CA2057534A1

CA2057534A1 - Acid amides

Info

Publication number: CA2057534A1
Application number: CA002057534A
Authority: CA
Inventors: Horst Juraszyk; Claus J. Schmitges; Klaus-Otto Minck; Peter Raddatz
Original assignee: Merck Patent GmbH
Current assignee: Individual
Priority date: 1990-12-14
Filing date: 1991-12-12
Publication date: 1992-06-15
Also published as: HU913942D0; JPH0733724A; IE914359A1; PT99810A; ZA919851B; AU8961491A; EP0490259A2; EP0490259A3; HUT62012A; TW205505B; CS377591A3; KR920012109A; DE4040056A1

Abstract

A b s t r a c t Acid amides of the formula I

R1R2N-CmH2m-CO-Z-Y-NH-CHR3-CHR4-(CH2)n-CR5R6-X I
in which R1 to R6, Z, Y, X, m and n have the meanings indicated in patent Claim 1, and their salts inhibit the activity of human plasma renin.

Description

Merck Patent Gesellschaft 2 0 ~ 7 ~ ~ ~
mit beschr~nkter Haftung 6100 D a r m s t a d t -Acid amides The invention relates to novel acid amides of the formula I
R'R2N-C~H~-CO-Z-Y-NH-CHR3-CHR~-(CH2)~-CRsR6-X

in which Z i8 -W-CR7R~-Co, W is CH2, O or NH
Y is Abu, Ala, ~Ala, Arg, Asn, Asp, Bia, Cal, Cy8, (S-A~-Cys/ Dab, Gln, Glu, Gly, His, N(im)-A-His, Hph, Ile, Leu, tert.-Leu, Lys, Mal, Met, Met(O2), ~Nal, ~Nal, Nbg, Nle, Nva, Orn, Phe, Pia, Pro, Pya, Ser, (O-A)-Ser, (O-Ar-alkyl)-Ser, Isoser, Thr, Tia, Tie, Tiz, Trp, Tyr or Val, it also being possible for one of groups Y and Z to be absent, X is OH, OA, OR10, OSO2A or OSO2Ar, Rl, R2, R3 and R~
are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, cyeloalkyl having 3-7 C atoms, whieh i8 unsub-stituted or eyeloslkyl whieh is monosubstituted or poly~ub~tituted by A, AO and/or Hal, cyelo-alkylalkyl having 4-11 C atoms, bieyeloalkyl or tricyeloalkyl ~aeh having 7-14 C atoms, or bieycloalkylalkyl or tricyeloalkylalkyl each having 8-18 C atom~, R1R2N also is an unsub~tituted pyrrolidino, piperid-ino, morpholino or piperazino group or one whieh i3 substituted by A, OH, NH2, NHA, NA2, NHR10 NH-CO-C~H2,C-O-R~, NH-CO-O-C,CH2,-R~, hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl~
HAN-alkyl, A2N-alkyl, P~N~alkyl Ane, NH-CO-NH2, - 2 - 20~7~
NH-CO-NHA, guanidinyl or guanidinylalkyl, - R4 i~ OH or NH2, R5 and R6 are each A, alkenyl or alkynyl each having up to 8 C atoms, or Ar-aIkyl, - -R7 is H or A, _cR5~6 also is l,1-cycloalkylidene having 2-6 C atoms, R9 is H, A, Ar or Ar-alkyl, R10 is A-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH-CO-, m and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, n i~ O or 1, Ar i8 unsubstituted phenyl or phenyl which is monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA, NA2, NHRl, NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, aminoalkyl, HAN-alkyl, AzN-alkyl, A3N -alkyl Ane and/or guanidinylalkyl or unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, O and/or S
atoms, which can be fused to a benzene ring and/or monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NAz, NHRl, NH-COOA, NHCOOAr, NHCOOCH2Ar, NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONHz, CN, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl, A2N-~lkyl and/or A3Nr-alkyl An~ and/or whose N and/or S
heteroatoms can al80 be oxidised, Hal is F, Cl, Br or I, Ane is an anion, which can also be absent, if instead of this a carboxyl group contained in the compound of the formula I is present 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 in addition instead of one or more -NH-CO-groups there can also be one or more -NA-CO- groups, and their salts.
Similar compounds are disclosed in EP-A-189,203, - 3 - 2~5 7 ~ 2 EP-A-307,837, EP-A-311,012 and WO 90/07521.
The invention wa~ ba~ed on the ob~ect of finding novel compound~ having u~eful properties, in particular those which can be used for the preparation of medica-ments.
It has been found that the compounds of theformula I and their salts have very useful properties. In particular, they inhibit the activity of human plasma renin. This action can be detected, for example, by the method of F. Fyhrquist et al., Clin. Chem. 22, 250-256 (1976). It is noteworthy that these compounds are very specific inhibitors of renin; as a rule about 100 to 1000 times as high concentrations of these compounds are necessary for the inhibition of other aspartylproteinases (for example pepsin and cathepsin D) as for renin inhi-bition. The actions of the compounds on the blood pres-sure and/or on the heart rate and the inhibition of the renin activity in the blood plasma can additionally be determined in conscious monkeys, for exa~ple female monkeys (Nacaca fascicularis); in this connection blood pressure and heart rate can be mea~ured following the method of N.J. Wood et al., J. Hypertension 4, 251-254 (1985). To stimulate renin activity, the animals are in this case expediently pretreated with a saluretic. Blood samples for determining the plasma renin activity can be obtained by puncture of the femoral vein.
The compounds can be employed as medicament active compounds in human and veterinary medicine, in particular for the prophylaxis and for the treatment of cardiac, circulatory and vascular diseases, in particular hypertension, cardiac insufficiency and hyperaldo-steronism. In addition, the compounds can be used for diagnostic purpose~ in patients with hypertension or hyperaldosteronism in order to determine the possible contribution of the renin activity to the maintenance of the pathological condition. Such diagnostic tests can be carried out in a similar manner to that given in ~P-A-77,028.
The abbreviations of amino acid radical~

_ 4 _ 20~7~3~
mentioned above and below are for the radicals -NR'-R~-C0-, as a rule -NH-CHR-C0- (in which R, R' and R~' have the specific meaning known for each amino acid), of the following amino acids~
Abu 2-aminobutyric acid Ala alanine ~Ala ~-alanine Arg arginine A~n asparagine Asp aspartic acid Bia 3-(2-benzimidazolyl)alanine Cal 3-cyclohexylalanine Cys cysteine S-A-Cys S-alkylcysteine S-Ne-Cys S-methylcysteine Dab 2,4-diaminobutyric acid Gln glut~mine Glu glutamic acid Gly glycine His histidine N(im)-A-Hi~ 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 (3-amino-2-hydroxypropionic acid) Leu leucine tert.-Leu tert.-leucine Lys lysine Nal 3-(p-methoxyphenyl)alanine Met methionine Met( 2 ) methionine S,S-dioxide ~Nal 3-(~-naphthyl)alanine pNal 3-(p-naphthyl)alanine Nbg ?-norbornylglycine Nle norleucine N-Ne-Hi8 N-methylhistidine N-Me-Phe N-methylphenylalanine Nva norvaline s 20~7~
Orn ornithine Phe phenylalanine Pia 3-(piperidyl)alanine [for example 2-Pia =
3-(2-piperidyl)alanine]
Pro proline Pya 3-(pyridyl)alanine [for example 3-Pya =
3-(3-pyridyl)alanine]
Ser ~erine (O-A)-Ser O-alkyl~erine (O-Ar-slkyl)-Ser O-Ar-alkylserine - Thr threonine Tia 3-(thienyl)alan$ne tfor example 2-Tia =
3-(2-thienyl)alanine]
Tic 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid Tiz 3-(thiazolyl)alanine [for example 2-Tiz =
3-(2-thiazolyl)alanine]
Trp tryptophan Tyr tyrosine Val valine.
In addition, the following have the meaning below:
BOC tert.-butoxycarbonyl BOM b~nzyloxymethyl imi-BOM benzyloxymethyl in the l-position of the imldazole ring CBZ benzyloxycarbonyl DCCI dicyclohexylcarbodiimide DMF dimethylform~de DNP 2,4-dinitrophenyl imi-DNP 2,4-dinitrophenyl in the l-position of the imidazole ring ETOC ethoxycarbonyl FMOC 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole IPOC isopropoxycarbonyl Pla the radical of phenyIlactic acid -O-CH(CH2C~H5)-CO- (8-form) - 6 - 2~7~
POA phenoxyacetyl THF tetrahydrofuran.
If the abovementioned amino acids can occur in several enantiomeric form~, all these forms and also their mixtures (for example the DL-forms) are included above and below, for example as constituen~ of the compounds of the formula I. The L-forms are preferred. If individual compounds are mentioned below, the abbrevia-tions of these amino acids in each case relate to the L-form, if not expressly stated otherwise.
The invention further relates to a process for the preparation of an acid amide of the formula I accord-ing to Claim 1 and of its salts, characterised in that it is set free from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent or in that a carboxylic acid of the formula II

