.p. 131° 4-Dimethylam 5 anilide, hydrochloride m.p. 136-140 4-0 i met hyI am 4-0 imethylam 4-Dimethylam di hydrochlor 4-0imethylam 4-Dimethylam 4-Dimethylam 4-D imethylam 4-Dimethylam 4-D imethylami 4-D imethylam 5-Dimethylam 5-0 imethylam 5-D imethylami 5-D imethylam 5-D imethylam 5-0 imethylami 5-D imethylam 5-D imethylam 6-D imethylami no-hexanoyl-Phe 6-0 imethylamino-hexanoyl-Phe no-hexanoyl-Phe ■Phe ■Phe ■Phe •Phe 35 6-0 imethylami no-hexanoyl-Phe 30 6-Dimethylami 6-Dimethylam ino-hexanoyl 6-D imethylamino-hexanoyl- 6-D imethylami 6-D imethylami no-butyryl-Phe-Gly-AHCP-Ile p-sulfamoyl- no-butyryI-Phe-GIy-AH CP-Leu AMPA no-butyry I-Phe-G I y-AHCP-Leu ADPA no-butyryl-Phe-0Ala-AHCP-Ile AMPA, de m.p. 196° (decomposition) no-butyryl-Phe-BAla-AHCP-Ile ADPA no-butyryl-Phe-gAla-AHCP-Leu AMPA no-butyryl-Phe-BAla-AHCP-Leu ADPA nobutyryl-Mal-Gly-AHCP-Ile AMPA nobutyryI-Ma I-GIy-AHCP-11e ADPA nobutyryI-Ma I-BAI a-AHCP-11e AMPA nobutyry1-Ma I-BAI a-AHCP-11e ADPA no-pentanoyl no-pen t anoyI no-pent anoyI no-pen t anoy I ino-pentanoyl no-pen t anoy I ■ no-pentanoyl-ino-pentanoyl ■Phe-Gly-AHCP-Ile AMPA Phe-Gly-AHCP-Ile ADPA. Phe-Gly-AHCP-Leu AMPA Phe-Gly-AHCP-Leu ADPA Phe-BAla-AHCP-Ile AMPA Phe-BAla-AHCP-Ile ADPA Phe-BAIa-AHCP-Leu AMPA Phe-BAla-AHCP-Leu ADPA no-h ex anoyI no-h e x a noyI ■ -Gly-AHCP-Ile AMPA -Gly-AHCP-Ile ADPA -Gly-AHCP-Leu AMPA -Gly-AHCP-Leu ADPA -BAla-AHCP-IIe AMPA -BAIa-AHCP-Ile ADPA -BAla-AHCP-Leu AMPA -BAla-AHCP-Leu ADPA C6-Dimethylamino-hexanoyl-Phe]-propionyl-AHCP-Ile AMPA C6-Dimethylamino-hexanoyl-Phe]-propionyl-AHCP-Ile ADPA C6-0imethylamino-hexanoyl-Phe3-3-thiabutyryl-AHCP-Ile PAT LOG 14 060488 3-3-3- 22 87 0 7 AMPA 4-[6-DimethyLamino-hexanoyL-Phe]-3-thiabutyryl-AHCP-Ile ADPA 5 6-DimethyLamino-hexanoyL-MaL-GLy-AHCP-11e AMPA 6-Dimethylamino-hexanoyl-Mal-Gly-AHCP-Ile ADPA 6-Dimethylanuno-hexanoyl-Mal-BAla-AHCP-Ile AMPA 6-Dimethylamino-hexanoyl-Mal-BAla-AHCP-Ile ADPA 7-DimethyLamino-heptanoyl-Phe-GLy-AHCP-ILe AMPA 10 8-DimethyI amino-octanoyL-Phe-GLy-AHCP-11e AMPA (4-PiperidyI)-acetyI-Phe-GIy-AHCP-11e AMPA, dihydrochIoride m.p. 232° (4-Piperidyl)-acetyl-Phe-Gly-AHCP-Ile ADPA 15 (4-PiperidyI)-acetyI-Phe-BA I a-AH CP -11 e AMPA, dihydrochLoride m.p. 75° (4-Piperidyl)-acetyl-Phe-8Ala-AHCP-Ile ADPA Piperidinoacetyl-Phe-Gly-AHCP-Ile AMPA 20 Piperldino acetyI-Phe-GLy-AHCP-1Le ADPA Piperidinoacetyl-Phe-BAla-AHCP-ILe AMPA PiperidinoacetyL-Phe-BAla-AHCP-ILe ADPA 3-Piperidino-propionyl-Phe-Gly-AHCP-Ile AMPA 25 3-Piperidino-propionyL-Phe-GLy-AHCP-ILe ADPA 3-Piperidino-propionyI-Phe-BAI a-AHCP-11e AMPA, m.p. 188° 3-Piperidino-propionyL-Phe-BALa-AHCP-ILe ADPA 4-PyrroLidino-butyryL-Phe-GLy-AHCP-ILe AMPA , dihydrochloride , oil 30 4-PyrroLidino-butyryL-Phe-GLy-AHCP-ILe ADPA 4-PyrroLidino-butyryL-Phe-SALa-AHCP-ILe AMPA 4-PyrroIidino-butyryI-Phe-8AI a-AHCP-11e ADPA 4-Piperidino-butyryL-Phe-GLy-AHCP-ILe AMPA, dihydrochLoride 35 m.p. 79° 4-Piperidino-butyryl-Phe-Gly-AHCP-Ile ADPA 4-Piperidino-butyryI-Phe-8AI a-AHCP-11 e AMPA, m.p. 199° 4-Piperidino-butyryL-Phe-BALa-AHCP-ILe ADPA PAT LOG 14 060488 22 870 7 - 31 - 5-Pyrrol idino-pentanoyl-Phe-Gly-AHCP-Ile AMPA ,dihydrochloride, oil 5-Pyrrolidino-pentanoyl-Phe-Gly-AHCP-Ile ADPA 5-PyrroIidino-pentanoyI-Phe-BAIa-AHCP-ILe AMPA, m.p. 231° 5-Pyrrolidino-pentanoyl-Phe-BAla-AHCP-Ile ADPA 5 5-Piperidino-pentanoy I-Phe-GIy-AHCP-1 Ie AMPA, dihydrochIoride m.p. 62° 5-Piperidino-pentanoyl-Phe-Gly-AHCP-Ile ADPA 5-Piperidino-pentanoyI-Phe-BAIa-AHCP-11e AMPA, m.p. 202° 10 5-Piperidino-pentanoyl-Phe-BAla-AHCP-Ile ADPA 6-CBZ-amino-hexanoyl-Phe-Gly-AHCP-Ile AMPA, 6-CBZ-amino-hexanoyI-Phe-GIy-AHCP-11e ADPA,m.p. 167 - 168°' (decomposition) 15 6-CBZ-amino-hexanoyI-Phe-BAIa-AHCP-11e AMPA 6-CBZ-amino-hexanoyl-Phe-8Ala-AHCP-Ile ADPA 2-CBZ-amino-2-methyl-propionyl-Phe-Gly-AHCP-Ile AMPA, m.p. 128° 2-CBZ-amino-2-methyl-propionyl-Phe-Gly-AHCP-Ile ADPA 20 2-CBZ-amino-2-methyI-propionyI-Phe-BA Ia-AHCP-11e AMPA, m.p. 191-192° 2-CBZ-amino-2-methyl-propionyl-Phe-6Ala-AHCP-Ile ADPA 2-C8Z-amino-2-methyl-propionyl-Mal-Gly-AHCP-Ile AMPA, m.p. 185-186° 25 2-CBZ-amino-2-methyI-propionyI-Ma I-GIy-AHCP-11e ADPA 2-C8Z-amino-2-methyl-propionyl-Mal-BAla-AHCP-Ile AMPA, m.p. 191-192° 2-CBZ-amino-2-methyl-propionyl-Mal-BAla-AHCP-Ile ADPA. 30 Example 5 4-BOC-amino-piperidinocarbonyl-Phe-BAla-AHCP-Ile AMPA is obtained in analogy to Example 4 from 4-BOC-amino-piperidinocarbony I-Phe-0H (m.p. 158-159°) and H-BAla-AHCP-Ile AMPA (obtainable from BOC-BAI a-AHCP-11e AMPA (m.p. 35 163-164°)), m.p. 185° (decomposition). The following