AU618340B2

AU618340B2 - Amino acid derivatives

Info

Publication number: AU618340B2
Application number: AU33292/89A
Authority: AU
Inventors: Klaus-Otto Dr. Minck; Peter Dr. Raddatz; Claus J. Dr. Schmitges
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1988-04-28
Filing date: 1989-04-21
Publication date: 1991-12-19
Anticipated expiration: 2009-04-21
Also published as: EP0339483A3; ZA893199B; EP0339483A2; AU3329289A; KR890016063A; DE3814325A1; JPH0211548A; HUT53663A; HU208427B

Description

iLI-r-- i l Our Ref: 261688

AUSTRALIA

Patents Act 618 54F COMPLETE SPECIFICATION

(ORIGINAL)

Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: o Related Art: o A ca Applicant(s): o 0 0 Merck Patent Gesellschaft Mit Beschrankter Haftung Frankfurter Strasse 250 D-6100 DARMSTADT FEDERAL REPUBLIC OF GERMANY ARTHUR S. CAVE CO.

Patent Trade Mark Attori 2rys Level 10, 10 Barrack Stree, SYDNEY NSW 2000 Address for Service: Actual Inventors Dr. Peter Raddatz Dr. Claus J. Schmitges Dr. Klaus-Otto Minck 0 Complete specification for the invention entitled "Amino acid derivatives".

The following statement is a full description of this invention, including the best method of performing it known to me:- S0.69 63 21 /04/89 069163 21 04/89 1 5020 i la Amino acid derivatives The invention relates to new amino acid derivatives of the formula I R -Z-NR7- CHR 3_CR -_CR 2-CR 5R 6_y in which 64 I 6 6 46 6444 46 4 6 4 #4 44 4* 6 4 1 46 41 I 4 4 4(4* 66 .1 4* 1' 1 U It is H, R-O-C.H~mCOi, R 7 -C.H,-0-COD-, R-C.mCD 1

R

7 -S0 2

R

8 R'N-CmH 2

CO-

R'

0 -NH-C =NH) -N-m~_O R'OCC.~-C- R D 3 S-CmCD or 11-C, YCHa-L (R 7

-CPH~

Cr:H 2 rCD_ I is 1 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, pAla, Arg, Asn, Asp, Bia, Cal, Dab, Gln, Glu, Gly, His, N(im)-A-His, Hph, Ile, Leu, tert.-Leu, Lys, Mal, Met, aNal, PNal, Nbg, Nie, Din, Phe, Pia, Pro, Pyr, Ser, Thin, Tia, Tic, Trp, Tyr and Val, 2 5 8 8 R R, R R,

R

3

R

7

R

1

,R

is -CN, -CH 2 -NR 1251, -CH 2 -NR 1 2

-SD

2 R1 4

-CH

2

-NR'

2

-&OR'

4

-CH

2 -NR 12 -CO-NH-R 1 4 or 12 14

-CH

2 -NR -CS-NH-R R 9 and R 1 3 are each H or A, and R' 4 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, 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, -2 R" is also R 8

R

8 R'00C- or A 3 ND An R 4 is OH) NH 2 or =0, R 10 is H, A or CN, L is CH or N, T is 0, NH or NA, V is CHOH, CO, S, SO or SO., R 8 R 9 N and NR1 2 R 1 3 are also each a pyr:olidino, piperidino, morpholino or piperazino group which is unsubstituted or is substituted by A, OH,

NH

2 NHA, NA 2 NHAc, NHi-CO-CH 2 1 5

NH-

CO-O-Cfl 2

IR

1 hydroxyalkyl, COOH, COQA,

CONH

2 aminoalkyl, HAN-alkyl, A 2 N-alkyl,

A

3 alkyl An", NH-CO-NH 23NH-C 0-NHA, guanidinyt or guanidinyl-aikyl, R' is A or Ar-alkyl, s and y are each 0 or 1, 0~0 m, n, p, r and xare each 0, 1,2, 3,4, 5,6, 7, 8,9 or 000w 9 0 *Ar is phenyl which is unsubstituted or is 0 0: substituted one or more times by A, OA, Hal, CF 3 OH, NO 2 hydroxyalkyl, NH 2

NHA,

0 8 NA., NHAc, SA, SO-A, S0 2 S0 2

NH

2

SO

2

NHA,

COOH, CODA, CONH 2 CN, aiinoalkyl, HAN- Ij o...alkyl, A N-alkylAN alkyl Ano and/or S 0 25 guanidinyl-alkyl, or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6- 4 4 membered heterocyclic radical which has 1- 4 N, 0 and/or S atoms and can be fused with a benzene ring and/or be substituted 0 one or more times by A, OA, Hal, CF 3 1 OH, I 0NO 2 carbonyl oxygen, NH 2 NHA, NA 2

NHA,

SA, SO-A, S0 2

SO

2

NH

2

SO

2 NHA, COOH, COOA,

CONH

2 CN, NH-S0 2 Ar, Ar-alkyl, Aralkenyl, hydroxyalkyl, aminoalkyl, HANalkyl and/or A 2 N-alkyl, and/or whose N and/or S hetero atoms can also be oxidized, Hal is F, Cl, Br or I, 3 -3 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-COgroups, as well as the salts thereof.

Similar compounds 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 salts thereof have very valuable 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). The noteworthy point is that these compounds are very specific inhibitors of renin; as a rule, the concentrations of these compounds necessary for t 25 the inhibition of other aspartyl proteinases (for example pepsin and cathepsin D) are about 100 to 1000 times as high as for renin inhibition. The actions of the compounds on the blood pressure and/or on the heart rate, as well as the inhibition of renin activity in blood plasma can furthermore be determined in conscious monkeys, for example female monkeys (Macaca fascicularis); it is S. possible in this for the blood pressure and heart rate to be measured by a modification of the method of M.J. Wood et al., J. Hypertension 4, 251-254 (1985). In order to stimulate renin activity in this, the animals are preferably 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 i 1 i 1 4 active substances in human and veterinary medicine, in particular for the prophylaxis and for the treatment of diseases of the heart, circulation and vessels, especially of hypertension, cardiac insufficiency and hyperaldosteronism. In addition, the compounds can be used for diagnostic purposes in order to determine, in patients with hypertension or hyperaldosteronism, the possible contribution of the renin activity to maintaining the pathological state. The procedure for such diagnostic tests can be similar to that indicated in EP-A 77,028.