R R N-C,H~-CO-G -OH II

in which Gl (a) is absent, (b) is _z_, (c) i8 -Z-Y-, or one of its reactive derivatives is reacted with a compound of the formula III

H-G2-NH-CHR3-CHR~-~CH2)~-CR~R~-X III

in which G2 (a) i~ _z_y_, (b) is _y_, (c) i8 absent, and in that a functionally modified amino and/or hydroxy group is optionally set free in a compound of the formula I by treating with solvolysing or hydrogenolysing agents and/or a free amino group is acylated by treating with an acylating agent and/or a compound of the formula I is converted into one of its salts by treating with an acid.
Above and b~low, the radicals or parameters R1 to 2 ~ d 7 ~

Rl, W, X, Y, Z, m, n, x, Ar, Het, Hal, An, A, G' and G2 have the meanings indicated in the formulae I, II or III
unless expre~sly stated otherwise.
In the above formulae, A has 1-8, preferably 1, 2, 3 or 4 C atoms. A is preferably m~thyl, furthermore ethyl, propyl, i~opropyl, butyl, i~o~utyl, sec.-butyl, or tert.-butyl, additionally also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, l-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, ~,2-, 2,3- or 3,3 dLmethylhutyl~ 1- or 2-ethylbutyl, 1-ethyl-1 methylpropyl, 1-ethyl-2-methyl-propyl, 1,1,2- or 1,2,2-trimethylpropyl, heptyl, octyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but also, for example, 1-, 2- or 3-methylcyclopentyl, or 1 , 2-, 3- or 4-methylcyclohexyl.
Accordingly, cycloalkylalkyl is preferably cyclopropylmethyl~ 2-cy~lopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl,cyclopentylmethyl,2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, but al~o, for example, 1-, 2 or 3-methylcyclopentylmethyl, or l-, 2-, 3- or 4-methylcyclohexylmethyl.
Bicycloalkyl is preferably l- or 2-decalyl, 2-bicyclot2.2.1]heptyl or 6,6-dLmethyl-2-bicyclo[3.1.1]-heptyl.
Tricycloalkyl L~ preferably l-adamantyl.
- Hal i~ preferably F, Cl or Br, but al~o I.
Ar i~ preferably phenyl, in addition preferably o-, m- or p-tolyl, o- t 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-i.odophenyl, o-, m- or p-trifluoromethylphenyl, o-, m or p-hydroxyphenyl, o-, m- or p-sulfamoylphenyl, 2,3-, 2,4-~ 2,5-, 2,6-, 3,4 or 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, o-, m-, or p-aminophenyl, o-, m~
or p-aminomethylphenyl, o-, m- or p-dimethylaminomethyl-phenyl, o-, m- or p--guanidinomethylphenyl, 1- or 2-naphthyl.
Accordingly, ~r-alkyl i3 preferably benzyl, l- or - 8 - 2~57~3~
2-phenylethyl, o-, m- or p-methylbenzyl, 1- or 2-o-, -m-or -p-tolylethyl, o-, m- or p-ethylbenzyl, 1- or 2-o-, -m- or -p-ethylphenylethyl, o-, m- or p-methoxybenzyl, 1-or 2-o-, -m- or -p-methoxyphenylethyl, o-, m- or p-fluorobenzyl, 1- or 2-o-, -m- or -p-fluorophenylethyl, o-, m- or p-chlorobenzyl, 1- or 2-o-, -m- or -p-chloro-phenylethyl, o-, m- or p-bromobenzyl, 1- or 2-o-, -m- or -p-bromophenylethyl, o-, m- or p-iodobenzyl, 1- or 2-o-, -m- or -p-iodophenylethyl, o-, m- or p-trifluoromethyl-benzyl, o-, m- or p-hydroxybenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzyl, 3,4,5-trimethoxy-benzyl, o-, m- or p-aminobenzyl o-, m- or p-aminomethyl-benzyl, o-, m- or p-dimethylaminomethylbenzyl, o-, m- or p-guanidinomethylbenzyl, 1- or 2-naphthylmethyl.
lS Het i~ preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or S-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or S-oxazolyl, 3-, 4- or S-isoxazolyl, 2-, 4- or S-thiazolyl, 3-, 4- or S-isothi-azolyl, 2-, 3- or 4-pyridyl, 2-, 4-, S- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -S-yl, 1,2,4-triazol-1-, -3- or -S-yl, 1- or S-tetrazolyl, 1,2,3-oxadiazol-4- or -S-yl, 1,2,4-oxadiazol-3- or -S-yl, 1,3,4-thiadiazol-2- or -S-yl, 1,2,4-thiadiazol-3- or -S-yl, 2,1,5-thiadiazol-3- or -4-yl, 2-, 3-, 4-, S- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl r pyrazinyl, 2-, 3-, 4-, S-, 6- or 7-benzo-furyl, 2-, 3-, 4-, S-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, S-, 6- or 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-iso-indolyl, 1-, 2-, 4- or S-benzimidazolyl, 1-, 3-, 4-, S-, 6- or 7-benzopyrazolyl, 2-, 4-, S-, 6- or 7-benzoxazolyl, 3-, 4-, S-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, S-, 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-iso-quinolyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, S-, 6-, 7- or 8-cinnolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolyl. ~he heterocyclic radicals can al80 be partially or completely hydrogenated. Het can thus also be, for example, 2,3-di-2~ '7 ,~
hydro-2-, -3-, -4- or -5-fu~yl, 2,5-dihydro-2-, -3-, -4-or -S-furyl, tetrahydro-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 -S-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro~ 2- or -4-Lmidazolyl, 2,3-dihydro-1~, -2-, -3-, -4- or -5-pyrazolyl, tetra-hydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3-or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, 5-or 6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3-, -4-, -5-or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-di-oxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-l , -2-, -4- or -5-pyrLmidinyl, 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-i~oquinolyl.
The heterocyclic radicals can also be substituted 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-m~thyl-S-pyrimidinyl, 2-amino-5,6-dLmethyl-3-pyrazinyl, 4-carbamoylpiperidino, in addition, for example, 3-, 4-or 5-methyl-2--furyl, 2-, 4- or 5-methyl-3-furyl, 2,4-di-methyl-3-furyl, 5-nitro-2-furyl, 5- tyryl-2-furyl, 3-, 4-or 5-methyl-2-thienyl, ~-, 4- or 5-methyl-3-thienyl, 3-methyl-5-tert.-butyl-2-thienyl, 5-chloro-2-thienyl, 5-phenyl-2- or -3~thienyl, 1-, 3-, 4- or 5-methyl-2-pyrrolyl, l-methyl-4- or -S-nitro-2-pyrrolyl, 3,5-dimeth-yl-4-ethyl-:2-pyrrolyl, 4-methyl-S-pyrazolyl, 5-methyl-3-isoxazolyl, 3,4-dLmethyl-5-i3oxazolyl, 4- or 5-methyl-2-thiazolyl, 2- or 5-methyl-4-thiazolyl, 2- or 4-methyl-5-thiazolyl, 2,4-dimethyl-5-thiazolyl, 3-, 4-, 5- or 6-methyl-2-pyridyl, 2-, 4-, 5- or 6-methyl-3-pyridyl, 2- or 3-methyl-4-pyridyl, 3-, 4-, 5- or 6-chloro-2-pyridyl, 2-, 4-, 5- or 6-chloro-3-pyridyl, 2- or 3-chloro-4-pyridyl, 2,6-di~hloropyridyl, 2-hydroxy-3-, -4-, -5- or -6-pyridyl (= lH-2-pyridon-3-, -4-, -5- or -6-yl),5-phenyl-lH-2-pyridon-3-yl,5-p-methoxyphenyl-lH-2-pyridon-3-yl, 2-methyl-3-hydroxy 4-hydroxy~ethyl-5-- 10 - ~ ~J7 pyridyl, 2-hydroxy-4-amino-6-methyi-3-pyridyl, 3-N~-methylureido-lH-4-pyridon-5-yl, 4-methyl 2-pyrimidinyl, 4,6-dimethyl-2-pyrLmidinyl, 2 , 5- or 6-methyl-4-pyrimid-inyl, 2,6-dLmethyl-4-pyrimidinyl, 2,6-dihydro~y 4-pyrim-idinyl, 5-chloro-2~methyl-4-pyrLmidinyl, 3-methyl-2-benzofuryl, ~-ethyl-3-benzofuryl, 7-me~hyl-2-benzo-thienyl, 1-, 2-, 4-, 5-, 6- or 7-methyl-3-indolyl, l-methyl-5- or -6-benzimidazolyl, 1-ethyl-5- or -6-benz-Lmidazolyl, 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2-quinolyl, 2-oxopyrrolidino, 2-oxopiperidino, 2,5-dioxopyrrolidino or 3-benzyl-2,5-dioxopyrrolidino.
X is preferably OH, furthermore preferably OA
such as methoxy or ethoxy, OR1~ such as acetoxy or benzoyloxy, OSO~A such as methanesulfonyloxy or OSO~r such as benzene- or p-toluenesulfonyloxy.
The group Y is preferably one of the amino acid radicals indicated; however, it can also be absent. Y is pr~ferably ~Ala, His, S-Me-Cys or Nva, in addition preferably Gly, Ala, Leu, Met, Met(02) or Nle.
Rl and R2 are each preferably H or A, in par-ticular methyl; RlR2N i~ preferably al~o pyrrolidino, piperidino, morpholino, aminopiperidino such as 4-amino-piperidino, alkylaminopiperidino such as 4-methylamino-piperidino, dialkylaminopiperidino such a~ 4-dimethyl-aminopiperidino or BOC-aminopiperidino such as 4-BOC-aminopiperidino.
R8 i8 preferably Ar-alkyl, in particular benzyl or p-methoxybenzyl; in addition preferably A, in parti-cular n-butyl or isobutyl; cycloalkylalkyl, in particular cyclohexylmethyl; or Het-alkyl, in particular 2-thienyl-methyl. W i8 preferably NH, but also CH2 or 0. The group Z accordingly i8 prefer~bly one of the radical~ Phe, Pla or CH2CH(CHZC6H5)-CO-, in addition Cal, Leu, Mal, Nle or Tia, furthermore Z can preferably be absen~.
R3 L~ preferably cycloalkylal~yl, in particular cyclohexylme~hyl, in addition preferably alkyl, in particular n-butyl or isobutyl; AX-hlkyl, in particular benzyl or p-methoxybenzyl; Het-alkyl, for example 2-thienylmethyl; or cycloal~yl, in particular cyclohexyl.