are obtained analogously 3,6-Diox aheptanoyI-Phe-GIy-AHCP-11e AMPA, m.p. 130° [obtainable via BOC-GIy-AHCP-11e AMPA (m.p. 151°) and PAT LOG 14 060488 22 870 7 - 32 - H-Gly-AHCP-Ile AMPA] 3,6-Dioxaheptanoyl-Phe-Gly-AHCP-Ile ADPA 3,6-D ioxaheptanoyl-Phe-BALa-AHCP-Ile AMPA 3,6-Dioxaheptanoyl-Phe-BAla-AHCP-Ile ADPA 5 3,6,9-TrioxadecanoyI-Phe-GIy-AHCP-11e AMPA, m.p. 110°; hydrochloride m.p. 85° 3,6,9-Trioxadecanoyl-Phe-Gly-AHCP-Ile ADPA 3,6,9-Trioxadecanoyl-Phe-BAla-AHCP-Ile AMPA 10 3,6,9-Trioxadecanoyl-Phe-BAla-AHCP-Ile ADPA 4-BOC-amino-piperidinocarbonyl-Phe-Gly-AHCP-Ile AMPA, m.p. 152-15.3° 4-BOC-amino-piper idinocarbonyl-Phe-Gly-AHCP-Ile ADPA 15 4-B0C-amino-piperidinocarbony I-Phe-GIy-AHCP-Leu AMPA 4-BOC-amino-piper idinocarbonyl-Phe-Gly-AHCP-Leu ADPA 4-BOC-amino-piper idinocarbonyl-Phe-BAla-AHCP-Ile AMPA 4-BOC-amino-piper idinocarbonyl-Phe-BAla-AHCP-Ile ADPA, m.p. 173-174° 20 4-B0C-amino-piperidinocarbony I-Phe-BAI a-AHCP-11e N-2-pyridyI methyI amide 4-BOC-amino-piperidinocarbonyl-Phe-BAla-AHCP-Ile N-3-pyridyI methyI amide, m.p. 145° 4-BOC-amino-piper idinocarbonyl-Phe-BAla-AHCP-Leu AMPA,m.p. 181-182° 25 4-BOC-amino-piperidinocarbonyI-Phe-BAIa-AHCP-Leu ADPA 4-BOC-amino-piper idinocarbonyl-Phe-Gly-AHCH-Ile AMPA 4-BOC-amino-piperidinocarbonyl-Phe-Sta-Ile AMPA 4-BOC-amino-piperidinocarbonyl-Phe-AHPP-Ile AMPA 30 4-Dimethylamino-piperidinocarbonyl-Phe-Gly-AHCP-Ile AMP A, m.p. 124-125° 4-Dimethylamino-piperidinocarbonyl-Phe-Gly-AHCP-Ile ADPA 4-Dimethylamino-piperidinocarbonyl-Phe-BAla-AHCP-Ile AMPA dihydrochloride, m.p. 261° (dec.) 4-Dimethylamino-piperidinocarbonyl-Phe-BAla-AHCP-Ile ADPA 35 4-Ethoxycarbony I-piperidinocarbony I-Phe-GIy-AH CP-11e AMPA 4-Ethoxycarbonyl-piperidinocarbonyl-Phe-Gly-AHCP-Ile ADPA 4-Ethoxycarbonyl-piperidinocarbonyl-Phe-BAla-AHCP-IleAMPA, m.p. 132-133° 4-Ethoxycarbonyl-piperidinocarbonyl-Phe-BAla-AHCP-Ile ADPA PAT LOG 14 060488 228707 N-(Ethoxycarbonylmethyl)-carbamoyl-Phe-Gly-AHCP-Ile AMPA N-(Ethoxycarbonylmethyl)-carbamoyl-Phe-Gly-AHCP-Ile ADPA N-(Ethoxycarbonylmethyl)-carbamoyl-Phe-BAla-AHCP-Ile AMPA N-(Ethoxycarbonylmethyl)-carbamoyl-Phe~BAla-AHCP-Ile ADPA 5 N-(4-MethoxycarbonyIbutyI)-carbamoyL-Phe-GIy-AHCP-11e AMPA N-(4-Methoxycarbonylbutyl)-carbamoyl-Phe-Gly-AHCP-Ile ADPA N-(4-Methoxycarbonylbutyl)-carbamoyl-Phe-8Ala-AHCP-Ile AMPA N-(4-Methoxycarbonylbutyl)-carbamoyl-Phe-BAla-AHCP-Ile ADPA 10 N-(6-Methoxycarbonylhexyl)-carbamoyl-Phe-Gly-AHCP-Ile AMPA N-(6-Methoxycarbonylhexyl)-carbamoyl-Phe-Gly-AHCP-Ile ADPA N-(6-Methoxycarbonylhexyl)-carbamoyl-Phe-BAla-AHCP-Ile AMPA N-(6-Methoxycarbonylhexyl)-carbamoyl-Phe-BAla-AHCP-Ile ADPA. 15 Example 6 6-Methoxycarbonyl-hexanoyl-Phe-Gly-AHCP-Ile ADPA, m.p. 176-177°, is obtained in analogy to Example 4 by condensation of 6-methoxycarbonyI-hexanoyI-Phe-GIy-OH with 20 H-AHCP-Ile ADPA. The following are obtained analogously 3-Methoxycarbonyl-propionyl-Phe-Gly-AHCP-Ile AMPA 3-Methoxycarbonyl-propionyl-Phe-Gly-AHCP-Ile ADPA 25 3-Methoxycarbony I-propionyI-Phe-0AI a-AHCP-11e AMPA 3-Methoxycarbonyl-propionyl-Phe-BAla-AHCP-Ile ADPA 4-Ethoxycarboriyl-butyryl-Phe-Gly-AHCP-Ile AMPA 4-Ethoxycarbonyl-butyryl-Phe-Gly-AHCP-Ile ADPA 30 4-Ethoxycarbony I-butyryI-Phe-BAIa-AHCP-11 e AMPA 4-Ethoxycarbonyl-butyryl-Phe-BAla-AHCP-Ile ADPA 5-Ethoxycarbonyl-pentanoyl-Phe-Gly-AHCP-Ile AMPA 5-Ethoxycarbonyl-pentanoyl-Phe-Gly-AHCP-Ile ADPA 35 5-EthoxycarbonyI-pentanoyI-Phe-BA1a-AHCP-11 e AMPA 5-Ethoxycarbonyl-pentanoyl-Phe-BAla-AHCP-Ile ADPA 6-Methoxycarbonyl-hexanoyl-Phe-Gly-AHCP-Ile AMPA, m.p. 88-89° PAT LOG 14 060488 22 8 7 0 7 - 34 - 6-MethoxycarbonyL-hexanoyL-Phe-GLy-AHCP-Leu AMPA 6-MethoxycarbonyL-hexanoyl-Phe-GLy-AHCP-Leu ADPA 6-Methoxycarbonyl-hexanoyL-Phe-BAla-AHCP-ILe AMPA 6-Methoxycarbonyl-hexanoyl-Phe-BAla-AHCP-Ile ADPA 5 6-MethoxycarbonyL-hexanoyL-Phe-BALa-AHCP-Leu AMPA 6-MethoxycarbonyL-hexanoyL-Phe-BALa-Leu ADPA 4-CBZ-amino-butyryL-Phe-GLy-AHCP-ILe AMPA 4-CBZ-amino-butyryL-Phe-GLy-AHCP-ILe ADPA 10 4-CBZ-amino-butyryL-Phe-BALa-AHCP-ILe AMPA, m.p. 210-211° 4-CBZ-amino-butyryL-Phe-BALa-AHCP-ILe ADPA 5-CBZ-amino-pentanoyL-Phe-GLy-AHCP-ILe AMPA 5-CBZ-amino-pentanoyL-Phe-GLy-AHCP-ILe ADPA 15 5-CBZ-amino-pentanoyL-Phe-BALa-AHCP-ILe AMPA 5-CBZ-amino-pentanoyl-Phe-BALa-AHCP-ILe ADPA 6-CBZ-amino-hexanoyL-MaL-GLy-AHCP-ILe AMPA, m.p. 179-180° 6-CBZ-aniino-hexanoyl-MaL-GLy-AHCP-ILe ADPA, m.p. 186-187° 20 6-CBZ-amino-hexa noyI-MaL~BALa-AHCP-1Le AMPA, m.p. 208-209° 6-CBZ-amino-hexanoyL-MaL-BALa-AHCP-ILe ADPA, m.p. 244° (decomposition) 6-n'-Cyanoguanidino-hexanoyL-Phe-Gly-AHCP-ILe AMPA 