The abbreviations quoted hereinbefore and hereinafter for amino acid residues represent the radicals 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-(l-adamantyl)-alanine 0oo. Ala alanine S pAla p-alanine 0o 0 0 20 Arg arginine 00 00 0 0 Asn asparagine o Asp aspartic acid Bia 3-(2-benzimidazolyl)-alanine Cal 3-cyclohexylalanine 025 Dab 2,4-diaminobutyric acid S0° Gin 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 o"0. Hph homophenylalanine (2-amino-4-phenylbutyric acid) Ile isoleucine Leu leucine tert.-Leu tert.-leucine Lys lysine Mal 3-(p-methoxyphenyl)-alanine Met methionine aNal P Na 1 Nbg Nie N-Me-His N-Me-Phe Orn Phe Pia Pro Pya Ser Thr Tia *9 a a a a *1 *0*1 4 I 4* a *4 a 4 a *420 *4 *4 9 a p 4* 4* a as. a aa 25 aa Tic Trp Tyr Val1

BOC

BOM

imi- BOM 3- (a-naphthyi) -alanine 3- (B-naphthyl) -alanine 2 -norbornyl -glycime norleucine N-methyl-histidine N-methyl-phenylalanine ornithine phenylalanine 3-(piperidyl)-alanine 2-Pia =-2 piperidyl) -alanine] praline 3-(pyridyl)-alanine 3-Pya -3 pyridyl) -alaninel serine threonine 3-(thienyl)-alanine 2-Tia -2 thienyl )-alanine] 1, 2 ,3 ,4-tetrahydroisoquinoline-1-carboxylic acid tryptophan tyrosine valine.

Further meanings hereinafter are: tert. -butoxycarbonyl benzyloxyinethyl benzyloxymethyl in the 1 position of the imidazole ring benzyloxyc arbonyl dicyc lohexylcarbodiimide dimethyl formainide 2, 4-dinitrophenyl 2,4-dinitrophenyl in the 1. position of the imidazole ring ethoxycarbonyl 9 -fluorenylmethoxycarbonyl 1 -hydroxybenzotriazole isopropoxyVcarbonyl phenoxyacetyl tetrahydrofuran.

4414 144444 4 44 4 o a O 41 CB Z

DCCI

DMF

DNP

imi -DNP

ETOC

FMOC

HOBt

IPOC

POA

THF

-6- If the abovementioned amino acids can occur in several enantiomeric forms, then all these forms, as well mixtures 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 an amino acid derivative of the formula I, and of the salts thereof, characterized in that it is liberated from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, or in that a carboxylic acid of the formula II RI-Gi-OH II oo in which G 1 is absent, 000

Z,

0 o0

Z

1 96 20 or one of reactive derivatives thereof, o o is reacted with an amino compound of the formula III o 2 2 3 4 56 H-G -NR -CHR -CR -CH -CR R -Y III 2 I 0.0 in which G 2 is Z, *o 0 absent, 25 Z 2 and Z Z 2 are together Z, and in that a functionally modified amino and/or hydroxyl go roup in a compound of the formula I is liberated where 0 0 appropriate by treatment with solvolyzing or hydrogeno- 30 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 OH) or NHz), an amino keto acid derivative of the formula I, R 4 0, is reduced or reductively aminated, and/or a radical R is changed to another radical R and/or a compound of the formula I is converted by treatment with i; 1 -7an acid into one of the salts thereof.

Hereinbefore and hereinafter the radicals and paamtes 1 to R 5 Z, Y, L, TV, m. n.p,r, s, x. y, Ar, H-et, Hal, Ac, An, A, CG', Z' and Z' have the meanings indicated for the formulae I, II or III unless expressly indicated otherwise.

A in the abovementioned formulae has 1-8, prefer- 'Iably 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, 2- or 3-methylbutyl, 1,2- or 2,2-dimethyipropyl, 1ethylpropyl, hexyl, 3- or 4-methylpentyl, 1,1-, 2,3- or 3,3-diinethvlbutyl, 1- or 2ethylbutyl, 1-ethyl- 1-methyipropyl, 1-ethyl- 2-methylpropyl, 1,1,2- or l,2,2-trimethylpropyl, heptyl or octyl.

Cycloalkyl is preferably cyclopropyl, cyciobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but is also, for example, 2- or 3-methyicyclopenryi, or 3- or 4-methylcyclohexyl.

o 20 Correspondingly, cycloalkylalkyl is preferably cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2 -cyc lobutyl ethyl, cyclopenrylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, but is also, for example 2- or 3-methylcyclopentylmethyl, or 2-, 25 3- or 4-methylcyclohexylmethyl.

4 4. Bicycloalkyl is preferably 1- or 2-decalyl, 2-bicyclo[2.2.l]heptyl or 6,6-dimethyl-2-bicyclo[3,l,l]hept- I~L yl.

Tricycloalkyl is preferably 1-adarnantyl.

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

4 1 Ac is preferably A-CO-, such as acetyl, propionyl or butyiyl, Ar-CD- such as benzoyl, m- or p-methoxybenzoyl or 3,4-dimethoxybenzoyl, or A-NH-GO- such as Nmethyl- or N-ethylcarbamoyl.

Ar is preferably phenyl and is furthermore preferably m- or p-tolyl, m- or p-ethylphenyl, m- or p-methoxyphenyl, m- or p-f luorophenyl, o-, m- or p-chlorophenyl, m- or p-bromophenyl, m- or p-iodophenyl, m- or p-trifluoromethylphenyl, m- 8- O 04 0 04 04*440 0 0 00 00 00 j 00 00 00 00 or p-hydroxyphenyl, m- or p-sulfainoylphenyl, 2,3-, 2,59-, 3,4- or 3,5-dimethoxyphenyl, 3,4,5trimethoxyphenyl, mn- or p-aminophenyl, mn- or paminomethyiphenyl, m- or p-dirnethylamiinomethylphenyl, m- or p-guanidinomethylphenyl, or 1- or 2-naphthyl.

Correspondingly, Ar-alkyl is preferably benzyl, 1- or 2-phenylethyl, mn- or p-methylbenzyl, 1- or 2- -in- or -p-tolylethyl, in- or p-ethylbenzyl, 1- or -mn- or -p-ethylphenylethyl, in- or p-methoxybenzyl, 1- or -in- or -p-methoxyphenylethyl, in- or p-f luorobenzyl, 1- or -mn- or -p-f luorophenylethyl, in- or p-chlorobenzyl, 1- or -mn- or -p-chlorophenylethyl, mn- or p-broinobenzyl, 1- or -in- or *-p-broiophenylethyl, mn- or p-iodobenzyl, 1- or 2-o-, -in- or -p-iodophenylethyl, mn- or p-trifluoroinethylbenzyl, mn- or p-hydroxybenzyl, 2,6- 3,4- or 3,5-diinethoxybenzyl, 3,4,5-triinethoxybenzyl, o-, mn- or p-aminobenzyl, mn- or p-aminomethylbenzyl, o-, mn- or p-dimethylaninoinethylbenzyl, mn- or p-quanidinoinethylbenzyl, or 1- o:c 2-naphthylinethyl.

