CA2062065A1

CA2062065A1 - Peptide analogues

Info

Publication number: CA2062065A1
Application number: CA002062065A
Authority: CA
Inventors: Horst Juraszyk; Peter Raddatz; Johannes Sombroek; Joachim Gante; Claus J. Schmitges; Klaus-Otto Minck
Original assignee: Individual
Current assignee: Merck Patent GmbH
Priority date: 1991-03-01
Filing date: 1992-02-28
Publication date: 1992-09-02
Also published as: AU1130292A; HU9200678D0; JPH05117297A; EP0501280A2; MX9200862A; CS56992A3; IE920655A1; DE4106488A1; PT100179A; KR920018073A; ZA921541B

Abstract

Abstract New peptide analogues of the formula I

in which R1 to R6, Z and Y have the meanings indicated in Patent Claim 1, and the salts thereof, inhibit the activity of human plasma renin.

Description

2062~

Merck Patent Gesellschaft March 3, 1991 mit beschrankter Haftung D a r m s t a d t Peptide analogues The invention relates to new peptide analogues of the formula I

Rl-z-NR2-cHR3-cR4-cH2-cRsR6-y in which Rl is H, R7-o-CmH2m-Co-, R7-CmH2m-o-Co-, R7-CmH2m-Co- ~ R7-So2-, RaR9N-CmH2m-Co-, R10-NH-C(=NH)-NH-CmHzm-CO-, R8OOC-CmH2m-CO-, RBO3S-CmH2m-CO- or Rll--CmH2~--(T)~--(V)y~CnH2n~L(R7~Cp}12p)--CrH2r--CO~ ~
z is 0 to 4 amino acid residues which are linked together in the manner of a peptide and are selected from the group comprising Abu, Ada, Ala, ~Ala, Arg, Asn, Asp, Bia, Cal, Dab, Gln, Glu, Gly, His, N(Lm)-A-His, Hph, Ile, Isoser, Leu, tert.-Leu, Lys, Mal, Met, ~Nal, ~Nal, Nbg, Nle, Nva, Orn, Phe, Pia, Pro, Pya, Ser, Thr, Tia, Tic, Trp, Tyr and Val, Y i 8 -CN, -NO2, -CH2-NRl2Rl3, -CH2-NR12-So2Rl4, -cH2-NRl2-CoRl4, -CH2-NRl2-Co-NH-Rl4, -CH2-NRl2-CS-NH-Rl4 or -CORls, R2, R8, R9 and Rl3 are each H or A, R4 is (H, Rl7) or =O, R5 i OH oR7 oCoR7, osiRlSRl9R2o~ NRaR9 or -0-(2-tetrahydropyranyl), Rs is H, A, Ar or aralkyl, R5 and Rs together are also (=0), Rl8 is H~ OH, oR7, NR8R9, oSiR13R19R20 or -0-(2-tetrahydropyranyl), R17 i8 OH or NH2, 2062~6~

R5 and R17 together are also -Tl-(CR3R7)-T2-, R3, R7, Rll, Rl2 and Rl4 are each H, A, Ar, Ar-alkyl, Het or Het-alkyl, unsubstituted or singly or multiply, by A, AO and/or Hal, substituted cycloalkyl having 3-7 C atoms, cycloalkyl-alkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, or bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, R11 is also R8O-, R3R9N-, R3OoC- or A3N+ An9, R13, Rl9 and R20 are each A, Ar or aralkyl, R1~ is H, A or CN, L is CH or N, T, T1 and T2 are each O or NR6, V is CHOR2, CO, S, SO or SO2, R~R9N and NR12R13 are also each a pyrrolidino, piperidino, morpholino or piperazino group which is unsubstituted or is substituted by A, OH, NH2, N~A, NA2, NHAc, NH-Co-C~H2~-o-R15, NH-Co-o-C~H2r-R15, hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N~ alkyl Ane, NH-CO-NH2, NH-CO-NHA, guanidinyl or guanidinylalkyl, R15 is A or Ar-alkyl, s and y are each 0 or 1, m, n, p, r and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, Ar is phenyl which i8 unsubstituted or is substituted one or more times by A, OA, Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA, NA2, NHAc, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N+ alkyl Ane and/or guanidinyl-alkyl, or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical which has 1-4 N, O and/or S atoms and can be fused 2062~6~

~ with a benzene ring and/or be substituted one or more times by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NA2, NHAc, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, NH-SO2-A, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl and/or A2N-alkyl, and/or whose N
and/or S hetero atoms can also be oxid-ized, Hal is F, Cl, Br or I, Ac is A-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH-CO, Ane is an anion, which can also be absent if, in its place, 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, in which, furthermore, it is also possible for one or more -NH-CO- groups to be replaced by one or more -NA-CO-groups, with the provisos that a) in the case R1 = R11-CmH~-(T)~-V-CnH~-L(R7-CpH2p)-CrH2r-CO- with V = S, SO or SO2, and y = _CH2NR12R13 with R12 = Rl3 = H, R5 then is oCoR7, oSiR1aRl9R20, NRaR9 or -o-(2-tetrahydropyranyl)~
b) in the case R1 = R11-CmH~-(T)8-V-C~H~-L(R7-CH~H2p)-CrH2r-CO- with V = S, SO or SOz, and Y = CORl6, Rl6 then is H, OH, oR7, OSiR1aR19R20 or -0-(2-tetrahydro-pyranyl), as well as the salts thereof.
Similar compound4 are disclosed in EP-A 249,096.
The invention had the object of finding new compounds 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 saltc thereof have very valuable properties. In particular, they inhibit the activity of 2~206~

human plasma renin. This action can be detected, for example, by the method of F. Fyhrquist et al., Clin.Chem.
22, 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 of other aspartyl proteinases (for example pepsin and cathepsin D) are about 100 to 1000 tLmes as high as for renin inhibition. The actions of the com-pounds on the blood pressure and/or on the heart rate, as well as the inhibition of renin activity in blood plasma can furthermore 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 ~.J. Wood et al., J. Hypertension 4, ~51-254 (1985). In order to stimulate renin activity in this, the animals are prefer-ably pretreated 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 active substance~ in human and veterinary mPdicine, in particular for the prophylaxis and for the treatment of diseases of the heart, circulation and vessel~, especi-ally of hypertension, cardiac insufficiency and hyper-aldosteronism. 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 herein-after 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 Ada 3-(1-adamantyl)-alanine Ala alanine ~Ala ~-alanine 2062~6~

Arg arginine Asn a~paragine Asp aspartic acid Bia 3-(2-benzimidazolyl)-alanine S Cal 3-cyclohexylalanine Dab 2,4-diaminobutyric acid Gln glutamine Glu glutamic acid Gly glycine His histidine N(im)-A-His histidine substituted in the 1 or 3 position of the imidazole ring by A
Hph homophenylalanine (2-amino-4-phenylbutyric acid) Ile isoleucine Isoser isoserine Leu leucine tert.-Leu tert.-leucine Lys lysine Mal 3-(p-methoxyphenyl)-alanine Met methionine ~Nal 3-(~-naphthyl)-alanine ~Nal 3-(~-naphthyl)-alanine Nbg 2-norbornyl-glycine ?s Nle norleucine Nva norvaline N-Me-His N-methyl-histidine N-Me-Phe N-methyl-phenylalanine Orn ornithine Phe phenylalanine Pia 3-(piperidyl)-alanine ~e.g. 2-Pia = 3-(2-piperidyl)-alanine]
Pro proline Pya 3-(pyridyl)-alanine te.g. 3-Pya = 3-(3-pyridyl)-alanine]
Ser serine Thr threonine Tia 3-(thienyl)-alanine te.g. 2-Tia = 3-(2-thienyl)-alanine]

20~206~

Tic 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid Trp tryptophan Tyr tyrosine S Val valine.
Further meanings hereinafter are:
BOC tert.-butoxycarbonyl BOM benzyloxymethyl imi-BOM benzyloxymethyl in the 1 position of the imidazole ring CBZ benzyloxycarbonyl DAPECI dimethylaminopropylcarbodiimide DCCI dicyclohexylcarbodiimide DMF dimethylformamide ~5 DNP 2,4-dinitrophenyl imi-DNP 2,4-dinitrophenyl in the 1 position of the imidazole ring ETOC ethoxycarbonyl FMOC 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole IPOC isopropoxycarbonyl NMM N-methylmorpholine POA phenoxyacetyl THF tetrahydrofuran.
If the abovementioned amino acids can occur in several enantiomeric forms, then all these forms, as well as mixture~ thereof (for example the DL forms), are 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 otherwise.
The invention furthermore relates to a process for the preparation of a peptide analogue 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 hydrogenolyzing agent, or in that a carboxylic acid of the formula II

2~fi~0b'~

in which G1 is (a) absent, (b) z, (c) Z, or one of the reactive derivatives thereof, is reacted with an amino compound of th~ formula III