2~7~?~

R~ is preferably OH.
The groups R5 and R6 are preferably the same and are preferably each A, in particular methyl or ethyl.
R' is preferably H. W is preferably NH, but also CH2 or 0.
R9 is preferably H, A, in particular tert.-butyl, or Ar-alkyl, in particular benzyl.
Rl i8 preferably A-CO-, such as acetyl, propionyl or butyryl, Ar-CO-, such as benzoyl, o-, m- or p-methoxy-benzoyl or 3,4-dimethoxybenzoyl, A-NH-CO- such as N-methyl- or N-ethylcarbamoyl.
The parameter m is preferably 0, in addition preferably 1, 2, 3, 4 or 5; n is preferably 1; x is preferably 0, 1 or 2.
C~H~ and C~H~ are preferably straight-chain, that is to say preferably -(CH2)~- or -(CH2)~-.
Accordingly, the group RlR2N-C~H~-CO i8 in par-ticular preferably H2N-C~H~-CO- such as aminocarbonyl, aminoacetyl (H-Gly-), 3-aminopropionyl (H-~Ala-), 4-aminobutyryl, S-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-~minooctanoyl, 9-aminononanoyl, 10-aminodec~noyl, ll-aminoundecanoyl, but also, for example, 2-aminopropionyl (Ala), 2-amino-2-methylpropionyl, 3-amino-3-methylbutyryl; ANH-C~H~-CO- such as methylamino-carbonyl, methylaminoacetyl (sarcosyl), 3-methylamino-propionyl, 4-methylaminobutyryl, S-methylaminopentanoyl, 6-methylaminohexanoyl, 6-ethylaminohexanoyl, 7-methyl-aminoheptanoyl, 8-methylaminooctanoyl, 9-methylamino-nonanoyl, 10-methylaminodecanoyl, ll-methylaminoundecan-oyl, A~N-C.H~-CO- such as dimethylaminocarbonyl, dimethyl-aminoacetyl, 3-dimethylaminopropionyl, 4-dimethylamino-butyryl, 5-dimethylaminopentanoyl, 6-dimethylaminohexan-oyl, 6-diethylaminohexanoyl, 7-dimethylaminoheptanoyl, 8-dimethylaminooctanoyl, 9-dimethylaminononanoyl, 10-dimethylaminodecanoyl, ll-dimethylaminoundecanoyl;
pyrrolidino-C~H~-CO- such as pyrrolidinocarbonyl, pyrrolidinoacetyl,3-pyrrolidinopropionyl,4-pyrrolidino-butyryl, S-pyrrolidinopentanoyl, 6-pyrrolidinohexanoyl, 7-pyrrolidinoheptanoyl~ 8-pyrrolidinooctanoyl, 9-- 12 - 2~7~33~
pyrrolidinononanoyl, 10~pyrrolidinodecanoyl; piperidino-C~H~-CO- such as piperidinocarbonyl, piperidinoacetyl, 3-piperidinopropionyl, 4piperidinobutyryl, 5-piperidino-pentanoyl, 6~piperidinohexanoyl, 7-piperidinoheptanoyl J