25 6-N'-Cyanoguanidino-hexanoyL-Phe-GLy-AHCP-ILe ADPA 6-n'-Cyanoguanidino-hexanoyL-Phe-BALa-AHCP-ILe AMPA 6-n*-Cyanoguanidino-hexanoyL-Phe-8Ala-AHCP-Ile ADPA 3-BenzyloxysuLfonyL-propionyL-Phe-GLy-AHCP-Ile AMPA 30 3-BenzyLoxysuLfonyL-propionyL-Phe-GLy-AHCP-ILe ADPA 3-BenzyLoxysuLfonyL-propionyL-Phe-BALa-AHCP-ILe AMPA 3-BenzyLoxysuLfonyL-propionyL-Phe-BALa-AHCP-ILe ADPA 2S-Isopropyl-4S-hydroxy-5S-(80C-amino-piperidino-35 carbonyL-Phe-GLy-amino)-7-methyL-octanoyL-ILe AMPA 2S-IsopropyL-4S-hydroxy-5S-(B0C-amino-piperidino-carbonyL-Phe-GLy-amino)-7-methyL-octanoyL-ILe ADPA 2S-IsopropyL-4S-hydroxy-5S-(B0C-amino-piperidino-carbonyL-Phe-BALa-amino)-7-methyL-octanoyL-ILe AMPA,m.p. 199-200' PAT LOG 14 060488 m*- ~W- 10 15 20 22 870 7 - 35 - 2S-Isopropyl-4S-hydroxy-5S-(B0C-amino-piperidino-carbonyl-Phe-BAla-amino)-7-methyl-octanoyl-Ile ADPA. Example 7 8-B0C-amino-octanoyl-Phe-Gly-AHCP-Ile p-sulfamoylanilide, m.p. 154-157°, is obtained in analogy to Example 4 by condensation of 8-BOC-amino-octanoy I-Phe-Gly-AHCP-OH with H-Ile p-suIfamoyI aniIide. The following are obtained analogously 4-BOC-amino-butyryl-Phe-Gly-AHCP-Ile p-sulfamoylanilide 4-BOC-amino-butyryl-Phe-Gly-AHCP-Leu p-sulfamoylanilide 4-BOC-amino-butyryl-Phe-BAla-AHCP-Ile p-sulfamoylanilide 4-BOC-amino-butyryl-Phe-BAla-AHCP-Leu p-sulfamoylanilide 5-B0C-amino-pentanoyl-Phe-Gly-AHCP-Ile p-sulfamoylaniIide 5-B0C-amino-pentanoyl-Phe-Gly-AHCP-Leu p-sulfamoylani1ide 5-BOC-amino-pentanoyl-Phe-BAla-AHCP-Ile p-sulfamoylanilide 5-B0C-amino-pentanoyl-Phe-BAla-AHCP-Leu p-sulfamoylan iIide 6-BOC-amino-hexanoyl-Phe-Gly-AHCP-Ile p-sulfamoylanilide, m.p. 158-161° 6-BOC-amino-hexanoyl-Phe-Gly-AHCP-Leu p-sulfamoylanilide 6-BOC-amino-hexanoyl-Phe-BAla-AHCP-Ile p-sulfamoylaniIide 25 6-BOC-amino-hexanoyI-Phe-BAIa-AHCP-Leu p-sulfamoylanilide 7-BOC-amino-heptanoyl-Phe-Gly-AHCP-Ile p-sulfamoylaniIide 7-BOC-amino-heptanoyl-Phe-Gly-AHCP-Leu p-sulfamoylaniIide 7-BOC-amino-heptanoyl-Phe-BAla-AHCP-Ile-p-sulfamoylanilide 30 7-BOC-amino-heptanoyl-Phe-BAla-AHCP-Leu p-sulfamoylanilide 8-BOC-amino-octanoyl-F'ne-Gly-AHCP-Leu p-sulfamoylanil ide 8-BOC-amino-octanoyl-Phe-BAla-AHCP-Ile p-sulfamoylanilide 8-BOC-amino-octanoyl-Phe-BAla-AHCP-Leu p-sulfamoylani1ide 35 4-Dimethylamino-butyryl-Phe-Gly-AHCP-Abu AMPA 4-Dimethylamino-bu.tyryl-Phe-Gly-AHCP-Ala AMPA PAT LOG 14 060488 22 87 0 7 4- Dimethylami no -bu t y r y L -Phe -G I y- AHCP -C al AMPA 4- Dimethylami no -butyry I -Phe -Gly- AHCP -Met AMPA 4- Dimethylami no -b u t y r y L -Phe -G I y- AHCP -Nle AMPA 4- OimethyLami no -butyry L -Phe -G I y- AHCP -N va AMPA 5 4- Dimethylami no -butyryl -Phe -Gly- AHCP -Phe AMPA 4- OimethyLami no -butyryl -Phe -Gly- AHCP -Trp AMPA 4- Dimethylami no -butyryl -Phe -G I y- AHCP -Ty r AMPA 4- Dimethylami no -butyryl -Phe -G I y- AHCP -Va I AMPA . 10 Example 8 6-BOC-amino-hexanoyI-Phe-GIy-AHCP-11e-A I a AMPA is obtained in analogy to Example 4 from 6-BOC-aminohexanoyI-Phe-Gly-AHCP-Ile-OH and H-Ala AMPA. 15 Example 9 6-CBZ-amino-hexanoyl-Phe-BAla-AHCP-Ile AMPA, m.p. 200-201°, is obtained in analogy to Example 4 from 6-CBZ-amino-hexanoyI-Phe-BAI a-AHCP-11e-OH and 4-amino-5-aminomethyl-2-methylpyrimidine. 20 The following are obtained analogously: 4-Methyl-piperidino-carbonyl-Phe-8Ala-AHCP-Ile AMPA 4-Hydroxy-piperidino-carbonyl-Phe-BAla-AHCP-lie AMPA, hydrochloride, m.p. 176° (dec.) 25 4-MethyI amino-piperidino-carbonyl-Phe-BA I a-AHCP-11e AMPA 4-Acetamido-piperidino-carbonyl-Phe-BAla-AHCP-Ile AMPA^m.p. 183-187° 4-POA-amino-piperidino-carbony I-Phe-BAIa-AHCP-11e AMPA 4-(2-Hydroxyethyl)-piperaz ino-carbonyl-Phe-BAla-AHCP-Ile AMPA 30 4-Carbamoyl-piperidino-carbonyl-Phe-BAla-AHCP-Ile AMPA 4-(2-Trimethylammonia-ethyl)-piperazino-carbonyl-Phe-BAI a-AH CP-11e AMPA chloride. Example 10 35 A solution of 1.56 g of 5-dimethylaminopentyl iso- cyanate in 16 ml of THF is added dropwise at 20° to a stirred solution of 6.52 g of H-Phe-GIy-AHCP-11e AMPA in 65 ml of THF. The mixture is stirred at 20° for 3 hours, and the usual working out results in N-(5-dimethyI amino-40 pentyI)-carbamoyI-Phe-GIy-AH CP-11e AMPA. PAT LOG 14 060488 22 87 0 7 The following are obtained analogously with the corresponding isocyanates: N-(2-Dimethylaminoethyl)-carbamoyl-Phe-Gly-AHCP-Ile AMPA 5 N-(2-DimethyI a minoethyI)-carbamoyI-Phe-0AI a-AHCP-11e AMPA N-(3-Dimethylaminopropyl)-carbamoyl-Phe-Gly-AHCP-Ile AMPA N-(3-Dimethylaminopropyl)-carbamoyl-Phe-8Ala-AHCP-Ile AMPA N-(5-0imethylaminopentyl)-carbamoyl-Phe-8Ala-AHCP-Ile AMP A, m.p. 184-18 N-(5-0imethylaminopentyl)-carbamoyl-Mal-Gly-AHCP-Ile AMPA 10 N-(5-Dimethylaminopentyl)-carbamoyl-Mal-BAla-AHCP-Ile AMPA 3-[(N-(5-Dimethylaminopentyl)-carbamoyl-Phe]-propionyl-AHCP-Ile AMPA 4-[N-(5-Dimethylaminopentyl)-carbamoyl-Phe]-3-thiabutyryl-AHCP-Ile AMPA. 15 Example 11 A solution of 1 g of 4-BOC-amino-piperidinocarbony I -Phe-BAI a-AHCP-11e AMPA [obtainable by reaction of BOC-AHCP-Ile AMPA (m.p. 218-220°) with HCl/dioxane to give 20 H-AHCP-Ile AMPA and reaction with 4-BOC-amino-piperidino-carbon yI-Phe-fiAI a-OH ] in 20 ml of 4 N HCl in dioxane is stirred at 20° for 30 min and then evaporated. 