H-G2-NR2-CHR3-CR4-CE~2-CRSR6-y III
in which G2 is (a) Z, (b) absent, ( C ) Z2 and zl + z2 are together Z, and in that a functionally modified amino and/or hydroxyl group in a compound of the ormula I is liberated where appropriate by treatment with solvolyzing or hydrogeno-lyzing agents, and/or a free amino group is acylated by treatment with an acylating agent and/or for the preparation of a compound of the formula Il R4 = ~H, OH) or (H, NH2), an amino keto acid derivative of the formula I, R4 = O, is reduced or reductively aminated, and/or a 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.
~ereinbefore and hereinafter the radicals and parameters R~ to R20, Z, Y, L, T, T1, T2, V, m, n, p, r, s, x, y, Ar, Het, Hal, Ac, An, A, Gl, GZ, 31 and Z2 have the meanings indicated for the formulae I, II or III unless expressly indicated otherwise.
Aintheabovementionedormulaehas 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-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-l 2-, 3- or 4-methylpentyl, 1,1-l 1,2-, 1,3-, 2,2-, 2~3- or 3,3-dLmethylbutyl, 1- or 2-ethylbutyl, l-ethyl-l-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2- ~r 1,2,2-2~620~3 g trLmethylpropyl, heptyl or octyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyoloheptyl, but is also, for example, 1-, 2- or 3-methylcyclopentyl, or 1-, 2-, 3- or 4-methylcyclohexyl.
-alkyl- is an alkylene group having 1-8 C atoms, preferably 1, 2, 3 or 4 C atoms. -alkyl- is preferably methylene, ethylene, propylene, butylene, and furthenmore pentylene, hexylene, heptylene, octylene, isopropylene, l-ethylpropylene ox 1-, 2- or 3-methylbutylene.
Correspondingly, cycloalkylalkyl is preferably cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl,cyclopentylmethyl,2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, but is also, for example 1-, 2- or 3-methylcyclopentylmethyl, or 1-, 2-, 3- or 4-methylcyclohexylmethyl.
Bicycloalkyl is preferably 1- or 2-d~calyl, 2-bi-cyclo[2.2.1]heptyl or 6,6-dimethyl-2-bicyclo~3,1,1]hept~
yl .
Tricycloalkyl is preferably 1-adamantyl.
Hal is preferably F, Cl or Br, but is also I.
Ac is preferably A-CO-, such as acetyl, propionyl or butyryl, Ar-CO- such as benzoyl, o-, m- or p-methoxy-benzoyl or 3,4-dimethoxybenzoyl, or A-NH-CO- such as N-methyl- or N-ethylcarbamoyl.
Ar is preferably phenyl and is furthermore preferably G-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o , m- or p-bromophenyl, o-, m- or p-iodophenyl, o-, m- or p-trifluoromethylphenyl, o-, m-or p~hydroxyphenyl, o-, m- or p-sulfamoylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-d~ne~hoxyphenyl, 3,4,5-trimethoxyphenyl, o-, m- or p~aminophenyl, o-, m- or p-aminomethylphenyl, o-, m- or p-dimethylaminomethylphenyl~
o-, m- or p-~uanidinomethylphenyl, or 1- or 2-naphthyl.
Correspondingly, Ar-alkyl is preferably benzyl, 1- or 2-phenylethyl, o-, m- or p-me~hylbenzyl, 1- or 2-o-, -m- or -p-tolylethyl, o-, m- or p-ethylbenzyl, 1- or 2-o-,-m-or-p-ethylphenylethyl,o-,m-orp-me~hoxybenzyl, l- or 2-o-, -m- or -p-methoxyphenylethyl, o-, m- or p-fluorobenzyl, l- or 2-o-, -m- or -p-fluorophenylethyl, o-, m- or p-chlorobenzyl, 1- or 2-o-, -m- or -p-chloro-phenylethyl, o-, m- or p-bromobenzyl, 1- or 2-o-, -m- or -p-bromophenylethyl, o-, m- or p-iodobenzyl, l- or 2-o-, -m- or -p-iodophenylethyl, o-, m- or p-trifluoromethyl-benzyl, o-, m- or p-hydroxybenzyl, 2,3-, 2,4-, 2,5-, 2,6-3,4- or 3,5-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, o-, m- or p-aminobenzyl, o-, m- or p-aminomethylbenzyl, o-, m- or p-dimethylaminomethylbenzyl, o-, m- or p-guanidino-methylbenzyl, or 1- or 2-naphthylmethyl.
Het is preferably 2- or 3-furyl, 2- or 3-thienyl, l-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, l-, 3-, 4- or 5-pyrazolyl, 2-, 4- or S-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazo-lyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or 5-yl, 2,1,5-thiadiazol-3- or -4-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyrid-azinyl, pyrazinyl 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl, l-, 2-, 4- or 5-benzimidazolyl, l-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7- benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 1-, 2-, 3-, 4- or 9-carbazolyl, l-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolyl. The heterocyclic 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, tetrahydro-2- or 3-furyl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, 206206~

-2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-or -5-pyrazolyl, tetrahydro-l-, -3- or -4-pyrazolyl, 1,4-dihydro-l-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1,2,3,6-tetrahydro-l-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridaz-inyl, hexahydro-l-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl.
The heterocyclic radicals can also be ~ubstituted as indicated. Het can also preferably be, for example, 2-amino-4-thiazolyl, 4-carboxy-2-thiazolyl, 4-carbamoyl-2-thiazolyl, 4-(2-aminoethyl)-2-thiazolyl, 4-amino-2-methyl-5-pyrimidinyl, 2-amino-5,6-dimethyl-3-pyrazinyl, 4-carbamoylpiperidino, furthermore, for example, 3-, 4-or 5-methyl-2-furyl, 2-, 4- or 5-methyl-3-furyl, 2,4-dimethyl-3-furyl, 5-nitro-2-furyl, 5-styryl-2-furyl, 3-, 4- or 5-methyl-2-thienyl, 2-, 4- or 5-methyl-3-thienyl, 3-methyl-5-tert.-butyl-2-thienyl, 5-chloro-2-thienyl, 5-phenyl-2- or -3-thienyl, 1-, 3-, 4- or 5-methyl-2-pyr-rolyl, 1-methyl-4- or -S-nitro-2-pyrrolyl, 3,5-dimethyl-4-ethyl-2-pyrrolyl, 4-methyl-S-pyrazolyl, 5-methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 4- or 5-methyl-2-thiazolyl, 2- or S-methyl-4-thiazolyl, 2- or 4-methyl-S-thiazolyl, 2,4-dimethyl-5-thiazolyl, 3-, 4-, S- or 6-methyl-2-pyridyl, 2-, 4-, 5- or 6-methyl-3-pyridyl, 2-or 3-methyl-4-pyridyl, 3-, 4-, 5- or 6-chloro-2-pyridyl, 2-, 4-, 5- or 6-chloro-3-pyridyl, 2- or 3-chloro-4-pyridyl, 2,6-dichloropyridyl, 2-hydroxy-3-, -4-, -5- or -6-pyridyl (= lH-2-pyridon-3-, -4-, -5- or -6-yl), S-phenyl-lH-2-pyridon-3-yl, S-p-methoxyphenyl-lH-2-pyridon-3-yl, 2-methyl-3-hydroxy-4-hydroxymethyl-S-pyridyl, 2-hydroxy-4-amino-6-methyl-3-pyridyl, 3-N'-methylureido-lH-4-pyridon-S-yl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-~-206~06~

pyrimidinyl, 2-, 5- or 6-methyl-4-pyrLmidinyl, 2,6-dimethyl-4-pyrimidinyl, 2,6-dihydroxy-4-pyrimidinyl, 5-chloro-2-methyl-4-pyrimidinyl, 3-methyl-2-benzofuryl, 2-ethyl-3-benzofuryl, 7-methyl-2-benzothienyl, 1-, 2-, 4-, 5-, 6- or 7-methyl-3-indolyl, 1-methyl-5- or -6-ben-zimidazolyl, l-ethyl-5- or -6-benzimidazolyl, 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2-quinolyl, 2-oxo-pyrrolidino, 2-oxo-piperidino, 2,5-dioxopyrrolidino or 3-benzyl-2,5-dioxopyrrolidino.
Rl is, in general, preferably R8R9N-CmH2~-Co- or R7-CmH~-o-Co-, furthermore preferably R7-C~H2~-Co-, R~OOC-CmH2~-CO- or Rll-CmH2m--(T)~--(V)~~CnH2n~L(R -CpH2p)~CrH2r~C~-The group Z preferably consists of one or two of the stated amino acid residues; however, it can also contain three or four amino acid residues or be absent.
Z is preferably His, Phe or Phe-His, furthermore pre-ferably Cal-His, Mal-His, ~Nal-His, ~Nal-His, Phe-Abu, Phe-Ala, Phe-~Ala, Phe-Ser, Phe-Asn, Phe-Gln, Phe-Glu, Phe-Gly, Phe-Nle, Phe-Pya (especially Phe-3-Pya), Phe-Tia (especially Phe-3-Tia), Tia-His (especially 3-Tia-His), Trp-His, Tyr-His or Pro-Phe-His.
Y is, in general, preferably -CN or -CH2-NR12-So2Rl4, furthermore preferably -cH2-NRl2-Co-NHRl4 or --CH2--NRl2-CS -NHRl~ .
R2, R8, R9 and Rl3 are each preferably H and furthermore preferably methyl. R8R9N is also preferably pyrrolidino, piperidino, morpholino, amino-piperidino such as 4-aminopiperidino, alkylaminopiperidino such as 4-methylaminopiperidino, or dialkylaminopiperidino such as 4-dimethylaminopiperidino.
R3 is preferably cycloalkylalkyl, especially cyclohexylmethyl, furthermore preferably alkyl, especi-ally isobutyl; Ar-alkyl, especially benzyl; cycloalkyl, especially cyclohexyl.
R4 is preferably (H, R17), in which R17 is OH or NH2 .
R4 is especially preferably (H, OH).
R5 is preferably OH, oR7, oCOR7 or OSiRl8R19R20.
Preferably, R5 together with R17 also is 20~20~5 - 13 _ -Tl-(CR3R7)-TZ
R6 is pre~erably H or A, particularly methyl.
R5 and R6 together are also preferably (=O).
R7 is preferably A, especially methyl, ethyl, isopropyl or tert.-butyl; or Ar, especially phenyl, 1- or 2-naphthyl.
R10 is preferably H, methyl or CN.
Rl1 is preferably H; A, especially methyl or tert.-butyl; R8R9N, especially A2N such as (CH3~2N, piperi-dino or 4-aminopiperidino.
Rl2 and Rl3 are preferably H or A, especially methyl.
Rl4 is preferably A, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl or isopentyl; cycloalkylalkyl, especially cyclohexylmethyl; Ar-alkyl, especially benzyl; Ar, especially phenyl or aminophenyl such as p-aminophenyl.
R15 is preferably A having 1-4 C atoms, especially isopropyl or tert.-butyl; or Ar-alkyl, especially benzyl.
R16 is preferably H, OH or oR7.
Rl7 is preferably OH.
RlB, Rl9 and R2~ independently of one another are each preferably A, particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl or isopentyl; Ar, particularly phenyl or Ar-alkyl, particularly benzyl.
L is preferably CH, furthermore preferably N.
T is preferably O or NR6, in which R6 is H or A.
Tl and T2 are preferably O.
V is preferably CO or SO2.
The parameter s i8 preferably 0 but also 1; y is preferably 1 but also 0. The sum s + y is preferably 1 but also 0 or 2. The parameter m is preferably 1, 2, 3, 4 or 5; n is preferably 1; pH is preferably l; r is preferably 1 or 0. The groups CmH2~, CnH2n, CpH2p and C~2r are preferably straight-chain and thus are preferably -(CH2)m-, -(CH2)n-, -(CH2)p- or -~CH2~
Accordingly, the group Rl i~ specifically and preferably R8R~N-(CH2)m-CO-, especially H2N-CmH2m-CO- such 2 ~ 6 ~