8-piperidinocctanoyl, 9-piperidinononanoyl~ 10-piperi-dinodecancyl; morpholino-C3H~-CO- such as morpholino-carbonyl, morpholinoacetyl, 3-morpholinopropionyl, 4-morpholinobutyryl, 5-morpholinopentanoyl, 6-morpholino hexanoyl, 7-morpholinoheptanoyl, 8-morpholinooctanoyl, 9-morpholinononanoyl,l0-morpholinodecanoyl;4-aminopiperi-dino-C~H~-CO- such as 4-aminopiperidinocarbonyl, 4-aminopiperidinoacetyl,3-l4-aminopiperidino~propionyl/4-(4-aminopiperidino)butyrylr 5-(4 aminopiperidino)penta-noyl, 6-(4-aminopiperidino)hexanoyl, 7-(4-aminopiperi-dino)heptanoyl, 8-(4-aminopiperidino)octanoyl, 9-(4-aminopiperidino)nonanoyl, 10-(4-aminopipexidino)decanoyl;
4-BOC-aminopiperidino-C~H~-CO- such a~ 4-BOC-aminopiperi-dinocarbonyl, 4-BOC-aminopiperidinoacetyl, 4-dialkyl-aminopiperidino-C~H~-CO- ~uch as 4-dimethylaminopiperi-dinocarbonyl, 4-dimethylaminopiperidinoacetyl; 4-guani-dinopiperidino-CmH~-CO- ~uch as 4-guanidino-piperidinocarbonyl, 4-guanidinopiperidinoacetyl; 4-carb-oxypiperidino-C~H~-CO- ~uch a~ 4-carboxypiperidino~
carbonyl, 4-carboxypiperidinoacetyl; 4-alkoxycarbonyl-piperidino-C~H~-CO- such as 4-methoxycar~onylpiperidi~o-carbonyl, 4-ethoxycarbonylpiperidinocarbonyl, 4-methoxy-carbonylpiperidinoacetyl, 4-ethoxycarbonylpiperidino-acetyl; 4-AcNH-piperidino-CmH2m-CO- such as 4-acetamidopiperidinocarbonyl, 4-acetamidopiperidino~
acetyl; H2N-C(=NH)-C~H~-CO- such as guanidinoacetyl, 3-guanidinopropionyl, 4-guanidinobutyryl, 5-guanidino-pentanoyl, 6-guanidinohexanoyl, 7-guanidinoheptanoyl, 8-guanidinooctanoyl.
The compounds of the formula I can have one or more chiral centre~ and the.refore occur in different - optically active or optically inactive - form~. The formula I includes all these form~. For the C atom~ which carry the radical~ R3 and R~ in each case ~he S
configuration i~ preferred.

- 13 - 2~7i~
The abovementioned cycloalkyl and phenyl groups are preferably unsubstituted or preferably carry 1 to 3, in particular 1 or 2 substituents.
The invention accordingly relates in particular to those compound~ of the formula I in which at least one of the sa_d rzdicals has one of the abovementioned preferred meanings. Some preferred groups of compounds can be expressed by the following sub-formulae Ia to Ie:
Ia H2N-C~H~-CO-Z-Y-NH-CHR3-CHR~-(CHz)n-CRsR6-X;
Ib A2N-C~H2~-CO-Z-Y-NH-CHR3-CHR~-(CH2)n-CRsR6-X;
Ic 4-A~-CO-amino-piperidinocarbonyl-Z-Y-NH-CMR3-CHR~-(CHz)n-CRsR6-X
Id 4-BOC-amino-piperidinocarbonyl-Z-Y-NH-CHR3-CHR~-(CH2)n-CRsR6-X;
Ie 4-Amino-piperidinocarbonyl-Z-Y-NH-CHR3-CHR~-(CH2) n~
CRsR6-X .
Particularly preferred compounds are those of the sub-formulaes (a) Iaa to Iee which cGrrespond to the formulae Ia to Ie, but in which additionally Z i8 Phe, Pla, Mal or -CH2-CH(CH2C6H5)-CO-;
(b) Iab to Ieb and also Iaab to Ieab, which correspond to the formulae Ia to Ie and also Iaa to Iea, but in which additionally Y is ~Ala, S-Me-Cys, Gly, His, Leu, Met, Met(02), Nle, Nva.
(c) Iac to Iec, Iaae to Ieac, Iabc to Iebc and also Iaabc to Ieabc, which correspond to the formulae Ia to Ie, Iaa to Iea, Iab to Ieb and also Iaab to Ieab, but in which additionally R3 is cyclohexylmethyl.
Particularly preferred compounds are those of the sub-formulaes I and Ia~ to Ie~, which correspond to the formulae I and also Ia to Ie and those compounds which correspond to the other abovementioned sub-formulae, but in which addition~lly R~ is OH;
I' and Ia' to Ie', which correspond to the formulae I and also Ia to Ie and those compounds which correspond to the - 14 - 20~7~34 other abovementioned sub-formulae, but in which additionally CR5~6- is C(A)2-;
I~ and also Ia~ to Ie", which correspond to the formulae I and also Ia to Ie and those compounds which correspond to the other abovementioned s~b-formulae, but in which additionally X is OH.
A particularly preferred group of compounds corresponds to the formula I
in which RlR2N-CmH~-CO- is 4-POC-aminopiperidinocarbonyl or 4-aminopiperidinocarbonyl, Z-Y is Phe, Phe-~Ala, Phe-(S-Me-Cys), Phe-Gly, Phe-Leu, Phe-Met, Phe-Met(02), Phe-Nle or Phe-Nva, R3 is cyclohexylmethyl, R~ is OH, n is 1, R5 and R6 are each methyl or ethyl, and X is OH.
The compounds of the formula I and also the starting substances for their preparation are otherwi~e prepared by methods known per se, such as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie ~Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart;
and in addition EP-A-189,203, WO 90/07521), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se but are not mentioned here in greater detail.
The starting substances, if de~ired, can also be formed in situ, such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the fo~mula I.
The compounds of the formula I can be obtained by setting them free from their functional derivatives by solvolysi~, in particular hydrolysis, or by hydrogen-- 15 - ~ ~57 ol~si-~.
Preferred starting substance~ for the solvoly~i~
or hydrogenolysis are those which otherwi~e correspond to the formula I, but in3tead of one or more free amino and~or hydroxy groups contain correspondingly protected amino and/or hydroxy groups, prefera~ly tho~e which instead of an H atom which i3 bonded to an N atom, carry an amino protective group, for example those of the formula I, but instead of an His group contain an N(im)-R'-~is group (in which R~ is an amino protective group, for example BOM or DNP), those of the formula R1R2N-Cm-H~-CO-Z-Y-NH-CHR3-CH-(NHR')-(CH2)D-CR5R6-Xorthose which instead of a Dab, Lys or Orn group contain a corresponding group which instead of the terminal NH2 group contains an NH-R~ group (for example NH-CBZ).
In addition, starting substances are preferred which instead of the H atom of a hydroxy group carry a hydroxy protective group, for example tho~e of the formulae R1R2N-C~H~-Co-Z-Y-NH-CHR3-CHoR"-(CH~)~-CR5R6-X or RlR2N-C~H~-CO-Z-Y-NH-CHR3 -CHR4- (CH2)n-CR5R6-oR" in which R"
is a hydroxy protective group.
Several - identical or different - protect0d amino and/or hydroxy groups can also be pre~ent in the molecule of the starting ~ubstance. If the protective groups presen1 are different from one another, they can in many cases be removed selectively.
The expression ~amino protective group' i~
generally known and relates to groups which are suitable for protecting an amino group from chemical reactionc ~for blocking), but which are easily removable after the desired chemical reaction has been carried out in another site of the molecule. Typical of such groups are in particular unsubstituted or substituted acyl, aryl (for example DNP), aralkoxymethyl (for example BOM) or aralkyl groups (for example benzyl, 4-nitrobenzyl, triphenyl-methyl). Since the amino protecti~e groups are remoYed after the de~ired reaction [or reaction sequence), their nature and size i8 otherwise no~ critical; but those with 1-20 C atoms, in particular l-8 C atoms, are preferred.