Het is preferably 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 4- or 5-ixnidazolyl, l-, 4- or 5-pyrazolyl, 4- or 5-oxazolyl, 4- or isoxazolyl, 4- or 5-thiazolyl, 4- or 5-isothIA.c-7zo ~25 lyl, 3- or 4-pyridyl, 5- or 6-pyriinidinyl, furtheri 44 cre preferably l,2,3-triazol-l-, or l,2,4-triazol-l-, or -5-yl, 1- or l,2,3-oxadiazol-4- or -5-yl, l,2,4-oxadiazol-3- or 1,3,4-thiadiazol-2- or -5-yl, l,2,4-thiadiazol-3- or yl, 2,l,5-thiadiazol-3- or -4-yl, 5- or 6-211thiopyranyl, 3- or 4-411-thiopyranyl, 3- or 4-pyrid- 4 azinyl, pyrazinyl 6- or 7-benzofuryl, 6- or 7-benzothienyl, 4-, 6- or 7-indolyl, 6- or 7isoindolyl, 4- or 5-benziinidazolyl, 4-, 6- or 7-benzopyrazolyl, 6- or 7benzoxazolyl, 6- or 7-benzisoxazolyl, 2-, 6- or 7- benzothiazolyl, 6- or 7benzisothiazolyl, 6- or 7-benz-2,1,3-oxadiazolyl, 000 0 00 -9- 7- or 8-quinolyl, 7- or 8-isoquinolyl, 4- or 9-carbazolyl, 8- or 9-acridinyl, 4-, 7- or 8-cinnolyl, 7- or 8quinazolyl. The heterocyclic radicals can also be partially or completely hydrogenated. Thus, Het can also be, for example, 2,3-dihydro-2-, or 2,5-dihydro-2-, or -5-furyl, tetrahydro-2- or 3-furyl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-l-, or -5-pyrrolyl, 2,5-dihydro-l-, or -5-pyrrolyl, 2- or 3-pyrrolidinyl, tetrahydroor -4-imidazolyl, 2,3-dihydro-l-, -4or -5-pyrazolyl, tetrahydro-l-, or -4-pyrazolyl, 1,4dihydro-l-, or -4-pyridyl, 1,2,3,4-tetrahydroor -6-pyridyl, 1,2,3,6tetrahydro-l-, or -6-pyridyl, 1-, 3- or 4-piperidinyl, 3- or 4-morpoholinyl, tetrahydro-2-, or -4-pyranyl, 1,4-dioxanyl, 1,3- 4 9 1dioxan-2-, or -5-yl, hexahydro-l-, or -4-pyridaz- 9 1220 inyl, hexahydro-l-, or -5-pyrimidinyl, 2- or 5 3-piperazinyl, l,2,3,4-tetrahydro-l-, t or -8-quinolyl, l,2,3,4-tetrahydro-l-, or -8-isoquinolyl.

The heterocyclic radicals can also be substituted 4 25 as indicated. Het can also preferably be, for example, 2amino-4-thiazolyl, 4-carboxy-2-thiazoly.±, 4-carbamoyl-2thiazolyl, 4-(2-aminoethyl)-2-thiazolyl, 4-amino-2- 2-amino-5, 6-dimethyl-3-pyrazinyl, 4-carbainoylpiperidino, furthermore, for example, 4or 5-methyl-2-furyl, 4- or 5-rethyl-3-furyl, 2,4dimethyl-3-furyl, 5-nitro-2-furyl, 5-styryl-2-furyl, 3-, t 4 44- or 5-methyl-2-thienyl, 4- or 5-methyl-3-thienyl, -butyl-2-thienyl, 5-chloro-2-thienyl, phenyl-2- or -3-thienyl, 4- or 5-methyl-2-pyrrolyl, l-methyl-4- or -5-nitro-pyrrolyl, 3,5-dimethyl-4ethyl-2-pyrrolyl, 4-methyl-5-pyrazolyl, 5-methyl-3isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 4- or 5-methyl-2thiazolyl, 2- or 5-methyl-4-thiazolyl, 2- or thiazolyl, 2,4-dimethyl-5-thiazolyl, 5- or 6-methyl-2-pyridyl, 5- or 6-methyl.-3-pyridyl, 2or 3-methyl-4-pyridyl, 5- or 6-chloro-2-pyridyl, 5- or 6-chloro-3-pyridyl, 2- or 3-chloro-4pyridyl, 2, 6 -dichloropyr idyl, 2-hydroxy-3-, or -6-pyridyl 1H-2-pyridon-3-, or 4 phenyl- 1H-2-py-ridon-3-yl, 5-p-methoxyphenyl-1H-2-pyridon- 3-yl, 2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl, 2hydroxy-4 -amino- 6-methyl- 3-pyridyl, 3-N '-methylureido-1H- 4-methyl-2-pyrimidinyl, 4, 6-dimethyl-2pyrimidinyl, 5- or 6-methyl-4-pyrimidinyl, 2,6dimethyl-4-pyrimidinyl, 2 ,6-dihydroxy-4-pyrimidinyl, chloro-2-methyl-4-pyrimidinyl, 3-methyl-2-benzofuryl, 2ethyl-3-benzofuryl, 7-methyl-2-benzothienyl, 4-, 6- or 7-methyl-3-indolyl, 1-methyl-5- or -6-benzimidazolyl, 1-ethyl-5- or -6-benzimidazolyl, 4-, 7- or 8-hydroxy-2-quinolyl, 2-oxo-pyrrolidino, 2- I oxo-piperidino, 2,5-dioxopyrrolidino or 3-benzyl-2,5op dioxopyrrolidino.

R R is, in general, preferably R 8

R

9 N-CmHCO- or RlC.H2.(T)(V)CH,,nL(R-CHP)-CrHlr-COi preferably

R

7 -C.H2,.CO- or R'OOC-C.H,-CO-.

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. Z is preferably His or Phe-His, furthermore preferably Cal-His, Mal- His, aNal-His, fiNal-His, Phe-Abu, Phe-Ala, Phe-PAla, Phe- Asn, Phe-Gin, Phe-Glu, Phe-Gly, Phe-Nle, Phe-Pyr (especially Phe-3-Pyr), Phe-Tia (especially Phe-3-Tia), Tia-His (especially 3-Tia-His), Trp-His, Tyr-His, Pro- Phe-His or Pro-Phe-N-Me-His.

Y is, in general, preferably -CN or -CH 2

NR

12 o a S0 2

R

1 4 furthermore preferably -CH 2 -NR 2

C-NHR

4 o -CH,-NR 2

CS-NHR

4 R2, R5, R R9 and R13 are each pref erably H and furthermore pre~ferably methyl; R 5 is also preferably isopropyl or isobutyl. R 8

R

9 N is also preferably pyrrolidino, piperidino, morpholino, amino-piperidino such as 4aminopiperidino, alkylaminopiperidino such as 4-methylaminopiperidino, or dialkylaminopiperidino such as 4-dimethylaminopiperidino.1 1, aNal, pNal, Nbg, Nle, Orn, Phe, Pia, Pro, Pyr, Ser, Thr, Tia, Tic, Trp, Tyr and Val, is ,12 14 12 Y 14CN, -CH 2-NR 1-SO R -CH -NR2-CO-NH 20 12 2 14 2 or -CH 2-NR -CS-NH-R I a, 11

R

3 is preferably cycloalkylalkyl, especially cyclohexylmethyl, furthermore preferably alkyl, especially isobutyl; Ar-alkyl, especially benzyl; cycloalkyl, especially cyclohexyl.