as aminocarbonyl, aminoacetyl (H-Gly)-, 3-aminopropionyl (H-~Ala-), 4-aminobutyryl, 5-aminopentanoyl, 6-aminohex-anoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminonona-noyl, 10-aminodecanoyl, ll-aminoundecanoyl, but also, S for example, 2-amino-propionyl (Ala), 2-amino-2-methyl-propionyl; ANH-C~H~-CO- such as methylaminocarbonyl, methylaminoacetyl (sarcosyl~, 3-methylaminopropionyl, 4-methylaminobutyryl,5-methylaminopentanoyl,6-methylamin-ohexanoyl, 6~ethylaminohexanoyl, 7-methylaminoheptanoyl, 8-methylaminooctanoyl, 9-methylaminononanoyl, 10-methyl-aminodecanoyl, ll-methylaminoundecanoyl; ~2N-CmH~-CO-such as dimethylaminocarbonyl, dimethylaminoacetyl, 3-di methylaminopropionyl,4-dimethylaminobutyryl,5-dimethyl-aminopentanoyl, 6-dimethylaminohexanoyl, 6-diethylamino-hexanoyl, 7-dimethylaminoheptanoyl, 8-dimethylamino-octanoyl,9-dimethylaminononanoyl,10-dimethylaminodecan-oyl, 11-dimethylaminoundecanoyl; A O-CO-NH-C~H~-CO- such as BOC-Gly, ETOC-Gly-, IPOC-Gly, BOC-~Ala, ETOC-~Ala, IPOC-~Ala, 4-BOC-amino-butyryl, 5-BOC-amino-pentanoyl, 6-BOC-amino-hexanoyl, 7-BOC-amino-heptanoyl, 8-BOC-amino-octanoyl, 9-BOC-amino-nonanoyl, 10-BOC-amino-decanoyl, ll-BOC-amino-undecanoyl; ArCH2-O-CO-NH-CmH2m-CO~ ~uch as CBZ-Gly-, CBZ-~Ala, 4-CB~-amino-butyryl, 5-CBZ-amino-hexanoyl, 7-CBZ-amino-heptanoyl, 8-CBZ-amino-octanoyl, 9-CBZ-amino-nonanoyl, 10-CBZ-amino-decanoyl, ll-CBZ amino-undecanoyl; pyrrolidino-C~H~-CO- such as pyrrolidinocar-bonyl, pyrrolidino-acetyl, 3-pyrrolidino-propionyl, 4-pyrrolidino-butyryl, 5-pyrrolidino-pentanoyl, 6-pyrrolidino-hexanoyl, 4-pyrrolidino-heptanoyl/ 8-pyrrolidino-octanoyl, 9-pyrrolidino-nonanoyl, 10-pyrrolidino-decanoyl; piperidino-C~H~-CO- such as piperi-dinocarbonyl, piperidinoacetyl, 3-piperidino-propionyl, 4-piperidino-butyryl, 5-piperidino-pentanoyl, 6-piperi dino-hexanoyl, 7-piperidino-heptanoyl, 8-piperidino-octanoyl, 9-piperidino-nonanoyl, 10-piperidino-decanoyl;
morpholino-C~H~-CO- such as morpholinocarbonyl, mor-pholinoacetyl, 3-morpholino-propionyl, 4~morpholino-~utyryl, 5-morpholino-pentanoyl, 6-morpholino-hexanoyl, 7-morpholino-heptanoyl, 8-morpholino-octanoyl, 9-mor-2~6206~

pholino-nonanoyl,10-morpholino-decanoyl;4-amino-piperi-dino-CmH~-CO- such as 4-amino-piparidino-carbonyl, 4-amino-piperidino-acetyl, 3-(4-amino-piperidino)-propion-yl, 4 (4-amino-piperidino)-butyryl, 5-(4-amino-piperi-5 dino)-pentanoyl, 6-(4-amino-piperidino)-hexanoyll 7-(4-amino-piperidino)-heptanoyl, 8-(4 amino-piperidino)-octanoyl, 9-(4-amino-piperidino)-nonanoyl, 10-(4-amino-piperidino)-decanoyl; 4-dialkylamino-piperidino-C~H~-CO-such as 4-dim~thylamino-piperidinocarbonyl~ 4-dLmethyl-amino-piperidino-acetyl; 4-guanidino-piperidino-C~H~-CO-such as 4-guanidino-piperidino-carbonyl, 4-guanidino-piperidino-acetyl; 4-carboxy-piperidino-CmH~-CO- such as 4-carboxy-piperidino-carbonyl, 4-carboxy-piperidino-acetyl; 4-alkoxycarbonyl-piperidino-CmH~-CO- such as 4-lS methoxycarbonyl-piperidino-carbonyl, 4-ethoxycarbonyl-piperidino-carbonyl, 4-methoxycarbonyl-piperidino-acatyl, 4-ethoxycarbonyl~piperidino-acetyl; 4-AcNH-piperidino-C~H~-CO- such as 4-acetamido-piperidino-carbonyl, 4-acetamido-piperidino-acetyl; H2N-C(=NH~-NH-CmH~-CO- such as guanidinoacetyl, 3-guanidino-propionyl, 4-guanidino-butyryl, 5-guanidino-pentanoyl, 6-guanidino-hexanoyl, 7-guanidino-heptanoyl, B-guanidino-octanoyl; NC-NH-C(=NH)-Nff-C~H~-CO- such as N'-cyanoguanidino-acetyl, 3-(N'-cyanoguanidino)-propionyl, 4-(N'-cyanoguanidino)-butyryl, 5-(N'-cyano~lanidino)-pentanoyl, 6-(N'-cyanoguanidino)-hexanoyl, 7-(N~-cyanoguanidino)-heptanoyl, 8-(N' -cyano-guanidino)-oc:tanoyl; HOOC-C~H~-CO- such as malonyl, succinyl, glutaryl, adipyl, 6-carboxyhexanoyl, 7-carboxy-heptanoyl, 8-carboxyoctanoyl, 9-carboxynonanoyl, 10-carboxy-decanoyl, ll-carboxyundecanoyl; AOOC-C~H~-CO-such as methoxycarbonyl-acetyl, 3-methoxycarbonyl-prop-ionyl, 4-methoxycarbonyl-butyryl, 5 -me thoxycarbonyl-pentanoyl~6-methoxycarbonyl-hexanoyl,7-methoxycarbonyl-heptanoyl,8-methoxycarbonyl-octanoyl,9-methoxycarbonyl-nonanoyl, 10-methoxycarbonyl-decanoyl, ethoxycarbonyl-acetyl, 3-ethoxycarbonyl-propionyl, 4-ethoxycarbonyl-butyryl, 5-ethoxycarbonyl-pentanoyl, 6-ethoxycarbonyl-hexanoyl, 7-ethoxycarbonyl-heptanoyl, 8-ethoxycarbonyl-octanoyl, 9-ethoxycarbonyl-nonanoyl, 10-ethoxycarbonyl-- 16 - 206206~
decanoyl; H-S03-CmH2m-CO- such as sulfo-acetyl, 3-sulfo-propionyl, 4-sulfo-butyryl, 5-sulfo-pentanoyl, 6-sulfo-hexanoyl, 7-sulfo-heptanoyl, 8-sulfo-octanoyl, 9-sulfo-nonanoyl, 10-sulfo-decanoyl; A-SO3-C~Hzm-CO- such as methoxysulfonyl-acetyl, 3-methoxysulfonyl-propionyl, 4-methoxysulfonyl-butyryl, 5-methoxysulfonyl-pentanoyl, 6-methoxysulfonyl-hexanoyl, 7-methoxysulfonyl-heptanoyl, 8-methoxysulfonyl-octanoyl, 9-methoxysulfonyl-nonanoyl, 10-methoxysulfonyl-decanoyl, ethoxysulfonyl-acetyl, 3-ethoxysulfonyl-propionyl, 4-ethoxysulfonyl-butyryl, 5-ethoxysulfonyl-pentanoyl, 6-ethoxysulfonyl-hexanoyl, 7-ethoxysulfonyl-heptanoyl, 8-ethoxysulfonyl-octanoyl, 9-ethoxysulfonyl-nonanoyl, 10-ethoxysulfonyl-decanoyl;
R11-CmH2m-Co-CnH2n-CH(R7-CpH2p)-CrHzr-CO-, especially A-CO-CH2-CH(Ar-CH2)-CO- quch as 2-benzyl-4-oxo-5,5-di-methylhexanoyl, 2-(l-naphthylmethyl)-4-oxo-5,5-dimethyl-hexanoyl; furthermore R8RgN-CO-CH2-CH(Ar-CH2)-CO- such as 2-benzyl-3-(4-aminopiperidinocarbonyl)-propionyl, 2-(1-naphthylmethyl)-3-(4-aminopiperidinocarbonyl)-propionyl;
R11~CmH2m~S02~CnH2n~CH(R7~CpH2p)~CrH2r~CO~~ especially A-SO2-CH2-CH(Ar-CH2)-CO such as 2-benzyl-3-tert.-butylsul-fonylpropionyl, 2-(l-naphthylmethyl)-3-tert.-butylsul-fonylpropionyl; R1l-CmH2m-NH-CO-CnH2n-CH(R -CpH2p)-CrH2r-C0-, especially R9R9N-(CH2)~-NH-CO-CH2-CH(Ar-CH2)-C0- such as 2-benzyl-3-(N-3-dimethylaminopropyl-carbamoyl)-propionyl, 2-(1-naphthylmethyl)-3-(N-3-dimethylaminopropyl-car-bamoyl)-propionyl, 2-benzyl-3-(N-5-dimethylaminopentyl-carbamoyl)-propionyl; A-CH(R7-CpH2p)-CrH2r-Co-, especially A-CH(Ar-CH2)-CO- such as 2-benzylhexanoyl, 2-benzyl-heptanoyl; R11-CmH2m-NH-CO-, especially R~R9N-(CH2)m-NH-Co-such as N-3-dimethylaminopropyl-carbamoyl, N-5-dimethyl-aminopentyl-carbamoyl; R11-CmH2m- N(R7-CpH2p)-CrH2r-Co-, especially A-N(Ar-CH2)-CO- such as N-benzyl-N-butyl-carbamoyl, N-benzyl-N-isopentyl-carbamoyl; R7-CmH2m-o-Co-especially A-O-CO- such as ETOC, IPOC, BOC as well as Ar-CmH2m-O-CO- such as CBZ; R7-CmH2m-Co- ~uch as 3,3-di-methylbutyryl.
Accordingly, the group Y is specifically and preferably -CN; -CH2NH-SO2R1~, e~pecially -CH2-NH-SO2-A such - 17 _ 2 ~ ~2 ~ ~
as methane-, ethane-, propane-, 2-methylpropane- and butane-sulfonamidomethyl, furthermore, for e~ample, phenylmethane- and cyclohexylmethane-sulfonamidomethyl;
-CH2-NH-Co-NH-R14-, especially -CH2-NH-CO-NH-A such as N'-methylureidomethyl, Nr-propylureidomethyl, N'-butyl-ureidomethyl, N'-isopentylureidomethyl, furthermore -CH2-NH-CO-NH-Ar such as N'-phenylureidomethyl and N'-p-aminophenylureidomethyl; -CH2-NH-CS-NH-R 14~ especially -CH2-NH-CS-NH-A such as N'-methylthioureidomethyl;
-CH2-NH-CoR14, especially -CH2-NH-CO-A such as acetamido-methyl, propionamidomethyl and butyramidomethyl.
I f Rl = Rll-CmH2m- ( T ) a-V-CnH2n-L ( R7-CpH2p ) -CrH2r-CO-with V = S, SO or SO2 and at the same time Y = -CH2-NH2, R5 is oCoR7, OsiRlaRlsR2~ NRaRg or O (~ t t h d Furthermore, Rl5 is H, OH, OR7, OSiRl8R13R20 or -O-(2-tetrahydropyranyl), if R1 = Rll-C~H~-(T),-V-C H~-L(R7-CpH2p)-CrH2r-Co- with V = S, SO or SO2 and Y is COR16.
The compounds of the formula I may have one or more chiral centres and therefore exist in Yarious, optically active or optically inactive, forms. The formula I embraces all these forms, the S enantiomers genexally being preferred.
The abovementioned cycloalkyl and phenyl groups are preferably unsubstituted or carry preferably 1 to 3, especially 1 or 2, substituents~
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 com-pounds can be represented by the following part-formulae Ia to Ik:
Ia R7-CmH2m-o-Co-Z-NH-CHR3-CHoH-CH2-CHoH-Y;