4-Amino-piperidinocarbonyI-Phe-BAI a-AH CP-11e AMPA dihydrochIoride, m.p. 229° (decomposition), is obtained.2/3 citrate, m.p.172° 25 The following are obtained analogously from the correspnding BOC derivatives: H-BAla-Phe-Gly-AHCP-Ile AMPA H-BAla-Phe-Gly-AHCP-Ile ADPA 30 H-BAla-Phe-Gly-AHCP-Leu AMPA H-BAla-Phe-Gly-AHCP-Leu ADPA H-BAla-Phe-BAla-AHCP-Ile AMPA H-BAla-Phe-BAla-AHCP-Ile ADPA 35 H-BAla-Phe-BAla-AHCP-Leu AMPA H-BAla-Phe-BAla-AHCP-Leu ADPA 4-Aminobutyryl-Phe-Gly-AHCP-m.p. 215° (decomposition) PAT LOG 14 060488 lie AMPA, dihydrochIoride, 22 8 7 0 7 10 15 20 - 38 - 4-Aminobutyryl-Phe-Gly-AHCP-Ile ADPA 4-Aminobutyryl-Phe-Gly-AHCP-Leu AMPA 4-Aminobutyryl-Phe-Gly-AHCP-Leu ADPA 4-AminobutyryI-Phe-8AI a-AHCP-11e AMPA, dihydrochloride, m.p. 199° (decomposition) 4-Aminobutyryl-Phe-8Ala-AHCP-Ile ADPA 4-Aminobutyryl-Phe-8Ala-AHCP-Leu AMPA 4-Aminobutyryl-Phe-BAla-AHCP-Leu ADPA 4-Aminobutyryl-Mal-Gly-AHCP-Ile AMPA 4-Aminobutyryl-Mal-Gly-AHCP-Ile ADPA 4-Aminobutyryl-Mal-BAla-AHCP-Ile AMPA 4-Aminobutyryl-Mal-BAla-AHCP-Ile ADPA 5-Aminopentanoyl-Phe-Gly-AHCP-Ile AMPA 5-Aminopentanoyl-Phe-Gly-AHCP-Ile ADPA 5-Aminopentanoyl-Phe-BAla-AHCP-Ile AMPA 5-Aminopentanoyl-Phe-BAla-AHCP-Ile ADPA 6-Aminohexanoyl-Phe-Gly-AHCP-Ile amide 6-Aminohexanoyl-Phe-8Ala-AHCP-Ile amide 6-AminohexanoyI-Phe-GIy-AHCP-11e AMPA, dihydroch I oride, m.p. 180° (decomposition) 25 6-Aminohexanoyl-Phe-Gly-AHCP-Ile ADPA, m.p. 193-194°; dihydrochloride, m.p. 106-107° 6-Aminohexanoyl-Phe-Gly-AHCP-Leu AMPA 6-Aminohexanoyl-Phe-Gly-AHCP-Leu ADPA 6-AminohexanoyI-Phe-BAI a-AHCP-11e AMPA, m.p. 203° (de-30 composition); dihydrochloride, m.p. 206° (decomposition) 6-Aminohexanoyl-Phe-BAIa-AHCP-lie ADPA 6-AminohexanoyI-Phe-BAI a-AHCP-Leu AMPA 6-Aminohexanoyl-Phe-BAla-AHCP-Leu ADPA 35 6-Aminohexanoyl-Mal-Gly-AHCP-Ile AMPA, dihydrochloride, m.p. 201-202° 6-Aminohexanoyl-Mal-Gly-AHCP-Ile ADPA,dihydrochloride,m.p. 197-198° 6-A m i no h e x an oy I - M a I - B A I a-A H C P - 11 e AMP A , dihydrochloride, m.p. 192-193° 6-Aminohexanoyl-Mal-BAla-AHCP-Ile ADPA PAT LOG 14 060488 6-Aminohexanoyl-Phe-Gly-AHCP-Ile N-3-pyridylmet 22.8.7 0 7 dihydrochloride, m.p. 104° (dec.) 6-Aminohexanoyl-Phe-8Ala-AHCP-Ile N-3-pyridylmethylamide 6-Aminohexanoyl-Phe-Gly-AHCP-Ile N-m-aminomethyl-benzyl-5 amide 6-Aminohexanoyl-Phe-BALa-AHCP-ILe N-m-aminomethyl-benzyl-am i de 6-AminohexanoyL-Phe-GLy-AHCP-ILe N-p-dimethylaminomethyl-benzyI am i de 10 6-AminohexanoyL-Phe-8ALa-AHCP-11e N-p-dimethyI aminomethyI -benzylamide 6-AminoHexanoyl-Phe-Gly-AHCP-Ile N-5-tetrazoLyLmethyLamide 6-Aminohexanoyl-Phe-8Ala-AHCP-Ile N-5-tetrazolylmethylamide 6-AminohexanoyL-Phe-GLy-AHCP-ILe N-3-dimethylaminopropyl-15 amide 6-Aminohexanoyl-Phe-8ALa-Ile N-3-dimethylaminopropyl-am i de 6-AminohexanoyL-Phe-Gly-AHCP-ILe N-2-suLfo-ethyLamide 6-Aminohexanoyl-Phe-BAla-AHCP-Ile N-2-sulfo-ethylamide 20 25 30 3-[6-Aminohexanoyl-Phe]-propionyl-AHCP-Ile AMPA 3-[6-AminohexanoyL-Phe]-propionyL-AHCP-ILe ADPA 4-C6-Aminohexanoyl-Phe3-3-thiabutyryl-AHCP-ILe AMPA 4-C6-Aminohexanoyl-PheJ-3-th iabutyryl-AHCP-ILe ADPA 7-Aminoheptanoyl-Phe-Gly-AHCP-ILe AMPA 7-AminoheptanoyL-Phe-GLy-AHCP-ILe ADPA 7-A(ninoheptanoyl-Phe-0ALa-AHCP-ILe AMPA 7-Aminoheptanoyl-Phe-BALa-AHCP-Ile ADPA 8-AminooctanoyL-Phe-GLy-AHCP-ILe-AMP A, dihydrochLoride , m.p. 165° (riec.