R is preferably OH).

R

7 is preferably A, especially methyl, ethyl, isopropyl or tert.-butyl; or Ar, especially phenyl, 1- or 2-naphthyl.

R1 0 is preferably H, methyl or CN.

R

1 is preferably H; A, especially methyl or tert.-butyl; R 8

R

9 N, especially A 2 N such as (CH,) 2 N, piperidino or 4-aminopiperidino.

4 R12 and R 1 3 are preferably H or A, especially methyl.

R

4 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.

L is preferably CH, furthermore preferably N.

T is preferably O or NH.

V is preferably CO or SO2.

The parameter s is 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 1; r is preferably 1 or 0. The groups CH m' n' C H2p and m m 2 m"n2n' p 2p 30 C H2n'(c)~or-C1.1 30 r 2r are preferaly straight-chain and thus are preferably -(CH2 m, -(CH or -(CH) 4 4 2 n 2 p 2 r *Accordingly, t- group R is specifically and preferably R 8

R

9

N-(CH

2 especially HN-CH-CO- such as aminocarbonyl, aminoacetyl 3-aminopropionyl (H-pAla-), 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl, 11-aminoundecanoyl, but also, for example, 2-amino-propionyl (Ala), 2-amino-2-methyl-

K

CLL,f A 2 N-ajJkYl A 3 111 alkyl An' and/or guanidinyl..alkyl, or is uflsubstituted nap hthyl, is a saturated or unsaturated 5- or 6- He t /3 t~i' 12- 9, ~s 94 *49 4 t 94 a 4 I 41 .9 a I

I,

propionyl; ANH-C.H2.-CO_ such as methylaminocarbonyl, methylaminoacetyl (sarcosyl), 3-methylaminopropionyl, 4methylaminobutyryl, 5-methylaminopentanoyl, 6-methylaminohexanoyl, 6-ethylaminohexaloyl, 7-methylaminoheptanoyl, 8-methylaminooctaloyl, 9-methylaminononaloyl, aminodecanoyl, li-methylaminoundecanoyl; A 2 N-C~Hm-COsuch as dimethylamilocarbolyl, dimethylaminoacetyl, 3-dimethylaminopropioflyl, 4-dimethylaininobutyryl, aminopentanoyl, 6-dimethylaminohexanoyl, 6-diethylaminohexanoyl, 7-dimethylamiloheptaloyl, 8-dimethylamiiooctanoyl, 9-dimethylamir~onotianoy10 l-dinethylaminodecancyl, 11-dimethylaminoundecanoyl; A--ON-C~-O such as BOC-Gly, ETOC-Gly-, IPOC-Gly, BOC-fiAla, ETOC-#Ala, IPOC-fiAla, 4-BOC-amino-butyryl, 5-BOC-amino-pentanoyl, 6- BOC-ainino-hexanoyl, 7 -BOC- amino -heptanoyl, 8-BOC-aminooctanoyl, 9-BOC-amino-nonanoyl, 11-BOC-amino-undecanoyl; ArCH 2 -O-CO-NH-CmH~m-CQ- such as CBZ-Gly-, CBZ-p8Ala, 4-CBZ-amino-butyry'L, hexanoyl, 7-CBZ-axnino-heptanoyl, 8-CBZ-amino-octaniyl, 9- 20 CBZ-ainino-nonanoyl, 10-CBZ-amino-decanoyl, 11-CBZ-aminoundecanoyl; pyrrolidino-CmH2,,-CO- such as pyrrolidinocarbonyl, pyrrolidino-acetyl, 3-pyrrolidino-propionyl, 4pyrrolidino-butyryl, 5-pyrrolidino-pentanoyl, 6pyrrolidino-hexanoyl, 4-pyrrolidino-heptanoyl, 8- 25 pyrro'Lidino-octanoyl, 9-pyrrolidino-nonanoyl, pyrrolidino-decanoyl; piperidino-CmH2,-CO- such as piperidinocarbonyl, piperidinoacetyl, 3-piperidino-propioflyl, 4-piperidino-butyryl, 5-piperidino-pentanoyl, 6-piperidino-hexanoyl, 7-piperidino-heitcdnoy1, 8-piperidinooctanoyl, 9-piperidino-nonanoyl, lo-piperidino-decanoyl; morpholino-c 1 ,Hz,-co such as morpholinocarbonyl, morpholinoacetyl, 3-morpholino-propionyl, 4-morpholinobutyryl, 5-morpholino-pentanoyl, 6-morpholino-hexanoyl, 7-morpholino-heptanoyl, 8-morpholino-octanoyl, 9-marpholino-nonanoyl, lO-morpholino-decanoyl; 4-amino-piperidinlo-CmH2,,CO- such as 4 -amino -piperidino -c arbonyl,~ 4amino-piperidino-acetyl, 3- (4 -amino-piperidilo) -propionylF 4- (4-amino-piperidino) -butyryl, 5- (4-amino-piperidio) -pentanoyl, 6- (4-amino-piperidino) -hexanoyl, *941 9 1 a 9.9 I 9 -1 I I 4. 4.1 11,11hili- 13 4 4 4 4 4 0) 4 44 4 0 0 44 04 40 o o 4 4 44 o 4 7 4 -amino -piperidino) -heptanoyl 8- (4-ainino-piperidino) octanoyl, 9 4 -amino -piper idino) -nonanoyl, 4-aminopiperidino) -dec anoyl; 4 -di alkylmino- piperid ino-CH2-COsuch as 4-dixethylamino-piperidinocarbonyl, 4-dimethylamino -piperidino -ac etyl; 4-guanidino-piperidino-C.H,.-COsuch as 4-guanidino-piperidino-carbonyl, 4-guanidinopiperidino-acetyl; 4-abx-ieidn-.2,-O such as 4-carboxy-piperidino-carbonyl, 4-c arboxy-piperidinoacetyl; 4-alkoxycarbonvl-viperidino-CH2-CO- such as 4methoxycarbonyl-piperidino-carbonvl, 4-ethoxycarbonylpipoeridino-carbonyl, 4-methoxycarbonyl-piperidino-acetyl, 4-ethoxycarbonyl-piperidino-acetyl; 4-AcNH-piperidinosuch as 4-acetamido-piperidino-carbonyl, 4acetaanido-piperidino-acetyl; H 2 N-C=NHi) -NHi-CH~m-CO- such as guanidinoacetyl, 3 -guanidino -prop ionyl, 4-guanidinobutyryl, 5-guanidino-pentanoyl, 6-guanidino-hexanoyl, 7guanidino-heptanoyl, 8-guanidino-octanoyi; NC-NH-C NH-CmHz,-CO- such as N'-cyanoguanidino-acetyl, cyanoguanidino) -propionyl, 4- -cyanoguanidino) -butyryl, 20 5- -cyanoguanidino) -pentanoyl, -cyanoguanidino) hexanoyl, 7- -cyanoguanidino) -heptanoyl, -cyanoguanidino)-octanoyl; HOOC-C 1 0 ,H2-CO- such as malonyl, succinyl, glutaryl, adipyl, 6-carboxyhexanoyl, 7-carboxyheptanoyl, 8-carboxyoctanoyl, 9-carboxynonanoyl, 25 carboxy-decanoyl, 11-carboxyundecanoyl; AOOC-CmH2 -COsuch as methoxycarbonylt-acetyl, 3-methoxycarbonyl-propionyl, 4-methoxycarbonyl-butyryl, pentanoyl, 6-methoxycarbonyl-hexanoyl, 7-methoxycarbonylheptanoyl, 8-methoxycarbonyl-octanoyl, 9-methoxycarbonylnonanoyl, 1O-methoxycarbonyl-decanoyl, ethoxycarbonylacetyl, 3-ethoxycarbonyl-propionyl, 4-ethoxycarbonylbutyryl, 5-ethoxycarbonyl-pentanoyl, 6-ethoxycarbonylhexanoyl, 7-ethoxycarbonyl-heptanoyl, 8-ethoxycarbonyloctanoyl, 9-ethoxycarbonyl-nonanoyl, 1O-ethoxycarbonyldecanoyl; H-SO 3 -CH,-CO- such as sulfo-acetyl, 3-su.'.fopropionyl, '4-sulfo-butyryl, 5-sulfo-pentanoyl, 6-sulfohexanoyl, 7-sulfo-heptanoyl, 8-sulfo-'octanoyl, 9-sulfononanoyl, 10-sulfo-decanoyl; such as methoxysulfonyl-acetyl, 3-methoxysulfonyl-propionyl,