Ib R7-CmH2m-Co-Z-~H-CHR3-CHoH-CH2-CHoH-Y;

Ic R~R9N-CmH2~-Co-z-NH CHR3-CHoH-CH2-CHoH-Y;

Id R -NH-C(=NH)-NH-CmH2m-Co-Z-NH-CHR3-C~oH-CH2-CHoH-Y;

Ie R800C-C ~ 2m-CO-Z-MH CHR3-CHoH-CH2-CHoH-Y;

- 18 - 2062~6~

If R3R9N-C H2 -Co-z-NH-cHR3-cH-cH -CH-Y

Tl-CR3R7 T2 Ig 3CmH2m (T)s (V)y-cnH2n-L(R -cpH2p)-crH
CHR -CHOH-CH2-CHR -Y;

Ih 4-Aminopiperidinocarbonyl-Z-NH-CHR3-CHOH-CH2-CHOH-Y;

Ii A-CO-CH2-CH(ArCH2)-CO-Z-NH-CHR3-CHOH-CH2~CHOH-Y;

Ij A-SO2-CH2-CH(ArCH2)-CO-Z-NH-CHR3-CHOH-CH2-CHR5-Y;
Ik R3R9N-CgH2m-NH-CO-CH2-CH(ArCH2)-CO-Z-NH-CHR3-CHOH-CH2-CHR -Y.
Particularly preferred are compounds of the part-formulae:
(a) Iaa to Ika, which corre~pond to the formulae Ia to Ik but in which additionally Z is His, Phe, Phe-~Ala, Phe-Ser or Phe-His;
(b) Iab to Ikb and Iaab to Ikab, which correspond to the formulae Ia to Ik and Iaa to Ika but in which additionally R3 is isobutyl or cyclohexylmethyl.
Especially preferred are compounds of the part-formulae:
I* and Ia* to Ik*, which correspond to the formulae I and Ia to Ik, as well as those compounds which correspond to the other abovementioned part-formulae but in which additionally Y is -CN, -CH2-NH-CO-NH-R1~, -CH2-NH-Co-R14 or -CH2-NH-So2-R14 and R1~ is A, Ar-alkyl or cycloalkylalkyl I~ and Ia~ to Ik~, which correspond to the formulae I and Ia to Ik, as well as those compounds which correspond to the other abovementioned part-formulae but in which additionally Y is -CH2-NH-SO2-A.
The compounds of the formula I, as well as the 19 206206~
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 (Methods of Organic Chemistry), published by Georg Thieme, Stuttgart; as well aq EP-A
45665, 2P-~ 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 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 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 hydrogenoly-sis.
Preferred starting materials for the solvoly~isor hydrogenolysis are ~hose which correYpond to the formula I apart from containing, in place of one or more free amino and/or hydroxyl groups, corresponding protec-ted amino and/or hydroxyl groups, preferably those whichcarry 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 an His group an N(im)-R'-His group (in which R~ is an amino protective group, for example BO~ or DNP), or those of the formula Rl-Z-NR2-CHR3-CH(NHR')-CHz-CR6(NHR~)-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 formula Rl-Z-NR2-CHR3-CHoR~-CH~-CR6oRn-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 be present in the molecule of the ~tarting material. If 6 ~

the protective groups which are present differ from one another it is possible in many cases to eliminats them selectively.
The term 'amino protective ~roup" is generally 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 par-ticular, unsubstituted or substituted acyl, aryl (forexample DNP), aralkoxymethyl (for example BOM) or aralkyl groups (for example benzyl, 4-nitrobenzyl, triphenyl-methyl~. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size are not 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 ~he widest sense. -It embraces acyl groups derived from aliphatic, aralipha-tic, aromatic or heterocyclic carboxylic acids or sul-fonic acids, as well as, in particular, alkoxycarbonyl, aryloxycarbonyl and, especially, aralko~ycarbonyl groups.
Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl;
aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ETOC, 2,2,2-trichloroethoxycarbonyl, IPOC, BOC, 2-iodoethoxycarbonyl;
aralkyloxycarbonyl such as CBZ, 4~methoxybenzyloxycar-bonyl, FMOC. Preferred amino protective groups are BOC, DNP and BOM, as well as C~Z, 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 reaction~
but which can easily be removed after tha desired chemi-cal reaction has been carried out elsewhere in themolecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl~ aralkyl or acyl groups, as well as alkyl groups. The nature and size of the hydroxyl protecti~e groups are not critical because - 21 - 2062~65 they are removed again after the desired chemical reaction or reaction sequence; preferred groups have 1-20, especially 1-10, C atoms. Examples of hydroxyl protective groups are, inter alia, tert.-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl 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 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 on the protective group used - for example with strong acids, preferably with trifluoroacetic 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 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 acetic acid, ethers such as tetrahydrofuran or diox-ane, amides such as dimethylformamide (DMF), halogenatedhydrocarbons such a~ dichloromethane, as well as alcohols such as methanoI, ethanol or isopropanol, and water.
Furthermore suitable are mixtures of the abovementioned solvents. 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, preferably between 15 and 30 (room temperature).
The BOC group can be eliminated, for example, preferably with 40% trifluoroacetic acid in dichloromethane or with about 3 to 5 N HCl in dioxane at 15-30, and the FMOC group with an approximately 5-20%

solution of dimethylamine, diethylamine or piperidine in DMF at 15-30. Elimination of the DNP group i8 effected, for example, also with an approximately 3-10% solution of 2-mercaptoethanol in DMF/water at 15-30.
Protective groups which can be removed by hydro-genolysis (for example BOM, CBZ or benzyl) can be elimin-ated, for example by treatment with hydrogen in the presence of a catalyst (for example a noble metal cata-lyst such as palladium, preferably on a support such as carbon). Solvents suitable for this are those mentioned above, especially, 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, prefer-ably at 20-30 and under 1-10 bar. Hydrogenolysis of the CBZ group is effected satisfactorily, for example, on 5-109~ 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). Examples of suitable carboxylic acid components are those of the part-formulae (a) Rl-OH, (b) Rl-Z-OH, and of amine components are those of the part-formulae (a) H-Z-NR2-CHR3-CR~-CH2-CR5R6-Y, (b) H-NR2-CHR3-CR4-CH2-CR5R6-Y. The peptide linkage can, however, also be formed within the group Z; this entails a carboxylic acid of the formula Rl-Z1-OH being reacted with an amino compound of the formula H-Z2-NRZ-CHR3-CR~-CH2-CR5R5-Y, where z~ + Z2 = Z. The methods preferably used for this are those customary in peptide synthesis, as are described, for example, in Houben-Weyl, l.c., Volume 15/II, paqes 1-806 (1974).
The reaction i~ preferably effected in the presence of a dehydrating agent, for example a carbodi-imide such as DCCI or dimethylaminopropylethylcarbodi-imide, or else propanephosphonic anhydride (compare Angew. Chem. 92, 129 (1980)), diphenyl phosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as THF or dioxane, an - 23 - 2~ 6~
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 o II or III, to use suitable reactive derivatives of these substances in 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-hydroxysuccinimide.
Urea derivatives of the formula I [R1 = R3-NH-Co-or Rl1-C~H~-(T)a-(V)y--CnH~-NH~CO~] can be obtained, for example, by reacting an appropriate isocyanate (for example of the formula RB-NCO; can be prepared from an amine of the formula R8-NH2 and phosgene) with an amine of the formula H-Z-NR2-CHR3-CR4-CH2-CR5R6-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 the formulae II and III
are 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 g:roups.
The amino component of the formula IIIb can be obtained, for example, in accordance with the following general scheme.
~C~2~
R3~ -C1~2-C~0 C113N02 R3-CX-C~}I-C82-CH N2 > l l l BOC-N O ~a~ BOC-N O OH
~C~ C
(b) 2 ~ ~ ~

R3-CII~ CH2-C~-CN 2 2 I I I I I i BOC-N ~O OH BOC-N O OSiR R19R
~C~ \C/

~CH

BOC-N O OSiR R 9R 3~ BOC-N O OSiRR 9R2 ,C ~C~

(c) The compound (c) can be varied as required on the substituent CH2NH2 (corresponds to Y) by known methods.
ElLmination of the silyl group, of the BOC protective group and cLeavage of the oxa~olidinyl ring result in, for example, the amine component H2N-CHR~-CHOH-CH2-CHOH-CH2NH2. Pept:ide coupling with, for example, Rl-Z-OH is then subsequently carried out by customary methods.
If cle~ired, it is possible for a functionally modified amino and./or hydroxyl group in a compound of th~
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
which contains an R15-CrH2l-o-Co-NH-, an AcNH-, an ArCH2-S03- or an AOOC- group can be converted into the corresponding compound of the formula I which contains in its stead an H2N-, an HS03- or an HOOC- group, preferably by selective solvolysi~ by one of the method~ indicated above. AOOC- groups can be hydrolyzed, for example, with NaO~ or KOH in water/dioxane at temperatures between O
and 40, preferably 10 and 30.