- 16 - 2 ~
The expression ~acyl group~ is to be interpreted in the widest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carbo~ylic acids or sulfonic acids and also in particular alkoxycarbonyl, aryloxy-carbonyl and especially aralkoxycarbonyl groups. ~xample~
of acyl groups of thi~ type are alkanoyl such as acetyl, propionyl or bukyryl; aralkanoyl such as phenylacetyl;
aroyl ~uch as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ETOC, 2,2,2-trichloroethoxycarbonyl, IPOC, BOC, 2-iodoethoxy-carbonyl; aralkyloxycarbony] such a~ CBZ, 4-m~tho~y-benzyloxycarbonyl and FMOC. Preferred amino protective groups are BOC, DNP and BOM, and in addition CBZ, FMOC, benzyl and acetyl.
The expres~ion 'hydroxy protective group' is likewise g~nerally known and relates to groups which are suitable for protecting a hydroxy group from chemical reactions, but which are easily removable after ~he desired chemical reaction has been carried out in another site of the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and in addition also alkyl ~roups. The nature and ~ize of ~he hydroxy protective groups iB not critical, since they are removed again after the desired chemical reaction or reaction ~equence; groups with 1-20, in particular 1-10 C atoms are preferred. ExampleR of ~ydroxy prote!ctive groups are, among other~, tert.-butyl, benzyl, p-nitrobenzoyl, p-toluene~ulfonyl and acetyl, benzyl and acetyl being particularly preferred.
The functional derivative~ of the compounds of the formula I to be used as starting sub~tances can be prepared by cu~tomary methods of amino acid and peptide synthesis, ~uch as, for example, are described in the said standard work~ and patent applications~ for ~xample also by the ~olid phase method according to Merrifield.
The compound~ of the formula I are set free from their functional derivative~ - depending on the protec-tive group used - for example with strong acids, - 17 - 2~7~
expediently with trifluoroacetic acid or perchloric acid, - but also with other strong inorganic acid~ such as hydro-chloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluene~ulfonic acid. The presence of an additional inert solvent is po~sible, but not always necessary.
Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbon such a~ dichloromethane, and in addition also alcohols such as methanol, ethanol or isopropanol and also water. In addition, mixtures of the abovementioned solvents are suitable. Trifluoroacetic acid i8 preferably u~ed in excess without addition of a further solvent, 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 expedi-ently between about O and about 50-C; the reaction is preferably carried out between 15 and 30- (room tempera-ture).
The BOC group can, for example, preferably be removed with 40 ~ trifluoroacetic acid in dichloromethane or with about 3 to 5 N HCl in dioxane at 15-30-C, the FMOC group with an about 5-20 ~ solution of dimethyl-amine, diethylamine or piperidine in DMF at lS-30-. The DNP group i8 also removed, for example, with an about 3-10 ~ solution of 2-mercaptoethanol in DMP/water at 15-30-.
Protective groups which can be removed by hydro-genolysis (for example BO~, CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst ~for example a noble metal cata-lyst such as pslladium, expediently on a support such as carbon). Suitable solvents in this case are the above-mentioned, in particular, for example, alcohols such as methanol or ethanol or amides such as DMP. The hydrogen-olysi~ is as a rule carried out at temperatures between O and 100- and at pressures between about 1 and 200 bar, - 18 - 2~7 ~ ~
prefersbly at 20-30- and at 1-10 bar. The CBZ group i9 easily hydrogenolysed, for example, on 5-10 ~ Pd-C in methanol at 20-30.
Compounds of the formula I can also be obtained by direct condensation (peptide synthesis) from a car-boxylic ac-d component (formul~ II) and a hydroxyl or amino component (formula III). Suitable carboxylic acid components are, for example, those of the sub-formulae (a) RlR2N-C~H~-COOH, (b) RlR2N-CmH~-CO-Z-OH, (c) RlR2N-C~H~-CO-Z-Y-OH, Quitable hydroxy or amino components are those of the sub-formulae (a) H-Z-Y-NH-CR3-CHR~-(CH2)n-CR5R~-X (in which W = NH or 0, that i~ to say Z i~ -NH-CR7R~-Co- or -o-CR7R8-Co-), (b) H-Y-NH-CHR3-CHR~-(CH2) n~
CR5R6-X or (c) H2N-CHR3-CHR~-(CH2)n-CR5R8-X.
The reaction is expediently carried out in thi~ case by customary methods of peptide synthesis, such as are described, for example, in Houben-Weyl, loc.cit., Volume 15/II, psges 1-806 (1974); these methods can also be transferred, if W = O, to the condensation according to (a)~ an ester bond being formed.
The reaction is prefer~bly carried out in the presence of a dehydrating agent, for example of a carbo-diimide such as DCCI or dimethylaminopropylethyl-carbodiimide, and in addition propanephosphonic anhydride (cf. Angew. Chem. 92, 129 (1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydro-carbon such a~ dichloromethane, an ether such as THF or dioxane, an amide such as DNF or dimethylacetamide, or a nitrile such a8 acetonitrile, at temperatures between about -10 and 40, preferably between O and 30-.
Instead of II or III, suitable reactive deriva-tives of these substances can also be employed in the reaction, for example those in which reactive groups are intermediately blocked by protective groups. The acid derivatives II can be used, for example, in the form of their activated esters, which are expediently formed in situ, for example by addition of HOBt or N-hydroxy-succinimide.