I

o 0 0 o.~ 4 .4 ~4 4*40 ~4 4 4 4 4.4 21. /O4/~*9 5020 -14 4-methoxysulfonyl-butyryl, 5-methoxysulfonyl-pentanoy1, 6-methoxysulfonyl-hexanoyl, 7-methoxysulfonyl-heptanoyl, 8-methoxysulfonyl-octanoyl, 9-methoxysulfonyl-nonanoyl, lO-methoxysulfonyl-decanoyl, ethoxysulfonyl-acetyl, 3ethoxysulfonyl-propionyl, 4-ethoxysulfonyl-butyryl, ethoxysulfonyl-pentanoyl, 6-ethoxysulfonyl-hexanoyl, 7ethoxysulfonyl-heptanoyl, 8-ethoxysulfonyl-octanoyl, 9-* ethoxysulfonyl-nonanoyl, 1O-ethoxysulfonyl-decanoyl;

R'

1 'CmH2.mCO)CH2znCH(R 7

-CPH

2 )-Cr:H 2 -CO- especially A-CO-CH.-CH(Ar-CH 2 -Ca- such as 2-benzyl-4-oxo-5, methyihexanoyl, 1-naphthy'l.Methyl) -4-oxo-5,5-dimethylhexanoyl; furthermore R8R 9

N-CO-CH

2 -CH(Ar-CH 2 such as 2-benzyl-3-( 4-aminopiperidinocarbonyl) -propionyl, naphthylmethyl) (4-axinopiperidinocarbonyl) -propionyl;

R

1 1 CmH,-SO, 2 CrH,.CH R 7 CPH2p)-CH 2 especially A-S0 2 -CH.-CH(Ar-CH 2 -CO such as 2-benzyl-3-tert.-butylsulfonyipropionyl, 2-(l-naphthylmethyl)-3-tert.-butylsulfonyiprop ionyl; R"CH-HC-,H C(R R 7 -C H 2 p) _CrHi 2

CO'I

especially RaR 9 N- (CH 2 m-NH-CO-CH 2 -CH(Ar-CH 2 such as 2benzyl-3- (N-3-dimethyaninopropyl-carbanoyl) -propionyl, 2-(l-naphthylnethyl)-3-(N-3--diiethylaminopropyl-carbamoyl)-propionyl, 2-benzyl-3- carbamoyl) -propionyl; A-CH(R 7 _C Pi 2 P) _CrH 2 rCO_ I especially It A-CH(Ar-CH 2 such as 2-benzylhexanoyl, 2-benzyl- 4 t125 heptanoyl; R1-H,-HC- especially R 8

R

9

N-(CH

2 1

-NH-CO-

such as N-3-dixnethylaininopropyl-carbanoyl, aminopentyl-cc-rbamoyl; R" -CmH 2 m.-N (R R 7

_CH

2 P) -CzCespecially A-N(Ar-C- 2 such as N-benzyl-N-butylcarbamoyl, N-benzyl-N-isopentyl-carbamoyl; R _j2"__o 4430 especially A-O-CO- such as ETOC, IPOC, BOC as well as Ar-CmH2.-O-CO- such as CBZ; R 7 _C.nHCo_ such as 3,3-di- 4 methylbutyryl.

Accordingly, the group Y is specifically and preferably -CN; -CH 2

NH-SO

2

R'

4 especially -CH 2 -NH-s0 2 -A such as methane-, ethane-, propane-, 2-methylpropane- and butane-sulfonamidomethyl, furthermore, for example, phenylmethane- and cyclohexylmethane-sulfonamidomethyl;

-CHZ-NH-CO-NH-R'

4 especially -CH 2 -NH-CO-NH-A such as methylureidomethyl, N'-propylureidomethyl, N'-butyli i YIIIYI--~- 15 ureidomethyl, N'-isopentylureidomethyl, furthermore

-CH

2 -NH-CO-NH-Ar such as N'-phenylureidomethyl and N'-paminophenylureidomethyl; -CH 2 -NH-CS-NH-R 14, especially -CH -NH-CS-NH-A such as N'-methyithioureidomethyl;

-CH

2

-NH-COR

1 4 especially -CH 2 -NH-CO-A such as acetamidomethyl, propionamidomethyl and butyramidomethyl.

The compounds of the formula I may have one or more chiral centres and therefore exist in various, optically active or optically inactive, forms. The formula I embraces all these forms. If R 3 is different from H, and/or R is OH) or the 3S-hydroxy, 3S-amino, 4S-amino, 3S-hydroxy-4S-amino and 3S,4S-diamino enantiomers are preferred (where the C atom which carries the radical R 4 is assigned to the 3 position and that which carries the radicals R 1

-Z-NR

2 and R is assigned to i P the 4 position).