20620~

It is al~o possible to acylate a compound of the formula I which contains a free primary or secondary amino group. Thus, in particular, compounds of the formula I in which Y is a CH2-NH-Rl2 group can be reacted S with acylating agents of the formulae Rl4-SO2Cl, ~l4-COCl or Rl4-NCo, preferably in the presence of an inert solvent such as THF and/or of a base such as pyridine or tri-ethylamine at temperatures between -10 and +30.
Furthermore, for example, keto compounds of the formula I (R4 = O and/or R5R8 = O) can be reduced to compounds of the formula I (R4 = (H, OH) and/or R5R6 = H, OH), for example with a complex metal hydride such as NaBH4 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 = O and/or R5R6 = o) can also be converted into compounds of the formula I (R4 = H, NH2 and/or R5R6 = H, NH2) by reductive amination. The reductive amination 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 NaCNBH3, preferably in an inert solvent, for example an alcohol such as methanol, at temperatures between about O and 50, in particular between 15 and 30.
It is furthermore possible initially to convert the keto compound into the oxime, using hydroxylamine in a cus-tomary manner, and to reduce the oxime to the amine, for example by catalytic hydrogenation on Raney nickel.
A base of the formula I can be converted into the relevant acid addition salt u ing an acid. Particularly suitable acids for this reaction are those which provide physiologically acceptable salts, thus it is po~sible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acid~ such as orthophos-phoric acid, sulfamic acid, as well as organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, 20~206~

- propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphtha-lene-mono- and -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 physiologically 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 compound(s), into a suitable dosage form. The composi-tions obtained in this 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 not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatine, soya lecithin, carbohydrate~ such as lactose or starch, magnesium stearate, talc and cellulose. Used orally are, in particular, tablets, coated tablets, capsules, syrups, elixirs or drops; specifically of interest are lac~uered tablets and capsules with enteric coatings or capsule shells. Used rectally are suppositories, and for parenteral administration are solutions, preferably oily or aqueous solutions as well a~ 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 mixture (for example chlorofluorohydrocarbons). The active substance is preferably used for this in - 27 - 206206~
micronized form, with one or more additional physiologi-cally tolerated solvents po~sibly being present, for example ethanol. Solutions for inhalation can be administered with the aid of customary inhalers. The new compounds can also be freeze-dried and the resulting lyophilisates 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, 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, as a rule, administered in analogy to other known, commer-cially available peptides, but especially in analogy to the compounds described in EP-A 249,096, preferably in dosages between about 10 mg and 1 g, in particular between 50 and 500 mg, per dosage unit. The daily dosage is preferably between about 0.2 and 20 mg/kg, in par-ticular between 1 and 10 mg/kg, of body weight. The specific dose for each particular pa~ient 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 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 i8 preferred.
Renin-dependent hypertension and hyperaldo-steronism can be effectively treated by administration of dosages between, in particular, about 1 and 300, prefer-ably between 5 and 50, mg/kg of body weight. For diagnos-tic purposes, it is possible and preferable for the new compounds to be administered in single doses, particu-larly in about 0.1 and 10 mg/kg of body weight.
All temperature~ stated hereinbefore and herein-after are in C. In the examples which follow, ~usual working up" means: if necessary, water is added, the pH

is ad~usted to between 2 and 8, depending on the con-stitution of the final product, extraction i8 carried out with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate, filtered and concentrated, and purification is carried out by chrom-atography on silica gel and/or crystallization.
Exam~le 1 a) A mixture of 380 mg (0.45 mmol) of N-t5S-(BOC-Phe-(imi-BOM-His)-amino)-6-cyclohexyl-2S,4S-dihydroxy-hexyl]-propanesulfonamide (m.p. 159-161) [obtainable by reaction of (4S,5S)-3-BOC-4-cyclo-hexylmethyl-2,2-dimethyl-5-oxazolidinyl-acetaldehyde with NaCN in the presence of glacial acetic acid in THF at 4 to give 2-~(4S,5S)-3-BOC-4-cyclohexyl-methyl-2,2-dimethyl-5-oxazolidinyl]-(lR,S)-1-hydroxy-propionitrile; reaction with tert. butyl-dimethylchlorosilane in the presence of imidazole at room temperature to give 2-[~4S,5S)-3-BOC-4-cyclo-hexylmethyl-2,2-dimethyl-5-oxazolidinyl]-(lR,S)-l-(trimethylsilyloxy)-propionitrile; hydrogenation in methanol on Raney Ni at room temperature to give 3-~(4S,5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl-5-oxazolidinyl~-(2R,S)-2-(trimethylsilyloxy)-propyl-amine; reaction with l-propanesulfonyl chloride in THF in the presence of triethylamine at 10 to give N-[3-{(4S,5S)-3-BOC-4-cyclohexylmethyl-2,2-di~thyl-5-oxazolidinyl}-(2R,S)-2-trimethylsilyloxy-propyl]-propanesulfonamide, separation of the diastereomers by chromatography; elimination of the trimethylsilyl group from the 2S epimer by reaction with tetra-butylammonium fluoride in ether, cleavage with HCl-saturated ethyl acetate to give N-(5S-amino-6-cyclo-hexyl-2S,4S-dihydroxy-l-hexyl)-propanesulfonamide (m.p. 102-104-); condensation with BOC-(imi-BOM-His)-QH in the presence of HOBt, NMM and DAPECI in DNF to give N-t5S-BOC-(imi-His)amino-6-cyclohexyl-2S,4S-dihydroxy-l-hexyl)-propanesulfonamide (m.p.
131-133); elimination of the BOC group with HCl/ethyl acetate and condensation with BOC-Phe-OH

20~2n6~
- 29 ~
in the presence of HOBt, NMM and DAPECI hydro-chloride in DMF], 590 mg (9.3 mmol) of ammonium formate and 480 mg of Pd-carbon in 38 ml of methanol is stirred at room temperature for 20 hours. The mixture is filtered, the solution is concentrated, 27 ml of a 5~ NaHCO3 solution are added~ and the mixture is stirred and filtered with suction.
Purifica~ion of the crystals results in N-[5S-(BOC-Phe-His-amino)-6-cyclohexyl-2S,4S-dihydroxyhexyl]-propanesulfonamide, m.p. 125-127.
b) This and the followin~ compounds can likewi~e be obtained from the corresponding Lmi-DNP-His deriva-tive~ by elimination of the DNP group in the fol-lowing way: a mixture of the corresponding DNP
deriva~ive with 2-mercaptoethanol in DMF and water is adjusted to pH 8 with aqueous Na2CO3 solution while ~tirring at 20 and is stirred for 2 hours.
The usual working up results in the required final product.
The following are obtained analogously from the corresponding imi-BOM or imi-DNP derivatives:
N-[5S-(BOC Phe-His~amino)-2R,4S-dihydroxy-6-cyclo-hexylhexyl]-propanesulfonamide/ m.p0 165-168 N-[2S,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl~-propanesulfon~mide N-[2S,4S-dihydroxy-5S-~4-BOC-amino~piperidinocarbonyl-Pho-His-amirlo)-6-cyclohexylhexyl]-3-methylbutanoamide, m.p. 120 130~ (decomposition) N-~2R,4S-dihydroxy-5S-(4-BOC-amino~piperidinocarbonyl-3~ Phe-His-amino)-6-cyclohexylhexyl]-3-methylbutanoamide, m.p. 120-130 (decomposition) N-[2S,4S-dihydroxy-5S-(4-BOC-amino piperidinocarbonyl-Phe-Hi~-amino)-6-cyclohexylhexyl]-N'-isopropylurea, m.p.

N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Phe-Hi~-amino)-6-cyclohexylhexyl]-3-methylbutanoamide, m.p. 137-140 N-[2S,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Phe-Hi~-amino)-6-cyclohexylhexylJ-N~-ethylurea/m.p.129 (decomposition) N-~2R,4S-dihydroxy-SS-(4-BOC-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-N~-ethylurea,m.p.143 (decomposition) N-t2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butyl-sulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-methane~ulfon-amide N-t2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butyl-sulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-amide N-t2S,4S-dihydroxy-SS-(2-benzyl-3-tert.-butyl-sulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-butanesulfonamide N-t2S,4S-dihydroxy-SS-(2-benzyl-heptanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-SS-(2-benzyl-4-oxo-5,5-dimethyl-hexanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-t2S,4S-dihydroxy-SS-(2-benzyl-3-tert.-butyl-sulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-amide N-t2S,4S-dihydroxy-5S-(2-benzyl-3-morpholinocarbonyl-propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-amide N-[2S,4S-dihydroxy-SS-(2-~1-naphthylmethyl)-3-morpholino-carbonyl-propionyl-His-amino)-6-cyclohexylhexyl]-propane-sulfonamide N-[2S,4S-dihydroxy-5S-(N-benzyl-N-isopentyl-carbamoyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-SS-(2-(1-naphthylmethyl)-3-(N-(3-dimethylaminopropyl)-carbamoyl-propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-SS-(2-benzyl-3-(4-BOC-aminopiperidino-carbonyl)-propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-SS-(2-(1-naphthylmethyl)-3-(4-BOC-amino-piperidinocarbonyl)-propionyl-His-amino)-6-cyclo-hexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(CBZ-Phe-His-amino)-6-cyclo-hexylhexyl]-propanesulfonamide ~2~