19- 20~7~3~
The starting substances of the formulae II and III are for the greatest part known. If they are not known, they can be prepared by known methods, for example the abovementioned methods of condensation and removal of protective groups.
If desired, the functionally modified amino and/or hydroxy group in a compound of the formula I can be set free by solvolysis or hydrogenolysis according to one of the methods described above.
Thu~, for example, a compound of the formula I
which contains an Ra-C~H~-O-CO-NH-, an RlNH-, an AOOC-, an -ORl-, an -OSO~A- or an -OSO~Ar group can be converted into the corresponding compound of the formula I which instead of this contains an H2N-, an HOOC- or an OH group, expediently by selective ~olvolysis according to one of the abovementioned methods. AOOC-groups can be hydrolysed, for example, with NaOH or ROH in water-dioxane at temperatures between O and 40-, preferably 10 and 30.
It is also possible to acylate a compound of the formula I which contains a free primary or secondary amino group, for example by reaction with acylating agents of the formula Rl-Cl, expediently in the presence of an inert solvent such as THF and/or of a base such as pyridine or triethylamine at temperatures between -10 and +3~-.
A base of the formula I can be converted into the respective acid addition salt u~ing an acid. Suitable acids for this reAction are in particular those which give physiologically acceptable salts. Thus inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such a6 orthophos-phoric acid, sulfamic acid, and in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, trifluoroacetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic - 20 - 20~7~34 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, naphthalenemono- and -disulfonic acids, and laurylsulfuric acid. Salts with physiologic-ally unacceptable acids, for example picrates, can be used for the isolation and/or purification of the compounds of the formula I.
The novel compounds of the formula I and their physiologically acceptable salts can be used for the production of the pharmaceutical preparations by bringing them into a suitable dosage form together with at least one excipient or auxiliary and, if desired, together with one or more other active compound(s). The preparations thus obtained can be employed as medicaments in human or veterinary medicine. Suitable excipients 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 an inhalation spray and do not react with the novel 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 or eellulose. For oral adminl6tr~tion, t~blets, coated tablets, capsules, syrups, ~uices or drops are used; especially of interest are coated tablets and capsules having enteric-resistant coatings or capsule shells. Suppositories are used for rectal administration, and solutions, preferably oily or aquQous solutions, and in addition suspensions, emulsions or implants are used for parenteral administration. For administration as inhalation sprays, sprays can be used which cont~in the active compound either dissolved or suspended in a propellant gas mixture (for example fluorochlorohydrocarbons). The active compound in this case is expediently used in micronised form, it being possible for one or more additional physiologically - 21 ~ ~ 7 ~ ~3 ~
tolerable solvents to be present, for example ethanol.
Inhalation solutions can be admini3tered with the aid of customary inhalers. The novel compounds can also be lyophilised and the lyophilisates obtained u~ed, for example, for the production of in~ection preparations.
The preparations mentioned can be sterilised and/or can contain auxiliaries such as preservatives, stabili~er~
and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substance~, colourants and/or flavouxings. If desired, they can also contain one or more other active compounds, for example one or more vitamins.
The ~ubstances according to the invention are as a rule administered in analogy to other known commer-cially available peptides, but in particular in analogy to the compounds described in the patent applications mentioned, preferably in dosage~ between about 10 mg and 1 gl in particular between 50 and 500 mg per dosage unit.
The daily dosage is preferably between about 0.2 and 20 mg/kg, in particular between 1 and 10 mg/kg of ~ody weight. The specific dose for each specific patient, however, depends on a wide variety of factors, or example on the activity of the specific compound employed, on the age, body weight; general 3tate of health, SQX, on the diet, on the time and route of administration, and on the excretion rate, medicament combination and severity of the particular disease to which the treatment applies. Parenteral administration is preferred. Renin-dependent hypertension and hyper-aldosteronism can be effectively treated by admini~tra-tion of dosages between, in particular, about 0.2 and 20, preferably between 1 and 10 mg/kg of body weight. For diagnostic purpose~ the novel compound~ can expediently be admini~tered in individual doses between about 0.1 and 10 mg/kg of body weight.
Above and below, all temperatures are indicated in C. In the following example~ 'cu~tomary working up' means: water i~ added if neces~ary, the pH is ad~usted to between 2 and 8, depending on the constitution of the - 22 - 2~7 - ~ 4 f inal product, the mixture is extracted with ethyl aeetate or dichloromethane, the organic phase i8 ~eparated off, dried over sodium sulfate and evaporated, and the residue is purif ied by chromatography on siliea S gel and/or crystallisation. FAB - mass spectrum by the ~Fast Atom Bombardment' method.
Example 1 1 g of (4S,5S)-5-[4-tert.-butyloxyearbonylamino-piperidinoearbonyl L-phenylalanyl-L-(N-imi)-benzyloxy-methylhi~tidylamino]-6-cyclohexyl-2-methylhexane-2,4-diol t=(4S, 5S)-5-t4-BOC-aminopiperidinoearbonyl-Phe-(imi-BOM-His)-amino]-6-eyelohexyl-2-methylhexane-2,4-diol];
obtainable by reaetion of (4S,5S)-3-BOC-4-cyclo-hexylmethyl-5-methoxycarbonylmethyl-2,2-dimethyloxa-zolidine with CH3MgBr in THF and subsequent hydrolysis togive (4S,5S)-3-~OC-4-cyclohexylmethyl-5-(2-hydroxy-2-methylpropyl)-2~2-dimethyloxazolidine~ elimination of the BOC group and the acetonide group to give (4S,5S)-5-amino-6-cyclohexyl-2-methylhexane-2,4-diol and reaetion with 4-BOC-aminopiperidinoearbonyl-Phe-(imi-BOM-His)-OH/DCCI/HOBt] is dissolved in 30 ml of ethanol, the solution is hydrogenated on 0.4 g of 10~ Pd-C at 20- and at 1 bar until uptake of hydrogen has stopped, filtered, evaporated and purified by ehromatography over siliea gel togive(4S,5S)-5-(4-BOC-aminopiperidinocarbonyl-Phe-His-amino)-6-cyclohexyl2-methylhexane-2,4-diol, m.p. 124-126-. FAB 740.

(3S,4S)-4-(4-BOC-aminopiperidinocarbonyl-Phe-His-amino)-5-cyelohexyl-2-methylpentane-2,3-diol is obtained analogously from (3S,4S)-4-t4-BOC-aminopiperid-inocarbonyl-Phe-(imi-BOM-His)-amino]-5-cyelohexyl-2-methylpentane-2,3-diol.

Example 2 A mixture of 907 mg of (4S,SS)-5-(4-BOC-aminopiperidinoearbonyl-Phe-(imi-DNP-His)-amino)-6-eyelohexyl-2-methylhexane-2,4-diol tobtained via (4S,5S)-5-BOC-(imi-DNP-His)-amino-6-eyelohexyl-2-me~hylhexane-2 Q ~ 7 ! ~ 4;

2,4-diol, m.p. 81-85 (decomposition), FAB 633, and (4S,5S)-5-H-(imi-DNP-~is~-amino-6-cyclohexyl-2-methylhexane-2,4-diol, m.p. 124-127 (decompoxition)], 2 g of 2-mercaptoethanol, 20 ml of DMF and 20 ml of water is ad~usted to pH 8 with aqueous Na2CO3 solu~ion while stir-ing and at 20, and is stirred for a further 2 hour~
at 20. Customary working up gives (4S,5S)-5-~4-BOC-amino-piperidino-carbonyl-Phe-His-amino)-6-cyclohexyl-2-methylhexane-2,4-diol, m.p. 124-126. FAB 740.

Example 3 1.01 g of N-methylmorpholine is added to a solution of 3.28 g of (4S,5S)-6-cyclohexy1-2-methyl-5-tH-Nva-amino)-hexane-2,4-diol (obtainable from the corre-~ponding BOC-Nva compound, FAB 429) in 60 ml of dichloro-methane. 3.91 g of 4-BOC-aminopiperidinocarbonyl-Phe~O~, 1.35 g of HOBt and a ~olution of 2.06 g of DCCI in 50 ml of methylene chloride are added while ~tirring, and the mixture i~ stirred for 12 hour~ at 0-5, the precipitated dicyclohexylurea is filtered off and the filtra~e i8 evaporated. Cu~tomary working up gives (4S,SS)-5~(4-BOC-aminopiperidinocarbonyl-Phe-Nva-amino)-6-cyclohexyl-2-methylhexane-2,4-diol, m.p. 113-116; FAB 702.

The following are obtained analogously:

From (4S,5S)--S-(H-Ala-amino)-6-cyclohexyl-2-methylhexane-2,4-dlol (oily, FAB 301; BOC derivative, FA~ 401) (4S,SS)-5-(4-BOC-aminopiperidinocarbonyl-Phe-Ala-amino)-6-cyclohexy1-2-methylhexane-2,4-diol, m.p. 125-132 D; FAB
675;

From (4S,5S)-5-(H-~Ala-amino)-6-cyclohexyl-2-methylhexane-2,4-diol (4S,SS)-5-(4-BOC-aminopiperidinoc-arbonyl-Phe-6-cyclohexyl 2-methylhexane-2,4-diol, m.p. 105-108~; FAB ~74;

From (4S,SS)-6-cyclohexyl-5-(H-~ly-amino)-2-methylhexane-2,4-dîol (oily, F~B 287; BOC derivative, FAB 387) 2~57~

(4S,5S)-5-(4-BOC-aminopiperidinocarbonyl-Phe-Gly-amino)-6-cyclohexyl-2-methylhexane-2,4-diol, m.p. 115-118, FAB 661;