^ 8-AminooctanoyL-Phe-GLy-AHCP-ILe ADPA 8-AminooctanoyL-Phe-BALa-AHCP-ILe AMPA 35 8-AminooctanoyL-Phe-BAla-AHCP-ILe ADPA 4-Amino-piperidinocarbonyL-Phe-GLy-AHCP-ILe AMPA, dihydrochloride, m.p. 160-161° 4-Amino-piperidinocarbonyl-Phe-Gly-AHCP-Ile ADPA 40 4-Amino-piperidinocarbonyl-Phe-Gly-AHCP-Leu AMPA PAT LOG 14 060488 2*2 8 7 0 7 - 40 - 4-Amino-piperidinocarbonyl-Phe-Gly-AHCP-Leu k 4-Amino-piperidinocarbonyl-Phe-BAla-AHCP-Ile AMPA 4-Amino-piperidinocarbonyl-Phe-BAla-AHCP-Ile ADPA, dihydrochloride, m.p. 159-160° 5 4-Amino-piperidinocarbonyI-Phe-8A I a-AHCP-I Ie N-2-pyridyl-methylamide 4-Amino-piperidinocarbonyl-Phe-BAla-AHCP-Ile N-3-pyridyl-methylamide, dihydrochloride, m.p. 176-177° 4-Amino-piperidinocarbonyl-Phe-8Ala-AHCP-Leu A M P Af 10 dihydrochloride,^m.p. 280° (dec.) 4-Amino-piperidinocarbonyl-Phe-8Ala-AHCP-Leu ADPA 4-Amino-piperidinocarbonyl-Phe-Gly-AHCH-Ile AMPA 4-Amino-piperidinocarbonyl-Phe-Sta-Ile AMPA 4-Amino-piperidinocarbonyl-Phe-AHPP-Ile AMPA 15 2S-Isopropyl-4S-hydroxy-5S-(4-amino-piperidino-carbonyl-Phe-Gly-amino)-7-methyl-octanoyl-I. e AMPA 2S-Isopropyl-4S-hydroxy-5S-(4-amino-piperidino-carbonyl-Phe-Gly-amino)-7-methyl-octanoyl-J. le ADPA 20 2S-Isopropyl-4S-hyaroxy-5S-(4-amino-piperidino- carbonyl-Phe-8Ala-amino)-7-methyl-oc tanoyI -lie AMPA, dihydrochloride, m.p. 182-183° 2S-Isopropyl-4S-hydroxy-5S-(4-amino-piperidino— carbonyl-Phe-8Ala-amino)-7-methyl-octanoyl-Ile ADPA 25 4-Amino-butyryl-Phe-Gly-AHCP-Ile p-sulfamoylanilide 4-Amino-butyryI-Phe-GIy-AHCP-Leu p-sulfamoylanilide 4-Am-ino-butyryl-Phe-BAla-AHCP-Ile p-sulfamc/Lanil ide 4-Amino-butyryl-Phe-8Ala-AHCP-Leu p-sulfamoylanilide 30 5-Amino-pentanoyI-Phe-GIy-AHCP-11e p-sulfamoylanilide 5-Amino-pentanoyl-Phe-Gly-AHCP-Leu p-sulfamoylanilide 5-Amino-pentanoyl-Phe-BAla-AHCP-Ile 'p-sulfsmoylanilide 5-Amino-pentanoyI-Phe-BAI a-AHCP-Leu p-sulfamoylanilide 35 6-Amino-hexanoyI-Phe-G I y-AHCP-11e p-sulfamoylanilide, dihydrochloride, m.p. 98° 6-Amino-hexanoyl-Phe-Gly-AHCP-Leu p-sulfamoylanilide 6-Amino-hexanoyl-Phe-BAla-AHCP-Ile p-sulfamoylanilide 6-Amino-hexanoyl-Phe-BAla-AHCP-Leu p - s u I f a m o I 2 n i I ide PAT LOG 14 060488 22 8 7 0 7 - 41 - 7-Amino-heptanoyl-Phe-Gly-AHCP-Ile p-sulfamoylaniIide 7-Amino-heptanoyl-Phe-Gly-AHCP-Leu p-sulfamoylanilide 7-Amino-heptanoyl-Phe-8Ala-AHCP-Ile p-sulfamoylani L ide 7-Amino-heptanoyl-Phe-8Ala-AHCP-Leu p-sulfamoylani L ide 5 8-Amino-octanoyl-Phe-Gly-AHCP-Ile p-sulfamoylaniIide, dihydrochloride, m.p. 102° 8-Amino-octanoyl-Phe-AHCP-Leu p-sulfamoylanilide 8-Amino-octanoyl-Phe-8Ala-AHCP-Ile p-sulfamoylanilide 10 8-Amino-octanoyl-Phe-8Ala-AHCP-Leu p-sulfamoylanilide. Example 12 A mixture of 1 g of 6-methoxycarbony I-hexanoyI -Phe-Gly-AHCP-Ile ADPA, 50 ml of dioxane and 20 ml of 2 N 15 NaOH (aqueous) is stirred at 20° for 3 hours. The usual working up results in 6-carboxy-hexanoyl-Phe-Gly-AHCP-Ile ADPA, m.p. 170-171°. The following are obtained analogously by hydrolysis 20 3-Carboxy-propionyI-Phe-GIy-AHCP-11e AMPA 3-Carboxy-propionyl-Phe-Gly-AHCP-Ile ADPA 3-Carboxy-propionyl-Phe-8Ala-AHCP-Ile AMPA 3-Carboxy-propionyl-Phe-BAla-AHCP-Ile ADPA 25 4-Carboxy-butyryI-Phe-GIy-AHCP-11e AMPA 4-Carboxy-butyryl-Phe-Gly-AHCP-Ile ADPA 4-Carboxy-butyryl-Phe-BAla-AHCP-Ile AMPA 4-Carboxy-butyryl-Phe-8Ala-AHCP-Ile ADPA 30 5-Carboxy-pentanoyI-Phe-GIy-AHCP-11e AMPA 5-Carboxy-pentanoyl-Phe-Gly-AHCP-Ile ADPA 5-Carboxy-pentanoyI-Phe-8A I a-AHCP-11e AMPA 5-Carboxy-pentanoyl-Phe-8Ala-AHCP-Ile ADPA 35 6-Carboxy-hexanoyI-Phe-GIy-AHCP-11e AMPA, m.p. 185-186° (decomposition); hydrochloride, m.p. 162° (decomposition) 6-Carboxy-hexanoyl-Phe-Gly-AHCP-Leu AMPA 6-Carboxy-hexanoyl-Phe-Gly-AHCP-Leu ADPA 6-Carboxy-hexanoyl-Phe-BAla-AHCP-Ile AMPA PAT LOG 14 060488 10 15 20 25 - 42 - 6-Carboxy-hexanoyL-Phe-BALa-AHCP-ILe ADPA 6-Carboxy-hexanoyl-Phe-BAla-AHCP-Leu AMPA 6-Carboxy-hexanoyL-Phe-BALa-AHCP-Leu ADPA 22 8 7 0 7 4-Carboxy-piperidinocarbonyl-Phe-Gly-AHCP-ILe AMPA 4-Carboxy-piperidinocarbonyL-Phe-GLy-AHCP-ILe ADPA 4-Carboxy-piperidinocarbonyL-Phe-BALa-AHCP-ILe AMPA, hydrochloride, m.p. 212°(dec.) 4-Carboxy-piperidinocarbonyL-Phe-BALa-AHCP-ILe ADPA N-(CarboxymethyL)-carbamoyL-Phe-GLy-AHCP-lLe AMPA N-(CarboxymethyL)-carbamoyL-Phe-GLy-AHCP-ILe ADPA N-(CarboxymethyL)-carbamoyL-Phe-BALa-AHCP-ILe AMPA N-(CarboxymethyL)-carbamoyL-Phe-BALa-AHCP-ILe ADPA N-(4-CarboxybutyL)-carbamoyL-Phe-GLy-AHCP-ILe AMPA N-(4-CarboxybutyL)-carbamoyL-Phe-GLy-AHCP-ILe ADPA N-(4-CarboxybutyL)-carbamoyL-Phe-0ALa-AriCP-ILe AMPA N-(4-CarboxybutyL)-carbamoyL-Phe-6ALa-AHCP-ILe ADPA N-(6-CarboxyhexyL)-carbamoyL-Phe-GLy-AHCP-ILe AMPA N-(6-CarboxyhexyL)-carbamoyL-Phe-GLy-AHCP-ILe ADPA N-(6-CarboxyhexyL)-carbamoyL-Phe-BALa-AHCP-ILe AMPA N-(6-Carboxyhexyl)-carbamoyl-P'he-BALa-AHCP-ILe ADPA. ExampLe 13 6-Amino-hexanoyL-Phe-BALa-AHCP-ILe AMPA, m.p. 203° (decomposition), is obtained in anaLogy to ExampLe 2 from 6-CBZ-amino-hexanoyL-Phe-BALa-AH CP-1Le AMPA by 30 hydrogenoLysis . The foLLowing are obtained anaLogousLy by hydro-genoLysis of the corresponding CBZ derivatives: 2-Amino-2-methyL-propionyL-Phe-GLy-AHCP-ILe AMPA 35 2-Amino-2-methyL-propionyL-Phe-GLy-AHCP-ILe ADPA 2-Amino-2-methyL-propionyL-Phe-BALa-AHCP-ILe AMPA( dihydrochloride, m.p. 