The abovementioned cycloalkyl and phenyl groups 4Era are preferably unsubstituted or carry preferably 1 to 3, especially 1 or 2, substituents.

T 20 Accordingly, the invention particularly relates to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated hereinbefore. Some preferred groups of compounds can be represented by the following part-formulae Ia to Ik: 7 3 5 Ia R -C H -O-CO-Z-NH-CHR -CHOH-CH -CHR -Y; m 2m 2 3 1b R -C H -CO-Z-NH-CHR -CHOH-CH -CHR -Y; m 2m 2 89 35 Ic R R N-C H 2m-CO-Z-NI-CHR -CHOHH,- CHR -Y; m 2m 2 Id R 10 -NH-C(=NH)-NH-C H 2 m-CO-Z-NH-CHR -CHOH-CH R 5

-Y;

Ie R OOC-C H -CO-Z-NH-CHR3 -CHOH-CH CR -Y; M 2m 2 8 3 5 If R 0 S-C H -CO-Z-NHCHR -CHOH-CH -CHR -Y; 3 3Y CHR -CHOH-CH 2 -CHR -Y; 1 ~ni *u IL: 16 Ih 4-Aminopiperidinocarbonyl-Z-NH-CHR3-CHOH-CH2-CHR

-Y;

Ii A-CO-CH 2 -CH(ArCH 2

)-CO-Z-NH-CHR

3

-CHOH-CH

2

-CHR

5 y; Ij A-SO2-CH2-CH(ArCH 2 )-CO-Z-NH-CHR3-CHOH-CH2-CHR5-Y; Ik R R N-C H2m-NH-CO-CH 2 -CH(ArCH 2 )-CO-Z-NH-CHR -CHOH- CH -CHR -Y.

Particularly preferred are compounds of the partformulae: Iaa to Ika, which correspond to the formulae Ia to Ik but in which additionally Z is His, Mal-His or Phe-His; Iab to Ikb and Iaab to Ikab, which correspond to the formulae Ia to Ik and Iaa to Ika but in which F additionally

R

3 is isobutyl or cyclohexylmethyl; Iac to Ikc, Iaac to Ikac, Iabc to Ikbc and Iaabc to i Ikabc, which correspond to the formulae Ia to Ik, Iaa to Ika, lab to Ikb and Iaab to Ikab, but in which additionally R is isopropyl.

Especially preferred are compounds of the partformulae: 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 or -CH 2 -NH-SOz-R" and

R

14 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 -CH 2 -NH-SOz-A.

The compounds of the formula I, as well as the starting materials for the preparation thereof, are furthermore prepared by methods which are known per se and as are described in the literature (for example in determination of the plasma renin activity can be obtained by puncture of the femoral vein.

The compounds can be used as pharmaceutically JI 2 L 1d iii -17the standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), published by Georg Thieme, Stuttgart; as well as EP-A 45665, EP-A 77028, EP-A 77029, EP-A 81783, EP-A 249096), specifically under reaction conditions which are known and suitable for the said reactions. In this connection it is also possible to make use of 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 o 015 liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolye sis.

Preferred starting materials for the solvolysis or hydrogenolysis are those which correspond to the 20 formula I apart from containing, in place of one or more free amino and/or hydroxyl groups, corresponding protected amino and/or hydroxyl groups, preferably those which ,carry 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 C A 4 N(im)-R'-His group (in which R' is an amino protective group, for example BOM or DNP), or those of the formula R -Z-NR 2

-CHR

3 -CH(NHR' )-CH 2

-CRR

5

-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 R'-Z-NR 2

-CHR

3

-CHOR"-CH,-CR

5

R

5 -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 starting material. If the protective groups which are present differ from one another it is possible in many cases to eliminate them selectively.

Lys lysine Mal 3-(p-methoxyphenyl)-alanine Met methionine -18- The term "amino protective group" 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 particular, unsubstituted or substituted acyl, aryl (for example DNP), aralkoxymethyl (for example BOM) or aralkyl groups (for example benzyl, 4-nitrobenzyl, triphenylmethyl). 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, I C atoms. The term "acyl group" in connection with the 15 present process is to be interpreted in the widest sense.

i 4 It embraces acyl groups derived from aliphatic, aralipha- 4 tic, aromatic or heterocyclic carboxylic acids or sulfonic acids, as well as, in particular, alkoxycarbonyl, aryloxycarbonyl and, especially, aralkoxycarbonyl groups.

Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; K, aroyl such as benzoyl or toluyl; axyloxyalkanoyl such as POA; alkoxycarbonyl such as methoxyc.irbonyl, ETOC, 2,2,2trichloroethoxycarbonyl, IPOC, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ, 4-methoxybenzyloxycarbonyl, FMOC. Preferred amino protective groups are BOC, DNP and BOM, as well as CBZ, FMOC, benzyl and acetyl.

The term "hydroxyl protective group" is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, as well as alkyl groups. The nature and size of the hydroxyl protective groups are n.'t critical because they are removed again after the desired chemical reaction or reaction sequence; preferred groups have 1especially 1-10, C atoms. Examples of hydroxyl i iii_ j 19 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 I o acid, but also with other strong inorganic acids such as .15 hydrochloric acid or sulfuric acid, strong organic So° carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluenesulfonic acid. The 2 presence of an additional inert solvent is possible but not always necessary. Suitable and preferred inert solvents are organic, for example carboxylic acids such o as acetic acid, ethers such as tetrahydroruran or diox- S°°ane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, as well as alcohols such as methanol, ethanol or isopropanol, and water.

Furthermore suitable are mixtures of the abovementioned solvents. 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 300 (room temperature).

The BOC group can be eliminated, for example, preferably with 40% trifluoroacetic acid in dichloromethane or with about 3 to 5 N HC1 in dioxane at 15-30°, and the FMOC group with an approximately 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-300. Elimination of the DNP group is effected, for example, also with an approximately 3-10% solution of 20 2-mercaptoethanol in DMF/water at 15-300.

Protective groups which can be removed by hydrogenolysis (for example BOM, CBZ or benzyl) can be eliminated, for example by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst such as palladium, preferably on a support such as carbon). Solvents suitable for this are those mentioned above, 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, preferably at 20-300 and under 1-10 bar. Hydrogenolysis of the 1; CBZ group is effected satisfactorily, for example, on 10% Pd-C in methanol at 20-300.