From (4S,SS)-6-cyclohexy1-5-(H-Leu-amino)-2-methylhexane-2,4-diol (BOC derivative, oily, FAB 443) (4S,5S)-5-(4-BOC-aminopiperidinocarbonyl-Phe-Leu-amino)-6-cyclohexyl-2-methylhexane-2,4-diol, m.p. 124-131-; FAB 717;

From (4S,5S)-6-cyclohexyl-5-(H-D-Leu-amino)-2-methylhexane-2,4-diol (4S,SS)-5-(4-BOC-aminopiperidinoc-arbonyl-Phe-D-Leu-amino)-6-cyclohexyl-2-methylhexane-2,4-diol, m.p. 107-111;

From (4s~5s)-6-cyclohexyl-5-(H-Met-amino)-2-methylhexane 2,4-diol (BOC derivative, m.p. 105-106-, FAB 461) (4S,SS)-5-(4-BOC-aminopiperidinocarbonyl-Phe-Met-amino)-2-methylhexane-2,4-diol, m.p. 90-91-; FAB 734;

From (4S,SS)-6-cyclohexyl-5-~H-Nle-A~ino)-2-methylhexane-2,4-diol (BOC derivative, oily, FAB 443) (4S,SS)-5-(4-BOC-aminopiperidinocarbonyl-Phe-Nle-amino)-2-methylhexane-2,4-diol, m.p. 108-110-; PAB 716;

From (4S,SS)-6-cyclohexyl-2-methyl-S-[H-(S-Me-Cys)-amino]-hexane-2,4-diol (4S,SS)-6-cyclohexyl-2-methyl-S-t4-BOC-aminopiperidinocarbonyl-Phe-(S-Me-Cy~)-amino]-6-cyclohexyl-2-methylhexane-2,4-diol;

From (4s~ss)-s-(H-cal-amino)-6-cyclohexyl-2-methylhexane-2,4-diol (4S,SS)-5-(4-BOC-aminopiperidinocarbonyl-Phe-Cal-amino)-6-cyclohexyl-2-methylhexane-2,4 diol.

Example 4 (4S,SS)-5-(4-BOC-aminopiperidinocarbonyl-Phe-amino)-6-cyclohexyl-2-methylhexane-2~4-diol~ m.p. 103-105-; FAB 603, i8 obtained analogou~ly to Example 3 from (4S,SS)-5-amino-6-cyclohexyl-2-m~thylhexane-2,4-diol and 4-BOC-aminop$peridinocarbonyl-Phe-OH.

20 ~7 ~ ~ ~
Example 5 (5S,6S)-6-(4-BOC-aminopiperidinocarbonyl-Phe-amino~-7-cyclohexyl-3-ethylhexane-3,5-diol, FAB 653 (NB
+ Na) and 597, i8 obtained analogously to Example 4 from S (SS,6S)-6-amino-7-cyclohexyl-3-ethylhexane-3,5-diol and 4-aoc-a~inopiperidinocarbonyl-phe-oH.
The following are obtained analogously:

with (5S,6S)-6-(H-~Ala-amino)-7-cyclohexyl-3-ethylhexane-3,S-diol (5S,6S)-6-(4-BOC-aminopip~ridinocarbonyl-Phe-~Ala-amino)-7-cyclohexyl-3-ethylhexane-3,5-diol~ m.p.
107-111-; FAB 702;

with (5S,6S)-6-(H-Nva-amino)-7-cyclohexyl-3-ethylhexane-3,5-diol (SS,6S)-6-(4-BOC-aminopiperidinocarbonyl-Phe-Nva-amino)-7-cyclohexyl-3-ethylhexane-3,5-diol, m.p. 95-103-; FAB 731.

Example 6 (3S,4S)-4-(4-BOC-aminopiperidinocsrbonyl-Phe-~-Ala-amino)-S-cyclohexyl-2-methylpentane-2,3-diol, m.p.
92-9S-; FAB 660, is obtained analogously to ~xample 3 from (3S,4S)-4-(H-gAla-amino)-S-cyclohexyl-2-methyl-pentane-2,3-diol and 4-BOC-aminopiperidinocarbonyl-Phe-OH.

~he following are obtained analogously from (3S,4S)-4-amino-S-cyclohexyl-2-methylpentane-2,3-diol and from the corresponding (3S,4S)-4-(Y-amino)-S-cyclohexyl-2-methyl-pentane-2,3-diolss (3S,4S)-4-(4-BOC-aminopiperidinocarbonyl-Phe-amino)-S-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-BOC-aminopiperidinocarbonyl-Phe-Ala-amino)-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-BOC-aminopiperidinocarbonyl-Phe-Cal-amino)-S-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-BOC-aminopiperidinocarbonyl-Phe-( S-Mb-Cy8 ) -amino)-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-BOC-aminopiperidinocarbonyl-Phe-Gly-amino)-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-~4-BOC-aminopiperidinocarbonyl-Phe-Leu-amino)-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-BOC-aminopiperidinocarbonyl-Phe-~et-amino)-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-BOC-aminopiperidinocarbonyl-Phe-Met( 2 ) -amino)-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-BOC-aminopiperidinocarbonyl-Phe-Nle-amino)-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-BOC-aminopiperidinocarbonyl-Phe-Nva-amino)-5-cyclohexyl-2-methylpentane-2,3-diol Example 7 A ~olution of 1 g of (4S,5S)-5-(4-BOC-aminopiperidinocarbonyl-Phe-Nva-amino)-6-cyclohexyl-2-methylhexane-2,4-diol in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid is stirred for 1 hour at 20- and thereafter evaporated. (4S,5S)-5-(4-aminopiperidinocarbonyl)-Phe-Nva-amino)-6-cyclohexyl-2-methylhexane-2,4-diol, m.p. 102-103- (decomposition), FAB
602, i8 obtained.
The following are obtained analogously from the corresponding BOC-amino derivatives (see above) with trifluoroacetic acid~

(4S,5S)-(4-aminopiperidinocarbonyl-Phe-amino)-6-cyclo-hexyl-2-methylhexane-2,4-diol, m.p. 91-4-; FAB 503 (4S, sæ ) - ( 4-aminopiperidinocarbonyl-Phe-Ala-amino)-6-cyclohexyl-2-methylhexane-2,4-diol (4S,5S)-(4-aminopiperidinocarbonyl-Phe-~Ala-amino)-6-cyclohexyl-2-methylhexane-2,4-diol, m.p. 109-118-;

(4S,5S)-~4-aminopiperidinocarbonyl-Phe-Cal-amino)-6-cyclohexyl-2-methylhexane-2,4-diol (4S,SS)-~4-aminopiperidinocarbonyl-Phe-(S-Me-Cys)-amino]-6-cyclohexyl-2-methylhexane-2,4-diol (4S,SS)-(4-aminopiperidinocarbonyl-Phe-Gly-amino)-6-- 27 - ~7 ~ ~ ~
cyclohexyl-2-methylhexane-2,4-diol (4S,5S~-(4-aminopiperidinocarbonyl-Phe-H~s-amino)-6-cyclohexyl-2-methylhexane-2,4-diol (4S,5S)-(4-aminopiperidinocarbonyl-Phe-Leu-amino)-6-cyclohexyl-2-methylhexane-2,4-diol (4S,SS)-(4-aminopiperidinocarbonyl-Phe-D-Lell-amino)-6-cyclohexyl-2-methylhexane-2,4-diol (4S,5S)-(4-aminopiperidinocarbonyl-Phe-Met-amino)-6-cyclohexyl-2-methylhexane-2,4-diol, m.p. 92-96-; FAB 634 t o (4S,5S)-(4-aminopiperidinocarbonyl-Phe-Nle-amino)-6-cyclohexyl-2-methylhexane-2,4-diol, m.p. 104-109 (3S,4S)-4-(4-aminopiperidinocarbonyl-Phe-amino)-5-cyclo-hexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-aminopiperidinocarbonyl-Phe-Ala-amino)-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-aminopiperidinocarbonyl-Phe-~Ala-amino)-S-cyclohexyl-2-methylpentsne-2,3-diol (3S,4S)-4-(4-aminopiperidinocarbonyl-Phe-Cal-amino)-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-[4-aminopiperidinocarbonyl-Phe-(S-Me-Cys)-amino]-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-aminopiperidinocarbonyl-Phe-Gly-amino)-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-aminopiperidinocarbonyl-Phe-Hi~-amino)-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-aminopiperidinocarbonyl-Phe-Leu-amino)-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-aminopiperidinocarbonyl-Phe-Met-amino)-5-cyclohexyl-2-~ethylpentane-2,3-diol (3S,4S)-4-(4-~minopiperidinocarbonyl-Phe-Met( 2 )-amino)-5-cyclohexy1-2-methylpentane-2,3-diol (3S,4S)-4-(4-aminopiperidinocarbonyl-Phe-Nle-amino)-5-cyclohexyl-2-methylpentane-2,3-diol (3S,4S)-4-(4-aminopiperidinocarbonyl-Phe-Nva-amino)-5-cyclohexyl-2-methylpentane-2,3-diol, The following examples relate to pharmaceutical preparations.