N-[2S,4S-dihydroxy-5S-(3,3-dimethylbutyryl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(2-BOC-amino-2-methyl-propionyl-Phe-His~amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(6-BOC-amino-hexanoyl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(6-methoxycarbonyl-hexanoyl-Phe-His-amino)-6 cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(N-(3-dimethylaminopropyl)-carbamoyl-Phe-His-amino)-6 cyclohexylhexyl]-propane-sulfonamide N-[2S,4S-dihydroxy-5S-(N-(5-dimethylaminopentyl)-carbamoyl-Phe-His-amino)-6-cyclohexylhexyl]- propane-sulfonamide N-[2S,4S-dihydroxy-5S-(BOC-Mal-His-amino)-6-cyclo-hexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(CBZ-Mal-His-amino)-6-cyclo-hexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(3,3-dimethylbutyryl-Mal-His-amino) 6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(2-BOC-amino-2-methyl-propionyl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(6 BOC-amino-hexanoyl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(6-methoxycarbonyl-he~anoyl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(N-(3-dimethylaminopropyl)-carbamoyl-Mal-Hi3-amino)-6-cyclohexylhexyl]-propane-sulfonamide N-[2S,4S-dihydroxy-5S-(N-(5-dimethylaminopentyl)-carbamoyl-Mal-Hi~-amino)-6-cyclohexylhexyl]-propane-sulfonamide N-[2S,4S-dihydroxy-5S-~4-BOC-aminopiperidinocarbonyl-Nal-His-amino)-6-cyclohexylhexyl]-methanesulfonamide N-~2S,45-dihydroxy-5S-(BOC Phe-His-amino)-6-cyclo-2062~6~

hexylhexyl]-2-methylpropanesulfonamide N-~2S,4S-dihydroxy-5S-tBOC-Cal-His-amino)-6-cyclo-hexylhexyl]-2-methylpropanesulfonamide N-[2S,4S-dihydroxy-5S-(BOC-~Nal-His-amino)-6-cyclo-hexylhexyl]-2-methylpropanesulfonamide N-[2S,4S-dihydroxy-5S-~BOC-2-~ia-His-amino)-6-cyclo-hexylhexyl]-2-methylpropanesulfonamide N-t2S,4S-dihydroxy-SS-(BOC-Trp-His-amino)-6-cyclo-hexylhexyl]-2-methylpropanesulfonamide N-[2S,4S-dihydroxy-SS-(BOC-Pro-Phe-His-amino)-6-cyclo-hexylhexyl]-2-methylpropanesulfonamide N-t2S,4S-dihydroxy-SS-(3,3-dimethylbutyryl-Pro-Phe-N-Me-His-amino)-6-cyclohexylhexyl]-2-methylpropanesulfonamide N-t2S,4S-dihydroxy-SS-(4-CBZ-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfonamide.

N-t2S,4S-dihydroxy-5S-(2-benzyl-2-tert.-butylsulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-methanesulfon-amide N-t2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butylsulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-butanesulfonamide N-t2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butylsulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-2-methylpropane-sulfonamide N-t2S,4S-dihydroxy-SS-(2-benzyl-3-tert.-butylsulfonyl-propionyl-Hi~-amino)-6-cyclohexylhexyl]-phenylmethane-sulfonamide N-t2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butylsulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-cyclohexyl-methanesulfonamide N-t2S,4S-dihydroxy-SS-(2-benzyl-3-tert.-butylsulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-N'-propylurea N-t2S,4S-dihydroxy-SS-(2-benzyl-3-tert.-butylsulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-N'-butylurea N-t2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butylsulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-N~-propylthiourea N-[2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butylsulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-N~-(p-amin phenyl)-urea N-[2S,4S-dihydroxy-5s-(2-benzyl-3-tert.-butylsulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-4-methyl-pentano-amide ExamPle ?
0.01 mol of N-methylmorpholine is added to a solution of 0.01 mol of N-[2S,4S-dihydroxy-5S-(H-~Ala--amino)-6-cyclohexylhexyl]-propanesulfonamide [obtainable by condensation of BOC-~Ala-OH with N-(2S,4S-dihydroxy-SS-amino-6-cyclohexylhexyl)-propanesulfonamide to give N-[2S,4S-dihydroxy-SS-(BOC-~Ala-amino)-6-cyclohexyl-hexyl]-propanesulfonamide and elimination of the BOC
group with 4 N HCl in dioxane] in 60 ml of dichloro-methane. While stirring, 0.01 mol of 4-dimethylamino-piperidinocarbonyl-Phe-OH, 1.35 g of HOBt and a solution of 2.06 g of DCCI in 50 ml of dichloromethane is added, the mixture is stirred at 2-6 for 14 h, the precipitated dicyclohexylurea is filtered off, and the filtrate is evaporated. The usual working up results in N-~2S,4S-dihydroxy-SS-(4-dimethylamino-piperidino-carbonyl-Phe-~Ala-amino)-6-cyclohexylhexyl]-propane-sulfonamide.
N-t2S,4S-dihydroxy-5S-(4-BOC-amino-piperidino-carbonyl-Phe-~Ala-amino)-6-cyclohexylhexyl]-propane-sulfonamide i8 analogou~ly obtained as a colorless foam with 4-BOC-amino-piperidinocarbonyl-Phe-OH.
The following are obtained analogously:
N-[2S,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Phe-~Ala-amino)-6-cyclohexylhexyl~-2-propanesulfonamide, colourless foam N-t2S,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Phe-2-Tia-amino)-6-cyclohexylhexyl]-propanesulfonamide N-t2S,4S-dihydroxy-5S-(N-(5-dimethylaminopentyl)-carbamoyl-Phe-~Ala-amino)-6-cyclohexylhexyl]-propane-sulfonamide N-[2S,4S-dihydroxy-5S-(N-(5-dimethylaminopentyl)-car-bamoyl-Phe-2-Tia-amino)-6-cyclohexylhexyl]-propane-~ulfonamide _ 34 _ 20620fi~

Example 3 In analogy to Example 2, N-(2S,4S-dihydroxy-5S-(BOC-Phe-Gly-amino)-6-cyclohexylhexyl)-propane-sulfonamide is obtained from BOC-Phe-Gly-OH and N-(2S,4S-dihydroxy-SS-amino-6-cyclohexylhexyl)-propane-sulfonamide.
The following are obtained analogously N-(2S,4S-dihydroxy-SS-(BOC-Phe-Abu-amino)-6-cyclo-hexylhexyl)-propanesulfonamide N-(2S,4S-dihydroxy-5S-(BOC-Phe-Ala-amino)-6-cyclo-hexylhexyl)-propanesulfonamide N-(2S,4S-dihydroxy-SS-(BOC-Phe-~Ala-amino)-6-cyclo-hexylhexyl)-propanesulfonamide N-(2S,4S-dihydroxy-5S-(BOC-Phe-Asn-amino)-6-cyclo-hexylhexyl)-propanesulfonamide N-(2S,4S-dihydroxy-5S-(BOC-Phe-Gln-amino)-6-cyclo-hexylhexyl)-propanesulfonamide N-(2S,4S-dihydroxy-SS-(BOC-Phe-Nle-amino)-6-cyclo-hexylhexyl)-propanesulfonamide N-2R,4S-dihydroxy-SS-(BOC-Phe-Ser-amino)-6-cyclo-hexylhexyl)-propanesulfonamide N-2R,4S-dihydroxy-5S-(BOC-Phe)-6-cyclohexylhexyl)-propanesulfonamide N-(2S,4S-dihydroxy-SS-(BOC-Phe-3-Pya-amino)-6-cyclo-hexylhexyl)-propanesulfonamide N-(2S,4S-dihydroxy-SS-(BOC-Phe-2-Tia-amino)-6-cyclo-hexylhexyl)-propanesulfonamide Example 4 ~n analogy to Example 2, N-[2S,4S-dihydroxy-5S-(4-BOC-aminopiperidinocarbonyl-Phe-Gly-amino)-7-methyl-octyl]-ethanesulfonamide is obtained from 4-BOC-aminopiperidinocarbonyl-Phe-OH and N-[2S,4S-dihydroxy-5S-(H-Gly-amino)-7-methyl-octyl]-ethanesulfonamide.

ExamE~le S
A solution of 1 g of N-[2S,4S-dihydroxy-5S-(4-BOC-aminopiperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfonamide in 20 ml of 4 N HCl 2 ~

in dioxane is stirred at 20 for 30 min and then evapora-ted. N-[2S,4S-dihydroxy-5S-(4-amino-piperidinOCarbonyl-Phe-His-amino)-6-cyclohexylhexyl~-propanesulfonamide, dihydrochloride is obtained.
The following are obtained analogously by cleavage of the corresponding BOC derivatives:
N-[2S,4S-dihydroxy-55-(2-benzyl-3-(4-aminopiperidino-carbonyl)-propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(2-(1-naphthylmethyl)-3-(4-amino-piperidinocarbonyl)-propionyl-His-amino)~6-cyclo-hexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-~Ala-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-2-Tia-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-~2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Mal-His-amino)-6-ryclohexylhexyl]-propanesulfonamide N-t2S,4S-dihydroxy-5S-(2-amino-2-methyl-propionyl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-~2S,4S-dihydroxy-5S-(2-amino-2-methyl-[propionyl-Mal-His-amino)-6-cyclohexylhexyl~-propanesulfonamide N-[2S,4S-dihydroxy-5S-(6-aminohexanoyl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-t2S,4S-dihydroxy-5S-(6-aminohexanoyl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe ~Ala-amino)-6 cyclohexylhexyl]-2-propanesulfonamide N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-3-methylbutanoamide N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-N'-isopropylurea N-t2S,4S-dihydroxy-5S-~4-aminopiperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-me~hanesulfonamide N- r 2S,4S-dihydroxy-5S-(4-c~inopiperidinocarbonyl-Mal-His-amino)-6-cyclohexylhe~yl]-methanesulfonamide.

2~2~

Example 6 Hydrogenolysis (on 10% Pd-C in ethanol at 20) of N-~2S,4S-dihydroxy-5S-(4-CBZ-~ninopiperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfonamide results in N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfonamide.