0 15 Compounds of the formula I can also be obtained by direct peptide synthesis from a carboxylic acid S component (formula II) and an amine component (formula SIII). Examples of suitable carboxylic acid components are those of the part-formulae R 1 -OH, R'-Z-OH, and of 4 1 20 amine components are those of the part-formulae H-Z-

NR

2 -CHR -CR 4

-CH

2

-CR

5 R-Y, H-NR-CHR3-CR 4

-CH

2

-CR'R

6 The Speptide linkage can, however, also be formed within the a group Z; this entails a carboxylic acid of the formula R-Z'-OH being reacted with an amino compound of the formula H-Z 2

-NR

2

-CHR

3

-CR

4

-CH

2

-CR

5

R

6 where Z I 2 Z. The methods preferably used for this are those customary in ,peptide synthesis, as are described, for example, in Houben-Weyl, Volume 15/11, pages 1-806 (1974).

The reaction is preferably effected in the presence of a dehydrating agent, for example a carbodiimide such as DCCI or dimethylaminopropylethylcarbodiimide, 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 amide such as DMF or dimethylacetamide, or a nitrile such as acetonitrile, at temperatures between about -10 and preferably between 0 and prereraDiy s A m- or p-methoxyphenyl, m- or p-fluorophenyl, q m- or p-chlorophenyl, m- or p-bromophenyl, m- or p-iodophenyl, m- or p-trifluoromethylphenyl, m- 21 It is also possible, in place of 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 R 8

-NH-CO-

or R"-CmHm-(T) 5 -(V)y-CnHz-NH-CO-] can be obtained, for example, by reacting an appropriate isocyanate (for example of the formula R7-NCO; can be prepared from an amine of the formula R -NH 2 and phosgene) with an amine of the formula H-Z-NR CHR CR'-CH2-CR -Y (IIa), preferably in an inert solvent such as THF at temperatures between S0 about -10 and 400, preferably between 10 and 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 aDovementioned methods of peptide synthesis and of elimination of protective groups.

If desired, it is possible for a functionally modified amino and/or hydroxyl group in a compound of the formula I to be liberated by solvolysis or hydrogenolysis by one of the methods described above.

which Thus, for example, a compound of the formula I .which contains an R"-C H 2 -O-CO-NH-, an AcNH-, an ArCH 2

SO

3 or an AOOC- group can be converted into the corresponding compound of the formula I which contains in A "30 its stead an H2N-, an HSO 3 or an HOOC- group, preferably by selective solvolysis by one of the methods indicated above. AOOC- groups can be hydrolyzed, for example, with NaOH or KOH in water/dioxane at temperatures between 0 and 400, preferably 10 and It is also 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 CH 2

-NH-R

1 2 group can be reacted with acylating agents of the formulae R"-SO z Cl, R 14 -COC1 benzoxazolyl, 6- or 7-benzisoxazolyl, 2-, 6- or 7- benzothiazolyl, 6- or 7benzisothiazolyl, 6- or 7-benz-2,1,3-oxadiazolyl, 22or R 4 -NCO, preferably 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 +300 Furthermore, for example, keto compounds of the formula I (R 4 0) can be reduced to compounds of the formula I (R 4 for example with a complex metal hydride such as NaBH 4 which does not simultaneously reduce the peptide carbonyl groups, in an inert solvent such as methanol at temperatures between about -10 and +300.

Keto compounds of the formula I (R 4 can also be converted into compounds of the formula I (R 4 H, NH 2 by reductive amination. The reductive amination can be Scarried out in one or more stages. Thus, for example, the o keto compound can be treated with ammonium salts, for example ammonium acetate and NaCNBH 3 preferably in an Sinert solvent, for example an alcohol such as methanol, 3 at temperatures between about 0 and 500, in particular between 15 and 30 0 It is furthermore possible initially to convert the keto compound into the oxime, using hydroxylamine in a customary manner, and to reduce the oxime to the amine, for example by catalytic hydrogenation on Raney nickel.

j r bA base of the formula I can be converted into the Srelevant acid addition salt using an acid. Particularly suitable acids for this reaction are those which provide physiologically acceptable salts, thus it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric 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, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric 1 acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, ao benzenesulfonic acid, p-toluenesulfonic acid, naphthaethyl-2-pyrrolyl, 4-methyl-5-pyrazolyl, 5-methyl-3isoxazolyl, 3 ,4-dimethyl-5-isoxazolyl, 4- or 5-methyl-2thiazolyl, 2- or 5-methyl-4-thiazolyl, 2- or thiazolyl, 2,4-dimethyl-5-thiazolyl, 5- or 23 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 compositions 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 "d 15 administration or for administration in the form of a °o 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, carbohydrates 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 lacquered m 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 as suspensions, emulsions or implants. For administration by spray for inhalation, it is possible to use sprays which contain the active substance either dissolved or suspended in a propellant gas mixture (for example chlorofluorohydrocarbons). The active substance is preferably used for this in micronized form, with one or more additional physiologically tolerated solvents possibly being present, for example ethanol. Solutions for inhalation can be administered with the aid 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 i u- illr iiUYWrUII- l s~ slllUCI 24 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, commercially 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 A is preferably between about 0.2 and 20 mg/kg, in par- 15 ticular between 1 and 10 mg/kg, of body weight. The specific dose for each particular patient depends, however, on a wide variety of factors, for example on the activity of the specific compound used, on the age, body weight, general state of health and sex, on the diet, on 20 the time and route of administration and on the rate of excretion, medicinal substance combination and severity 4 44 of the particular disease for which the therapy is Sapplied. Parenteral administration is preferred.

Renin-dependent hypertension and hyperaldosteronism can be effectively treated by administration of dosages between, in particular, about 1 and 300, preferably between 5 and 50, mg/kg of body weight. For diagnostic purposes, it is possible and preferable for the new Scompounds to be administered in single doses, particularly in about 0.1 and 10 mg/kg of body weight.

All temperatures stated hereinbefore and hereinafter are in In the examples which follow, "usual working up" means: if necessary, water is added, the pH is adjusted to between 2 and 8, depending on the constitution of the final product, extraction is 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 chromatography on silica gel and/or crystallization.

noyl, lO-aminodecanoyl, li-aminoundecanoyl, but also, for example, 2 -ainino-propionyl (Ala), 2 -amino- 2-methyl- Example 1 A mixture of 1038 mg of N-[2s-isopropyl-4S- (4-BOC-aminopiperidinocarbonyl-Phe- (imi-DNP- His)-amino)-6-cyclohexylhexyl]-propanesulfonamide (obtainable by reaction of 2,2-dimethyl-3-BOC-4S-cyclo- 9 30) with .1 isovaleronitrile in the presence of Li diisopropylamide in THF/phosphoric hexainethyltriainide at -78' to give 2,2dimethyl-3-BOC-4S-cyclohexylmethyl-5S- (2RS-cyano-3methylbutyl)-oxazolidine (oil), separation of the diastereomers by chromatography, hydrogenation of the 2S epimer on Raney Ni in methanolic Nil 3 at 200 to give 2,2dimethyl-3-BOC-4S-cyclohexvlmethvl-5S- (2S-aminomethyl-3mehybuyl -oxazolidine, reaction with Dropanesulfonyl chloride/triethyiamine to give 2,2-diinethyl-3-BOC-4S- OH (mo. 15l59rh)], -2S-g o 2-ercatoethamno, 20 l of ing alty)oai e 200,aa with aqeu NaCN soltio anisntrrda Ft 200 or 2 eh The usualveworking up roresults in N-[2S-o Hamino-6-cyclohhexyexy-propanesufonamide, mhyp.