212° 2-Amino-2-methyL-propionyL-Phe-BALa-AHCF-ILe ADPA 2-Amino-2-methyL-propionyL-MaL-GLy-AHCP-ILe AMPA 40 dihydrochloride, m.p.118° (dec.) 2-rtmino-2-methyL-propionyL-MaL-GLy-AHCP-ILe ADPA 2-Amino-2-methyL-propionyL-MaL-BALa-AHCP--ILe AMPA PAT LOG 14 060488 - 43 - 2-Amino-2-methyl-propionyl-Mal-BAla-AHCP- 22 8 7 0 7 lie ADPA. Example 14 3-SuIpho-propionyI-Phe-GIy-AHCP-11e AMPA is ob-5 tained in analogy to Example 2 from 3-benzyIoxysuIfonyI-propionyI-Phe-GIy-AHCP-11e AMPA by hydrogenolysis. The following are obtained analogously by hydrogenolysis of the corresponding benzyl esters: 1.0 3-Sulfo-propionyl-Phe-Gly-AHCP-Ile ADPA 3-Sulfo-propionyl-Phe-BAla-AHCP-Ile AMPA 3-Sulfo-propionyl-Phe-BAla-AHCP-Ile ADPA. Example 15 15 a) 3-0xo-4S-(4-dimethyI aminobutyryI-Phe-GIy-amino)-5- cycI ohexyI-pentanoyI-11e AMPA is obtained in analogy to Example 4 from 4-d i me t h y I am i nobu ty r y I-P h e-G I y-Oh(— and 3-oxo-4S-amino-5-cycIohexyI-pentanoyI-I Ie AMPA. 20 b) A solution of 1 g of the abovementioned keto amide in 25 ml of ch3oh is hydrogenated on 0.1 g of 10 % Pd-C at 20° and under 1 bar until H2 uptake ceases. Filtration and evaporation result in a mixture of 3R-25 and 3S-hydroxy-4S-(4-dimethyI aminobutyryI-Phe-G I y- amino)-5-cyclohexyl-pentanoyl-IleAMPA. Example 16 70 mg of hydr0xyI amine hydrochloride are added to 30 a solution of 763 mg of 3-oxo-4S-(4-dimethyI aminobutyryI -Phe-GIy-amino)-5-cycI 0hexyI pentanoyI -11 e AMPA and 1.43 g of Na2C03.10 H20 in 5 ml of methanol and 5 ml of water, and the mixture is stirred at 20° for 14 hours. The precipitated oxime is filtered off, dried, dissolved in 35 10 ml of methanol and hydrogenated on 0.5 g of Raney Ni at 20° and under 5 bar. The catalyst is filtered off, the filtrate is evaporated, the resulting mixture is separated on silica gel, and 3S-amino-4S-(4-dimethyI aminobu tyryI-Phe-GIy-amino)-5-cycI ohexyI pentanoyI-11e AMPA PAT LOG 14 060488 22 87 0 7 - 44 - ("4-dimethyIaminobutyryI-Phe-GIy-DA CP-ILe AMPA") is obtained; the 3R-amino epimer is also obtained. Example 17 Analogously to Example 4, the following are obtained: l-Methyl-4-piperidinyl-carbonyl-Phe-BAla-AHCP-Ile-AMPA, m.p. 187-189° 5 4-BOC-amino-piper idinocarbonyl-Phe-i3 Ala-St a- lie-AMPA, m.p. 151-152° 6-BOC-amino-hexanoyl-N-Me-Mal-Gly-AHCP-Ile-AMPA, m.p. 100° (dec.) 4-BOC-amino-piperidino-carbonyl-Phe-BAla-AHCP-Gly-AMPA, 10 m.p. 181° (dec.) 3-(l-Methyl-2-piperidyl)-propionvl-Phe-BAla-AHCP-Ile-AMPA, m.p. 202° 3-(l-Methyl-2-piperidyl)-propionyl-Phe-Gly-AHCP-Ile-AMPA, oil 4- (1-Methyl-2-piperidyl )-butyryl-Phe-Glv-AHCP-Ile-AMPA, 15 diacetate, oil 4-(l-Methyl-2-piperidyl)-butyryl-Phe-BAla-AHCP-Ile-AMPA, diacetate, m.p. 206° 4-BOC-amino-piperidinocarbonyl-Phe-BAla-AHCP-Ala-AMPA, m.p. 181-182° 20 Pyrrolidinocarbonyl-Phe-J3Ala-AHCP-1 le-AMPA, hydrochloride, m.p. 136-137° Morpholinocarbonyl-Phe-BAla-AHCP-Ile-AMPA, hydrochloride, m.p. 157-158° 4-BOC-amino-piperidinocarbonyl-Mai-Gly-AHCP-Ile-AMPA, 25 m.p. 193-194° Piperidinocarbonyl-Phe-BAla-AHCP-Ile-AMPA, hydrochloride, m.p. 140-141° 4-BOC-amino-piperidinoacetyl-Phe-Gly-AHCP-Ile-AMPA, m.p. 135° 4-BOC-amino-piperidinocarbonyl-Phe-BAla-AHCP-Nle-AMPA, 30 m.p. 145-146° 3-BOC-amino-3-methyl-butyryl-Phe-Gly-AHCP-Ile-AMPA, m.p. 102° (dec.) PAT LOG 4 170289/0001.0.0 12 8 7 0 7 - 45 - 4-BOC-amino-piperidinocarbonyl-Leu-BAla-AHCP-Ile-AMPA, m.p. 183° (dec.) 3-BOC-amino-3-methyl-butyryl-Phe-Gly-AHCP-Ile-(N-3-pyridyl-methyl-amide), m.p. 90° (dec.) 5 4-Methylsulfonamido-piperidinocarbonyl-Phe-BAla-AHCP-Ile-AMPA, hydrochloride, m.p. 159-160° 4-(3-Hydroxypropyl)-piperazinocarbonyl-Phe-BAla-AHCP-Ile-AMPA, dihydrochloride, m.p. 182° (dec.) 4-BOC-piperazinocarbonyl-Phe-BAla-AHCP-Ile-AMPA, m.p. 140-141° 10 Benzyl 4-BOC-amino-piperidinocarbonyl-Phe-6Ala-AHCP-Ile-amino-acetate Benzyl 3-(4-BOC-amino-piperidinocarbonvl-Phe-BAla~AHCP-Ile-amino)-propionate Benzyl 4-(4-BOC-amino-piperidinocarbonyl-Phe-BAla-AHCP-Ile-15 amino)-butyrate Benzyl 5- (4-BOC-amino-piperidinocarbonyl-Phe-BAla-AHCP-Ile-amino)-pentanoate, m.p. 102-103° Benzyl 6-(4-BOC-amino-piperidinocarbonyl-Phe-BAla-AHCP-Ile-amino)-hexanoate, m.p. 110-111° 20 4-Formamido-piperidinocarbonyl-Phe-£Ala-AHCP-Ile-AMPA 4-Trifluoroacetamido-piperidinocarbonyl-Phe-BAla-AHCP-Ile-AMPA 4-BOC-amino-piperidinocarbonyl-Phe-BAla-AHCP-D-Ile-AMPA, m.p. 164-165° 25 4-BOC-amino-piperidinocarbonyl-Mal-BAla-AHCP-Ile-AMPA, m.p. 183-184° 3-(4-BOC-amino-piperidinocarbonyl-Phe-amino)-3-methyl-butyryl-AHCP-Ile-AMPA, m.p. 136-137° 4-BOC-amino-piperidinocarbonyl-D-Phe-BAla-AHCP-Ile-AMPA, 