Example 7 The following are obtained in analogy to Example 1 from the corresponding imi-BOM-His derivatives:
N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Phe-His-amino)-6-cyclohexylhexyl~-propanesulfonamide N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-5S-(3~BOC-amino-3-methylbutyryl-Phe-N-Me-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Phe-His-amino)-6-cyclohexylhexyl]-1-methylethanesulfonamide N-~2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Mal-His-amino)-6-cyclohexylhexyl~-1-methylethanesulfonamide N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Phe-N-Me-His-amino)-6-cyclohexylhexyl]-1-methylethanesulfon-amide N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Phe-His-amino)-6-cyclohexylhexyl]-cyclohexanesulfonamide N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Phe~
Hi~-amino)-6-cyclohexylhexyl]-N'-ethyl-urea N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Phe-N-Me-His-amino)-6-cyclohexylhexyl]-N'isopropyl-urea N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-1-methylethanesulfon-amide N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Mal-His- mino)-6-cyclohexylhexyl]-1-methylethanesulfon-amide N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-cyclohexane-sulfonamide N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl~-cyclohexane-sulfonamide - 37 - 2062~
N-t2R~4s-dihydroxy-ss-(4-Boc-amino-piperidinocarbon Phe-His-amino)-6-cyclohexylhexyl]-N'-ethyl-urea N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl]-N~-ethyl-urea N-[2R,4S-dihydroxy-SS-(4-BOC-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-N'-isopropyl-urea N-[2R,4S-dihydroxy-SS-(4-BOC-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl]-N'-isopropyl-urea N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-N'-phenyl-urea N-t2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl]-N'-phenyl-urea N-t2R,4S-dihydroxy-SS-(4-BOC-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-3-methylbutyramide N-[2R,4S-dihydroxy-SS-(4-BOC-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl]-3-methylbutyramide N-t2R,4S-dihydroxy-5S-(2R-benzyl-4-(4-BOC-amino-piperi-dinocarbonyl)-propionyl-His-amino)-6-cyclohexylhexyl]-propane~ulfonamide N-t2R,4S-dihydroxy-SS-(2S-benzyl-4-(4-BOC-amino-piperi-dinocarbonyl)-propionyl-His-amino)-6-cyclohexylhexyl~-propanesulfonamide N-t2R,4S-dihydroxy-5S-(2R-(l-naphthylmethyl)-3-(4-BOC-amino-piperidinocarbonyl)-propionyl-Hi~-amino)-6-cyclo-hexylhexyl]-propanesulfonamide N-t2R,4S-dihydroxy-5S-(2S-(l-naphthylmethyl)-3-(4-BOC-amino-piperidinocarbonyl)-propionyl-His-amino)-6-cyclo-hexylhexyl]-propanesulfonamide N-t2R,4S-dihydroxy-SS-(2R-benzyl-5-N-BOC-N-methyl-amino-pentanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-amide N-t2R,4S-dihydroxy-5S-(2S-benzyl-5-N-BOC-N-methyl-amino-pentanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-amide N-t2R,4S-dihydroxy-SS-(2R-benzyl-5-N-BOC-N-methyl-amino-pentanoyl-His-amino)-6-cyclohexylhexyl~-1-methylethane-sulfonamide N-t2R,4S-dihydroxy-SS-(2S-benzyl-5-N-BOC-N-methyl-amino-pentanoyl-His-amino ) -6-cyclohexylhexyl ] -l-methylethane-sul f onamide N- [ 2R, 4S-dihydroxy-5S- ( 2R-benzyl-5-N-BOC-N-methyl-amino-pentanoyl-His-amino ) -6 -cyclohexylhexyl ] -N ~ -ethyl-urea N- [ 2R, 4S-dihydroxy-5S- ( 2S-benzyl-5-N-BOC-N-methyl-amino-pentanoyl-His-amino ) -6-cyclohexylhexyl ~ -N ~ -ethyl-urea N- [ 2R, 4S-dihydroxy-5S- ( 2R-benzyl-3-tert . -butylsulfonyl-propionyl-His-amino ) -6-cyclohexylhexyl ] -l-methylethane-sul f onamide N- [ 2R, 4S-dihydroxy-5S- ( 2S-benzyl-3-tert . -butylsulfonyl-propionyl-His-amino) -6-cyclohexylhexyl ] -1-methyl-ethane-sulfonamide N- [ 2R, 4S-dihydroxy-5S- ( 2R-benzyl-3-tert . -butylsulfonyl-propionyl-His-amino ) -6-cyclohexylhexyl ] -cyclohexane-sulfonamide N- t 2R, 4S-dihydroxy-SS- ( 2S-benzyl-3-tert . -butylsulfonyl-propionyl-His-amino ) -6-cyclohexylhexyl ] -cyclohexane-sulfonamide N- t 2R, 4S-dihydroxy-5S- ( 2R-benzyl-3-tert . -butylsulfonyl-propionyl-His-amino) -6-cyclohexylhexyl ] -N~ -ethyl-urea N- ~ 2R, 4S-dihydroxy-5S- ( 2S-benzyl-3-tert . -butylsulfonyl-propionyl-His -amino ) - 6 -cyc lohexylhexyl ] -N ~ -ethyl -urea N- [ 2R, 4S-dihydroxy-5S- ( 2R-benzyl-3-tert . -butylsulfonyl-propionyl-His-amino) -6-cyclohexylhexyl ] -N ' -isopropyl-urea N- t 2R, 4S-dihydroxy-5S- ( 2S-benzyl-3-tert . -butylsulfonyl-propionyl-His-amino) -6-cyclohexylhexyl ] -N~ -isopropyl-urea N- t 2R, 4S-dihydroxy-5S- t 2R-benzyl-heptanoyl-His-amino ) -6-cyclohexylhexyl ] -propanesulfonamide N- t 2R, 4S-dihydroxy-5S- ( 2S-benzyl-heptanoyl-His -amino ) -6-cyclohexylhexyl ] -propanesulfonamide N- t 2R, 4S-dihydroxy-5S- ( 2R- ( l-naphthylmethyl ) -3 -morpholinocarbonyl-propionyl-His-amino ) -6 -cyclohexylhexyl ] -propanesulfonamide N- t 2R, 4S-dihydroxy-5S- ( 2S- ( l-naphthylmethyl ~ -3 -morpholinocarbonyl-propionyl-His-amino ) -6 -cyc lohexylhexyl ] -propanesul f onamide N- 1 2R, 4S-dihydroxy-5S- ( 2R-benzyl-3-tert . -butylthio-propionyl -Hi~ -amino ) - 6 -cyclohexylhexyl ] -propanesul f on-amide N-[2R,4S-dihydroxy-5S-(2S-benzyl-3-tert.-butylthiopro-pionyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-sS-(2R-benzyl-3-tert.-butylsulfinyl-propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-amide N-[2R,4S-dihydroxy-SS-(2S-benzyl-3-tert.-butylsulfinyl-propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-amide N-[2R,4S-dihydroxy-5S-(2R-benzyl-4-oxo-5,5-dimethyl-hexanoyl-~is-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-5S-(2S-benzyl-4-oxo-5,5-dimethyl-hexanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-5S-(2R-benzyl-4-hydroxy-5,5-dimethyl-hexanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-5S-(2S-benzyl-4-hydroxy-5,5-dimethyl-hexanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-5S-(4-dimethylamino-piperidino-carbonyl-Phe-His-amino)-6-cyclohexylhexyl]-propane-sulfonamide N-[2R,4S-dihydroxy-5S-(4-dimethylamino-piperidino-carbonyl-Mal-His-amino)-6-cyclohexylhexyl]-propane-sulfonamide N-[2R,4S-dihydroxy-5S-(N-(5-dimethylaminopentyl)-car-bonyl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfon-amide N-[2R,4S-dihydroxy-5S-(N-~5-dimethylaminopentyl)-car-bonyl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfon-amide.

Example 8 The following are obtained in analogy to Example 5 from the corresponding BOC derivatives:
N-[2R,4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl~-propanesulfonamide, hydro-chloride N-[2R,4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-5S-(3-amino-3-methylbutyryl-Phe-His-~6206~

amino)-6-cyclohexylhexyl]-propanesulfonamide N-t2R,4S-dihydroxy-5S-(3-amino-3-methylbutyryl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-N-Me-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-His-amino)-6-cyclohexylhexyl]-1-methyl-ethanesulfonamide N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Mal-His-amino)-6-cyclohexylhexyl]-1-methyl-ethanesulfonamide N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-N-Me-His-amino)-6-cyclohexylhexyl]-1-methyl-ethanesulfonamide N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-His-amino)-6-cyclohexylhexyl]-cyclohexanesulfonamide N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-Mal-amino)-6-cyclohexylhexyl]-cyclohexanesulfonamide N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-His-amino)-6-cyclohexylhexyl]-N'-ethyl-urea N-~2R,4S-dihydroxy-5S-(3-amino-3-methylbutyryl-Phe-Mal-amino)-6-cyclohexylhexyl]-N'-ethyl-urea N-[2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-N-Me~
His-amino)-6-cyclohexylhexyl]-N~-isopropylurea N-t2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl3-1-methylethanesulfonamide N- E 2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl]-1-methylethanesulfonamide N-~2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-cyclohexanesulfonamide N-t2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl]-cyclohexanesulfonamide N-~2R,4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-N'-ethyl-urea N-t2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl]-N'-ethyl-urea N-[2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-N~-isopropyl-urea N-t2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl]-N'-isopropyl-urea N-12R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-N'-phenyl-urea 206~6~

N-[2R,4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl]-N'-phenyl-urea N-[2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-3-methylbutyramide N-[2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl]-3-methylbutyramide N-[2R,4S-dihydroxy-5S-(2R-benzyl-3-(4-amino-[piperidino-carbonyl)-propionyl-.His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-SS-(4-aminopiperidinocarbonyl-Phe-~Ala-amino)-6-cyclohexylhexyl]-2-propanesulfonamide N-[2R,4S-dihydroxy-SS-(2S-benzyl-3-(4-aminG-piperidino-carbonyl)-propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-SS-(2R-(l-naphthylmethyl)-3-(4-amino-piperidinocarbonyl)-propionyl-His-amino)-6-cyclo-hexylhexyl]-propanesulfonamide N-t2R,4S-dihydroxy-SS-(2S-(l-naphthylmethyl)-3-(4-amino-piperidinocarbonyl)-propionyl-His-amino)-6-cyclo-hexylhexyl]-propanesulfonamide N-t2R,4S-dihydroxy-5S-(2R-benzyl-5-N-methyl-amino-pentanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-amide N-t2R,4S-dihydroxy-5S-(2S-benzyl-5-N-methyl-amino-pentanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-amide N-~2R,4S-dihydroxy-SS-(2R-benzyl-5-N-methyl-amino-pentanoyl-His-amino)-6-cyclohexylhexyl]-1-methylethane-sulfonamide N-t2R,4S-dihydroxy-SS-(2S-benzyl-5-N-methyl-amino-pentanoyl-His-amino)-6-cyclohexylhexyl]-l-methylethane sulfonamide N-t2R,4S-dihydroxy-SS-(2R-benzyl-5-N-methyl-amino-pentanoyl-His-amino)-6-cyclohexylhexyl]-N~-ethyl-urea N-[2R,4S-dihydroxy-SS-(2S-benzyl-5-N-methyl-amino-pentanoyl-His-amino)-6-cyclohexylhexyl]-N~-ethyl-urea.

Example 9 A mixture of 730 mg of N-t2R,4S-dihydroxy-5S-2~3~2~

(4-aminopiperidino-carbonyl-Phe-His-amino)-6-cyclohexyl-hexyl]-propanesulfonamide, 90 mg of S-methylisothiourea, 5 ml of ethanol and 5 ml of watex is stirred at 50 for 2 h. The usual working up results in N-~2R,4S-dihydroxy-5S-(4-guanidino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfonamide.
N-[2R,4S-dihydroxy-5S-~4-guanidino-piperidino-carbonyl-Mal-His-amino~-6-cyclohe~ylhexyl]-propane-sulfonamide is obtained analogously.