- 28 ~ 7 ~ ~ ~
Example A: Tablet~
A mixture of 1 kg of (4S,SS)-5-(4-amino-piperidinocarbonyl-Phe-Nva-amino)-6-cyclohexyl-2-methylhexane-2,4-diol, 4 kg of lactose, 1.2 kg of maize S starch, 200 g of talc and 100 g of magne~ium stearate i~
compxessed to gi~P tablets in a customary manner in such a way that each tablet contains 100 mg of active compound.
Example B: Coated tablet~
Tablets are pressed analogously to Example A, and are then coated in a customary manner with a coating of sucrose, maize starch, talc, tragacanth and colourant.
Example C: Capsules 500 g of (4S,5S)-5-(4-aminopiperidinocarbonyl-Phe-Nle-amino)-6-cyclohexy1-2-methylhexane-2,4-diol are filled into hard gelatin capsules in a customary manner in such a way that each cap~ule contain~ 500 mg of active compound.
Example D: In~ection vials A ~olution of 100 g of (4S,5S)-5-(4-aminopiperi-dinocarbonyl-Phe-Nle-amino)-6-cyclohexy1-2-methylhexane-2,4-diol in 4 1 of doubly distilled water is ad~usted to pH 6.5 with 2N hydrochloric acid, ~terile filtered and poured into injection vials. The ~olution i~ lyophilised under ~terile conditions and the vials are sterile sealed. Each in~ection vial contains 50 mg of active compound.
Example E: Suppositorie~
A mixture of 50 g of (4S,5S)-5-(4-aminopiperi-dinocarbonyl-Phe-Nle-amino)-6-cyclohexy1-2-methylhexane-2,4-diol i8 fu~ed with 10 g of soya lecithin and 140 g of cocoa butter, poured into mould~ and allowed to cool.
Each suppoYitory contains 250 mg of acti~e compoundD

Claims

1. Acid amides of the formula I
R1R2N-CmH2m-CO-Z-Y-NH-CHR3-CHR4-(CH2)n-CR5R6-X I

in which Z is -W-CR7R8-CO, W is CH2, O or NH
Y is Abu, Ala, .beta.Ala, Arg, Asn, Asp, Bia, Cal, Cys, (S-A)-Cys, Dab, Gln, Glu, Gly, His, N(im)-A-His, Hph, Ile, Leu, tert.-Leu, Lys, Mal, Met, Met(O2), .alpha.Nal, .beta.Nal, Nbg, Nle, Nva, Orn, Phe, Pia, Pro, Pya, Ser, ( O-A)-Ser, (O-Ar-alkyl)-Ser, Isoser, Thr, Tia, Tic, Tiz, Trp, Tyr or Val, it also being possible for one of groups Y and Z to be absent, X is OH, OA, OR10, OSO2A or OSO2Ar, R1, R2, R3 and R8 are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, cycloalkyl having 3-7 C atoms, which is unsub-stituted or cycloalkyl which is monosubstituted or polysubstituted by A, AO and/or Hal, cyclo-alkylalkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, or bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, R1R2N also is an unsubstituted pyrrolidino, piperid-ino, morpholino or piperazino group or one which is substituted by A, OH, NH2, NHA, NA2, NHR10, NH-CO-C2H2x-O-R9, NH-CO-O-C2H2x-R9, hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N-alkyl Ane, NH-CO-NH2, NH-CO-NHA, guanidinyl or guanidinylalkyl, R4 is OH or NH2, R5 and R6 are each A, alkenyl or alkynyl each having up to 8 C atoms, or Ar-alkyl, R7 is H or A, -CR5R6- also is 1,1-cycloalkylidene having 2-6 C atoms, R9 is H, A, Ar or Ar-alkyl, R10 is A-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH-CO-, m and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, n is 0 or 1, Ar is unsubstituted phenyl or phenyl which is monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA, NA2, NHR10, NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N-alkyl Ane and/or guanidinylalkyl or unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, O and/or S
atoms, which can be fused to a benzene ring and/or monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NA2, NHR10, NH-COOA, NHCOOAr, NNCOOCH2Ar, NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl, A2N-alkyl and/or A3N?-alkyl An? and/or whose N and/or S
heteroatoms can also be oxidised, Hal is F, Cl, Br or I, An? is an anion, which can also be absent, if instead of this a carboxyl group contained in the compound of the formula I is present 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 in addition instead of one or more -NH-CO-groups there can also be one or more -NA-CO- groups, and their salts.

2. a) (4S,5S)-5-(4-BOC-aminopiperidinocarbonyl-Phe-Nva-amino)-6-cyclohexyl-2-methylhexane-2,4-diol;
b) (4S,5S)-5-(4-aminopiperidinocarbonyl-Phe-Nva-amino)-6-cyclohexyl-2-methylhexane-2,4-diol;
c) (4S,5S)-5-(4-BOC-aminopiperidinocarbonyl-Phe-Nle-amino)-6-cyclohexyl-2-methylhexane-2,4-diol;
d) (4S,5S)-5-(4-aminopiperidinocarbonyl-Phe-Nla-amino)-6-cyclohexyl-2-methylhexane-2,4-diol.

3. Process for the preparation of an acid amide of the formula I according to Claim 1 and of its salts, characterised in that it is set free from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent or in that a carboxylic acid of the formula II
R1R2N-CmH2m-CO-G1-OH II
in which G1 (a) is absent, (b) is -Z-, (c) is -Z-Y-or one of its reactive derivatives is reacted with a compound of the formula III
H-G2-NH-CHR3-CHR4-(CH2)n-CR5R6-X III

in which G2 (a) is -Z-Y-, (b) is -Y-, (c) is absent, and in that a functionally modified amino and/or hydroxy group is optionally set free in a compound of the formula I by treating with solvolysing or hydrogenolysing agents and/or a free amino group is acylated by treating with an acylating agent and/or a compound of the formula I is converted into one of its salts by treating with an acid.

4. Process for the production of pharmaceutical preparations, characterised in that a compound of the formula I and/or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or auxiliary.

5. Pharmaceutical preparation, characterised in that it contains at least one compound of the formula I and/or one of its physiologically acceptable salts.

6. Use of compounds of the formula I or of their physiologically acceptable salts for the production of a medicament.

7. Use of compounds of the formula I or of their physiologically acceptable salts in the control of renin-dependent hypertension or hyperaldosteronism.