30 m.p. 140-142° 4-B0C-amino-piperidinocarbonyl-Phe-BAla-AHCP-0Me, m.p. 72-74° 4-BOC-amino-piperidinocarbonyl-Phe-BAla-AHCP-Ile-OMe, m.p. 114-115° PAT LOG 4 170289/0002.0.0 IZ 8707 - 46 - 4-B0C-amino-piperidinoacetyl-Phe-8Ala-AHCP-Ile-AMPA, m.p. 78-81° 4-Cyano-piperidinocarbonyl-Phe-BAla-AHCP-Ile-AMPA 4-Dimethylaminomethyl-piperidinocarbonyl-Phe-BAla-AHCP-5 Ile-AMPA 4-BOC-aminomethyl-piperidinocarbonyl-Phe-lBAla-AHCP-1 le-AMPA 3-(2-Piperidyl)-propionyl-Phe-BAla-AHCP-Ile-AMPA, tris-(trifluoracetate), oil 3-(2-Piperidyl)-propionyl-Phe-Gly-AHCP-Ile-AMPA, tri-10 acetate, oil 4-(2-Piperidyl)-butyryl-Phe-BAla-AHCP-Ile-AMPA, triacetate, m.p. 110° 4-(2-Piperidyl)-butyryl-Phe-Gly-AHCP-Ile-AMPA, triacetate, oil. 15 Example 18 Analogously to Example 11, the following are obtained from the corresponding BOC derivatives: 4-Amino-piperidinocarbonyl-Phe-BAla-Sta-Ile-AMPA, dihydrochloride, m.p. 196° (dec.) 20 4-Amino-Piperidinocarbonyl-Phe-BAla-AHCP-Gly-AMPA, dihydrochloride, m.p. 266° (dec.) 4-Amino-piperidinocarbonyl-Phe-BAla-AHCP-Ala-AMPA, dihydrochloride, m.p. 126-127° 4-Amino-piperidinocarbonyl-Mal-Gly-AHCP-Ile-AMPA, dihydro-25 chloride, m.p. 192° (dec.) 4-Amino-piperidinoacetyl-Phe-Gly-AHCP-Ile-AMPA, trihydro-chloride, m.p. 174° 3-Amino-3-methyl-butyryl-Phe-Gly-AHCP-Ile-AMPA, dihydrochloride, m.p. 230° 30 4-Amino-piperidinocarbonyl-Leu-BAla-AHCP-Ile-AMPA, dihydrochloride, m.p. 269° (dec.) 3-Amino-3-methyl-butyryl-Phe-Gly-AHCP-lie-(N-3-pyridyl-methyl-amide), dihydrochloride, m.p. 100° (dec.) PAT LOG 4 170289/0003.0.0 ♦ 22870 47- 4-Amino-piperidinocarbonyl-Phe-J3Ala-AHCP-D-1 le-AMPA, dihydrochloride, m.p. 122° (dec.) 4-Amino-piperidinocarbonyl-Mai-J3Ala-AHCP-1 le-AMPA, dihydrochloride, m.p. 116° (dec.) 5 3-(4-Amino-piperidinocarbonyl-Phe-amino)-3-methyl-butyryl-AHCP-Ile-AMPA, dihydrochloride, m.p. 138° 4-Amino-piperidinocarbonyl-D-Phe-BAla-AHCP-Ile-AMPA, dihydrochloride, m.p. 178° (dec.) 4-Amino-piperidinocarbonyl-Phe-13Ala-AHCP-OH, hydrochloride, 10 m.p. 102-105° 4-Amino-piperidinocarbonyl-Phe-J3Ala-AHCP-Ile-OH, hydrochloride, m.p. 119-120° Piperazinocarbonyl -Phe-/3Ala-AHCP-Ile-AMPA, dihydrochloride, m.p. 183° (dec.) 15 4-Aminopiperidinoacetyl-Phe-BAla-AHCP-Ile-AMPA, trihydro-chloride, m.p. 208-209° 4-Amino-piperidinocarbonyl-Phe-BAla-AHCP-lie-amino-acetic acid 3-(4-Amino-piperidinocarbonyl-Phe-)3-Ala-AHCP-1le-amino)-20 propionic acid 4- (4-Amino-piperidinocarbonyl-Phe-J3-Ala-AHCP-lie-amino )-butyric acid 5-(4-Amino-piperidinocarbonyl-Phe-/3A1a-AHCP-Ile-amino)-pentanoic acid, hydrochloride, m.p. 146-148° 25 6- (4-Amino-piperidinocarbonyl-Phe-13A1 a-AHCP-lie-amino )-hexanoic acid, hydrochloride, m.p. 159-160° 4-Aminomethyl-piperidinocarbonyl-Phe-J3Ala-AHCP-Ile-AMPA. Example 19 Analogously to Example 2, the following are obtained by 30 hydrogenolysis of the corresponding benzyl esters: 4-BOC-amino-piperidinocarbonyl-Phe-BAla-AHCP^I le—aminos acetic acid f i - 48 - 22 8 7 0 7 3-(4-BOC-amino-piperidinocarbonyl-Phe-BAla-AHCP-Ile-amino)-propionic acid 4- (4-BOC-amino-piperidinocarbonyl-Phe-BAl a-AHCP-Ile-amino)-butyric acid 5 5-(4-BOC-amino-piperidinocarbonyl-Phe-BAla-AHCP-I1e-amino)-pentanoic acid, m.p. 157° 6-(4-BOC-amino-piperidinocarbonyl-Phe-BAla-AHCP-Ile-amino )-hexanoic acid, m.p. 167-168°. Example 20 10 Analogously to Example 12, the following are obtained by saponification of the corresponding methyl esters: 4-BOC-amino-piperidinocarbonyl-Phe-£Ala-AHCP-OH, m.p. 112-113° 4-BOC-amino-piperidinocarbonyl-Phe-£Ala-AHCP-Ile-OH, 15 m.p. 93-95°. Example 21 A mixture of 792 mg of 4-amino-piperidinocarbonyl-Phe-BAla-AHCP-Ile-AMPA, 90 mg of 5-methylisothiourea, 5 ml of ethanol and 5 of water is stirred for 2 hours at 50 °C. 20 After working up as usual, 4-guanidinyl-piperidinocarbonyl-Phe-BAla-AHCP-1 le-AMPA is obtained, m.p. 183°. Example 22 A mixture of 792 mg of 4-amino-piperidinocarbonyl-Phe-BAla-AHCP-Ile-AMPA, 115 mg (= 0.132 ml) of trimethylsilyl-25 isocyanate and 10 ml of THF is stirred for 16 hours at 20 °C. Thereafter, the mixture is stirred into water and worked up as usual, yielding 4-ureido-piperidinocarbonyl-Phe-BAla-AHCP-Ile-AMPA, hydrochloride, m.p. 126-128° (dec.). PAT LOG 4 170289/0005.0.0 - 49 - 22 8 7 0 7 The following are obtained with the corresponding alkyl isocyanates: 4- (N1 -Ethylureido) -piperidinocarbonyl-Phe-J3Ala-AHCP-1 le-AMPA, hydrochloride, m.p. 170-171°, 4- (N1 - Isopropylureido)-piperidinocarbonyl-Phe-iBAla-AHCP-lie AMPA, hydrochloride, m.p. 187° (dec.). PAT LOG 4 170289/0006.0.0 </div>