Example 10 A mixture of 730 mg of N-[2R,4S-dihydroxy-5S-(4-aminopiperidino-carbonyl-Phe-His-amino)-6-cyclo-hexylhexyl]-propanesulfonamide, 115 mg of trLme~hylsilyl isocyanate and 10 ml of THF is tirred at 20 for 16 h.
It is then stirred into water, and worked up in the usual way to result in N-[2R,4S-dihydroxy-5S-(4 ureido-piperi-dinocarbonyl-Phe-His amino)-6-cyclohexylhexyl]-propane-sulfonamide.
N-[2R,4S-dihydroxy-5S-(4-ureido-piperidino-carbonyl-Mal-His-amino)-6-cyclohexylhexyl]-propane-sulfonamide is obtained analogously, and, using ethyl isocyanate:
N-[2R,4S-dihydroxy-5S-~4-N'-ethylureido-piperidi.no-carbonyl-Phe-His amino)-6-cyclohexylhe~yl]-propane-sulfonamide N-[2R,4S-dihydroxy-5S-(4-N'-ethylureido-piperidino-carbonyl-Mal-His-amino)-6-cyclohexylhexyl]-propane-sulfonamide.

xample 11 a) 0.48 g (0~53 mmol) of2,2-dimethyl-4S-[2-cyclohexyl~
lS-(BOC-Phe-His(DNP)-amino)-ethyl]-6R-~3-isopropyl-ureido)-methyl-1,3-dioxane [obtainable by reaction of 3-[(45,5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl 5-oxazolidinyl]-(2R,S)-2-trimethylsilyloxy)-propyl-amine (see Ex~mple 1) wi~h isopropyl isocyanate in THF in the presence of triethylamine at 0 to give N-[3-{(4S,5S~ 3-BOC-4-cyclohexyLmethyl-2,2 dimethyl-43 20~206~

5-oxazolidinyl~-(2R,S)-trimethylsilyloxypropyl]-N'-isopropylurea, separation of the diastereomers by chromatography; elimination of the trimethylsilyl groups from the 2R epimer by reaction with tetra-butylammonium fluoride at 0, this product i8 stirred in ethyl acetate with HCl-saturated ethyl acetate at 0 for 48 hours, water is added and extraction is carried out with 3296 NaOH, the organic phase is worked up and, after purification by chromatography on silica gel, 2,2-dimethyl-4S-[2-cyclohexyl-lS-aminoethyl]-6R-(3-isopropyl-ureido)-methyl-1,3-dioxane is obtained; condensation with BOC-Phe-His(DNP)-OH in DMF in the presence of HOBt, NMM and DAPECI] in 5 ml of DMF is mixed with 0.2 ml of 5% NaHCO3 solution, and then 0.14 ml (2 mmol) of 2-mercaptoethanol is added. After 12 hours, 50 ml of H20 are added, and the precipitate which forms is taken up in CH2C12. The crystalline residue is purified on silica gel to result in 2,2-dimethyl-4S-t2-cyc lohexyl-lS-(BOC-Phe-His-amino) -ethyl] -6 R- ( 3 - isopropylureido)methyl-1,3-dioxane, m.p. 134-140 (decomposition).

The following is obtained analogously:
4S-[2-cyclohexyl-lS-{(4-BOC-amino-piperidino-carbonyl ) -Phe-His-amino~-ethyl ]-2-methyl-6R-(3-methylbutyryl-aminomethyl)-1,3-dioxane.
b) The following are obtained by elimination of the BOC
group in a known manner 2,2-dimethyl-4S-t2-cyclohexyl-lS-(Phe-His-amino)-ethyl]-6R-(3-isopropylureido)-methyl-1,3-dioxane and 4S-t2-cyclohexyl-lS-{(4-aminopiperidinocarbonyl)-Phe-His-amino}-ethyl]-2-methyl-6R-(3-methylbutyryl-aminomethyl)-1,3-dioxane.
The examples which follow relate to pharmaceu-tical compositions.
Example As Tablets A mixture of 1 kg of N-~2R,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-His-amino)-6-cyclo-20~206S
hexylhexyl]-3-methyl-butyramide~ 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 give tablets in such a way that each tablet contains 100 mg of active compound.
Example B: Coated tablets Tablets are compressed in analogy to Example A
and are then coated in a customary manner with a coating composed of sucrose, maize starch, talc, tragacanth and colorant.
Example C: Capsules 500 g of N-t2S-,4S-dihydroxy-SS-(4-a~inopiperi-dinocarbonyl-Phe-~Ala-amino)-6-cyclohexylhexyl]-propane-sulfonamide hydrochloride are dispensed in a customary manner into hard gelatine capsules so that each capsule contains 500 mg of active compound.
Example D: Injection ampoules A solution of 100 g of N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-His-amino)-6-cyclo-hexylhexyl]-propanesulfonamide dihydrochloride in 4 1 of double distilled water i~ ad~usted to pH 6.5 with 2 N
hydrochloric acid, filtered sterile and dispensed into in~ection ampoules. These are lyophilized under sterile conditions and sealed sterile. Each in~ection ampoule contains 50 mg of active compound.
Example E: Suppositorie~
A mixture of 50 g of N-t2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butylsulfonylpropionyl-His-amino)-6-cyclohexylhexyl]-methanesulfonamide hydrochloride with 10 g of soya lecithin and 140 g of cocoa butter is melted, poured into moulds and left to cool. Each sup-pository contains 250 mg of active compound.

Claims

1. Peptide analogues of the formula I

in which R1 is H, R7-O-CmH2m-CO-, R7-CmH2m-O-CO-, R7-CmH2m-CO-, R7-SO2-, R8R9N-CmH2m-C
R10-NH-C(=NH)-NH-CmH2m-CO-, R8OOC-CmH2m-Co-, R8O3S-CmH2m,-CO- or R11-CmH2m- (T)5, - (V)y-CnH2n,-L(R7-CpH2p) -CrH2r-CO-, Z is 0 to 4 amino acid residues which are linked together in the manner of a peptide and are selected from the group comprising is CN, -NO2, -CH2-NR12R13, -CH2-NR12-SO2R14 -CH2-NR12-COR14, -CH2-NR12-CO-NH-R14 -CH2-NR12-CS-NH-R14 or -COR16, R2, R8, R9 and R13 are each H A
R4 is (H, R17) or =O, R5 i OH, OR7, OCOR7, OSiR16R18R20, NR8R9 or -O-(2-tetrahydropyranyl), R6 is H, A, Ar or aralkyl, R5 and R6 together are also (=O), R16 is H, OH, OR7, NR3R9, OSiR18R19R20 or -O-(2 tetrahydropyranyl), R17 is OH or NH2, R5 and R17 together are also -T1-(CR3R7)-T2-, R3, R7, R11, R12 and R14 are esch H, A, Ar, Ar-alkyl, Het or Het-alkyl, unsubstituted or singly or multiply, by A, AO and/or Hal, substituted cycloalkyl having 3-7 C atoms, cycloalkylalkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, or bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C
atoms, R11 is also R8O-, R8R8N-, R8OOC- or A3Ne Ane, R18, R19 and R20 are each A, Ar or aralkyl, R10 is H, A or CN, L is CH or N, T,T1 and T2 are each 0 or NR6, V is CHOR2, CO, S, SO or SO2, R8R9N and NR12R13 are also each a pyrrolidino, piperidino, morpholino or piperazino group which is unsubstituted or is substituted by A, OH, NH2, NHA, NA2, NHAc, NH-CO-CxH2x-O-R15, NH-CO-O-CxH2x-O-R15, hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl, HAN-alkyl, A2N-alkyl, A3Ne alkyl Ane, NH-CO-NH2, NH-CO-NHA, guanidinyl or guanidinylalkyl, R15 is A or Ar-alkyl, s and y are each 0 or 1, m, n, p, r and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, Ar is phenyl which is unsubstituted or is substituted one or more times by A, OA, Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA, NA2, NHAc, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N+ alkyl Ane and/or guanidinyl-alkyl, or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical which has 1-4 N, O and/or S atoms and can be fused with a benzene ring and/or be substituted one or more times by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NA2, NHAc, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, NH-SO2-A, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl and/or A2N-alkyl, and/or whose N
and/or S hetero atoms can also be oxid-ized, Hal is F, Cl, Br or I, Ac is A-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH-CO-, Ane is an anion, which can also be absent if, in its place, 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, in which, furthermore, it is also possible for one or more -NH-CO- groups to be replaced by one or more -NA-CO-groups, with the provisos that a) in the case R1 -CrH2r-CO- with V = S, SO or SO2, and Y = -CH2NR12R13 with R12 = R13 = H, R5 then is OCOR7, OSiR18R19R20, NR8R9 or -0-(2-tetrahydropyranyl), b) in the case R1 = R11-CmH2m-(T)5-V-CnH2n-L(R7-CHpH2p)-CrH2r-CO- with V - S, SO or SO2, and Y = COR16, R16 then is H, OH, OR7, OSiR18R19R20 or -0-(2-tetrahydro-pyranyl), as well as the salts thereof.

2. Process for the preparation of a peptide analogue 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 hydrogeno-lyzing agent, or in that a carboxylic acid of the formula II

in which G1 is (a) absent, (b) Z, (C) Z1, or one of the reactive derivatives thereof, is reacted with an amino compound of the formula III

in which G2 is (a) Z, (b) absent, (C) Z2 and z1 + z2 are together Z, 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 hydrogeno-lyzing agents, and/or a free amino group is acylated by treatment with an acylating agent and/or for the preparation of a compound of the formula I, R4 = (H, OH) or (H, NH2), an amino keto acid derivative of the formula I, R4 = O, is reduced or reductively aminated, and/or a radical R1 is converted into a compound of the formula I
is converted by another radical R1 and/or treatment with an acid into one of the salts thereof

3. Process for the preparation of pharmaceutical compositions, characterized in that a compound of the formula I 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.

4. Pharmaceutical composition characterized by containing at least one compound of the formula I and/or one of the physiologically acceptable salts thereof.

5. Use of compounds of the formula I or of physio-logically acceptable salts thereof for the preparation of a medicament.

6. Use of compounds of the formula I or of the physiologically acceptable salts thereof for controlling renin-dependent hypertension or hyperaldosteronism.