Claims

<div id="claims" class="application article clearfix printTableText">



22 8 7 0 7 

- 50 - 

The examples which follow relate to pharmaceutical compositions. 

5 Example A: Tablets 

A mixture of 1 kg of 4-aminopiperidinocarbonyI-Phe~BAI a-AHCP-11e AMPA dihydrochloride, 4 kg of lactose, 1.2 kg of maize starch, 200 g of talc and 100 g of magnesium stearate is compressed in a customary manner to 10 give tablets in such a way that each tablet contains 100 mg of active compound. 

Example 8: Coated tablets 

Tablets are compressed in analogy to Example A and are then coated in a customary manner with a coating 15 composed of sucrose, maize starch, talc, tragacanth and colourant. 

Example C: Capsules 

500 g of 6-aminohexanoyI-Phe-GIy-AHCP-11e AMPA dihydrochloride are dispensed in a customary manner into 20 hard gelatin capsules so that each capsule contains 500 mg of active compound. 

Example D: Injection ampoules 

A solution of 100 g of the Na salt of 6-carboxy-hexanoyI-Phe-GIy-AHCP-11e ADPA in 4 I of double-distilled 25 water is adjusted to pH 6.5 with 2 N hydrochloric acid, filtered sterile and dispensed into injection ampoules. These are lyophilized under sterile conditions and sealed sterile. Each injection ampoule contains 50 mg of active compound. 

30 Example E: Suppositories 

A mixture of 50 g of 4-dimethylaminobutyryl-Plre-Gly-AHCP-Ile AMPA dihydrochloride with 10 g of soya lecithin and 140 g of cocoa butter is melted, poured into moulds and left to cool. Each suppository contains 250 mg 35 of active compound. 

PAT LOG 14 060488 

what we CLAIM IS: 1 A compound of the formula I 

228707 

Rl-CF,H3p-(NH)y-CO-NH-CHR2-CO-Z-CrnH2[n-CO-NH-CHR3-CR4-(CHR5)n-CO-E-Q-Y 

wherein 

R1 

-NH-CHR2-CO- 

-Z-CJi2m-CO-R3 

R" 

— (CHR5) n— 

E 

Q-Y 

R6 and R7 

R7 

R*> 

R6R7N 

R11 

y 

P r t 

-alkyl-A 

is R6R7N—, R6OOC- or R«-0- (CH2CH20) r-; 

is Leu, Mai, p—F-Phe, Phe, D-Phe, 3-Pya, 2-Tia, Tyr or D-Tyr,-is (JAla or Gly; 

is isobutyl, benzyl or cyclohexyImethyl; is (H, OH); 

is -CH2-, -CH2CH2 or —CH2-CHA-; 

is missing or is Ala, lie, Leu, Nle or 

Ile-Val; 

is OH, OA, NHA, NH-CtH2t-R", NH-CcH2t-OH or NH-CcH2c-NA2; 

are each independently H or A; 

is also R9-0-C0-; 

is A or benzyl; 

is also a piperidinyl, morpholinyl, piperazi— nyl or pyrrolidinyl group which is unsubstituted or substituted by A, OH, N'H2, NHA, NA2, NH-CO-A, NH-CO-OA, NH-S02-A, hydroxyalkyl, COOH, COOA, NH-CO-NH2, NH-CO-NHA or guanidi-nyl; • 

is p-aminosulfonylphenyl, 1 -benzy 1-4-piperid-inyl, 3-pyridyl, 4-amino-2-methyl-5-pyrimidi-nyl, 2-amino-5, 6-dimethyl-3-pyrazinyl or 5-tetrazolyl; 

is 0 or 1; 

is 0, 1, 2, 3, 4, 5, 6 or 7; 

is 1 or 2; 

is 1, 2, 3, 4 or 5; 

is an alkylene group having 1-8 C atoms; and is alkyl having 1-8 C atoms; 

and a physiologically acceptable salt thereof. 

N.Z. PATCNTOFFIC, 

-2 DEC 199] 

- 52 - 

228707
2. a) 6-(BOC-amino)-hexanoyI-Phe-GIy-AHCP-11 e AMPA; 

b) 6-Amino-hexanoyI-Phe-G I y-AHCP-11e ADPA; 

c) 4-Dimethylamino-butyryl-Phe-Gly-AHCP-Ile AMPA; 

d) 4-AminopiperidinocarbonyI-Phe-GIy-AHCP-11e AMPA; 

e) 6-MethoxycarbonyI-hexanoyI-Phe-GIy-AHCP-11e ADPA; 

f) 6-Carboxy-hexanoyL-Phe-GLy-AHCP-11e ADPA; 

g) 4-Aminopiperidinocarbonyl-Phe-BAla-AHCP-Ile AMPA.
3. Process for the preparation of an amino acid derivative of the formula I as claimed in claim 1, and of the salts thereof, characterized in that it is Liberated from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, or in that a carboxylic acid of the formula II 

2p -OH J J 

wherein R1, p and y are as defined in claim 1 and 

G1 is (a) absent, 

(b) -NH-CHR2-C0, 

(c) -NH-CHR2-CO-Z-CmH2(11-CO-, 

(d) -NH-CHR2-CO-Z-CmH2m-CO-W-, 

(e) -NH-CHR2-CO-Z-CmH2m-CO-W-E1-, or 

(f) -NH-CHR2-CO-Z-CnH2m-CO-W-E-t where 

W is -NH-CHR3-CR4-(CHR5)n-CO- whereinR3, R4 and -(CHR5)„- are as defined in claim 1, -NH-CHR2-CO, -Z-CmH2m"CO-, and E are as defined in claim 1, and E1 stands for 0 to 1 amino acid residue selected from the group given in the definition of E, or one of the reactive derivatives thereof, is reacted with an amino compound of the formula III 

H-G2 111 

in which G2 is (a) -NH-CHR2-C0-Z-CmH2m-C0-W-E-Q-Y, 

(b) -Z-CmH2m-CO-W-E-Q-Y, 

(c) -W-E-Q-Y, 

// 

(d) -E-Q-Y, 

(e) -E2-Q-Y, or 

(f) -NR10-Y,and 

-NH-CHR2-CO, Q-Y, E, Y and -Z-C^H^-CO- are as defined in claim 1, 

E2 stands for 0 to 1 amino acid residue selected from the group given in the j definition of E, and W is as defined above, \\2*29 JAN 1992 

and in that a functionally modified amino and/or hydroxyl group in a K /» A o , 

* C p i y"1 

compound of the formula I is, liberated where appropriate, by treatment with solvolyzing or hydrogenolyzing agents, and/or for the preparation of a compound of the formula I, R4 = (H, OH), an amino keto 

' * ... 228707 

acid derivative of the formula 1/ R = 0, is reduced or reductively aminated,Wnd/or one radical R1 is converted to another radical R1 and/or a compound of the formula I is converted by treatment with an acid into one of the salts thereof.
4. Process for the preparation of pharmaceutical compositions, characterized in that a compound of the formula I as claimed in claim 1 and/or one of the physiologically acceptable salts thereof is converted together with at least one solid, liquid or semi-liquid vehicle or auxiliary and, 

where appropriate, in combination with one or more other active compound(s) into a suitable dosage form.
5. Pharmaceutical composition characterized by containing at least one compound of the formula I as claimed in claim 1 and/or one of the physiologically acceptable salts thereof.
6. Use of compounds of the formula I as claimed in claim 1 or of phy-siologically acceptable salts thereof for the preparation of a medicament.
^« A compound of the formula I as claimed in claim 1 or a physiologically acceptable salt thereof suitable for use in controlling renin-depen.dent hypertension or hyperaLdosteronism.
8. Amino acid derivatives according to claim 1 substantially as herein described or exemplified.
9. A process according to claim 3 or 4 substantially as herein described or exemplified.
10. A pharmaceutical composition according to claim 5 substantially as herein described or exemplified. 

MERCK PARENT/GESELLSCHAFT mit beschrankten HAFTUNG .. 

By TheiJ HENRY ffljlfc: By: 

it 

fcorneys e:; ltd 

I 

V 29 JAN1992 \ * 



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