choreponingp m-63PHi codeivatives: hBO-(m-DP (d co po it on Nis-O [o iei2S-isopropyl-4S-hy~roxy-5-(2bny--rt-utysufnylHi)-prmaopin-Hs-amno) -6-cclheyl h poae syl f-methne sulfconamdesto ih4-BC 2apmr, min 1160 (hdocoride, h O (MP. 18-19")] 2 of -mecaptethnol,20 l o aUtLIUo-plperano..acetyl, 3- (4-amino-piperidino) -propionyl, 4 4 -amino-piperidino)-butyryl, 4-amino-piperidmo) -pentanoyl, 6- (4 -amino-piperidino) -hexanoyl, f~i 26j m.p. 1120)) and m.p. 1220 (hydrochloride, m.p. 107') [via N-(2S-isopropy1-4S-hydroxy-5S-amino-6-cycohexyhecyl)methane sul fonanide (hydrochloride, m.p. 780) and N-(2Sisopropyl-4S-hydroxy-9S-BOC- (imi-DNP-His) -amino-6-cyclohexylhdxyl)-methanesulfonamide 1200)]; N-[2S-isopropy1-4S-hYdroxy-5S- (2-benzyl-3-tert. -butylsulfonyipropionyl-His-amilo) -6-cyclohexylhexyllpropane- I sulfonamide, 2 epimers, m.p. 700 (hydrochloride, m.p. 99- 1000) and m.p. 1030 (hydrochloride, m.p. 104-105'); N-[2S-isopropyl-4S-hydroxy-5S-(2-benzyl-3-tert.-butylsulfonyl-propionyl-His-amino) -6-cyclohexylhexyl]butane- 4 sulfonamide, 2 epimers, m.p. 790 (hydrochloride, m.p.

1090) and m.p. 970 (hydrochloride, m.p. 1220) [via N-(2Sisopropyl-4S-hydroxy-5S-amino-6-cyclohexylhexyl) -butanesulfonamide (hydrochloride, m.p. 560) and N-(2S-isopropyl- 0 0 4S-hydroxy-5S-BOC- (iiDPHs-mn6cylhxhel) 0 a butanesulfonamide 900)]; 0 N- [2S-isopropyl-4S-hydroxy-5S- (2-benzyil-heptanoyl-Hisamino) -6-cyclohexyihexyl] -propanesulfonamide N-[2S-isopropyl-4S-hydroxy-5S-(2-benzyl-4-oxo-5,5-dimethy1-hexanoyl-His-amino) -6-cyclohexyihexyl] -propane- ~0 sulfonamide N- [2S-isopropyl-4S-hydroxy-5S- (2-benzyl-3-tert. -butylsulfonyl-prop ionyl -His -amino) 6-cyc lohexylhexyl I-propanesulfonamide N-[2S-isopropyl-4S-hydroxy-5S-(2-benzyl-3-morpholinccarbonyl-propionyl-His-amino) -6-cyclohexyihexyl] -propanesulfonamide N- [2S-isopropyl-4S-hydroxy-5S- -naphthylmethyl) -3morpholinocarbonyl-propionyl-His-anino) -6-cyclohexylhexyl] -propanesulfonanide N-[2S-isopropyl-4S-hydroxy-5S-(N-benzyl-N-isopentylcarbamoyl-His-amino) -6-cyclohexylhexyl ]propanesulfonanide N- 2S-isopropyl-4S-hydroxy-5S- (1-naphthylmethyl) (Nk3-dimethylaminopropyl)-carbamoyl-propionyl-His-amino)- 6-cyclohexyihexyl ]-propanesulfonamide N-[C2S-isopropyl-4S-hydroxy-5S- (2-benzyl-3- (4-BOC-amfiflopiperidinocarbonyl )-propionyl-His-amino) -6-cyclohexylhexyl ]-propanesulfonamide -27 N-[2S-isopropyl-4S-hydroxy-5S-(2-( 1-naphthylmethyl)-3-(4- BOC-amino-piperidinocarbonyl) -propionyl-His-amino) -6cyclohexyihexyl]I-propane sulfonamide N-[2S-isopropyl-4S-hydroxy-5S-(BOC-Phe-His-amino)-6-, cyclohexyihexyl]I-propanesulfonamide N-[2S-isopropyl-4S-hydroxy-5S-(CBZ-Phe-His-amino)-6cyclohexyihexyl] -propanesulfonamide N- [2S-isopropyl-4S-hydroxy-5S- 3-dimethylbutyryl-Phe- His-amino) -6 -cyc lohexyihexyl]I-propanesulfonamide N- [2S-isopropyl-4S-hydroxy-5S-( 2-BOC-amino-2-iuethylpropionyl-Phe-His -amino) 6-cyc lohexyihexyl propanesulfonamide 0 2S-isopropyl-4S-hydroxy-5S- (6-BOC-amino-hexanoyl-Phe- 0 oo~oHis-axnino)-6-cyclohexyihexyl]propanesulfonamide 015 N- [2S-isopropyl-4S-hydroxy-5S- (4-BOC-amino-piperidinocarbonyl-Phe-His-'amino) -6-cyclohexyihexyl ipropanesulf onamide N- [2S-isopropyl-4S-hydroxy-5S-( 6-methoxycarbonyl-hexanoyl-Phe-His-amino) -6-cyclohexyihexyl ]propanesulfonamide N-[2S-isopropyl-4S-hyiroxy-5S-(N-( 3-dimethylaminopropyl)- 0 :baoy-Phe-is-amino)-6-cyclohexyihexyl ]propanesulf on- N- [2S-isopropyl-4S-hydroxy-5S- (5-dimethylaminopentyl) c arbaxnoyl -1he -His -amino) 6-cyc lohexyihexyl ]propane sul fonamide N-[2S-isopropyl-4S-hydroxy-5S-(BOC-Mal-Hic-amino)-6cyclohexylhexyl]propanesulfonamide 4 N-[2S-isopropyl-4S-hydroxy-5S-(CBZ-Mal-iis-amino)-6cyclohexyihexyl ]propanesulfonamide N-[2S-isopropyl-4S-hydroxy-5S-( 3, 3-dimethylbutyryl-Mal- His-amino) -6-cyclohexy].hexyl ]propanesultonamide N- [2S-isopropyl-4S-hydroxy-5S- (2-BOC-amino-2-methyipropionyl-Mal-His-amino) -6-cyclohexyihexyl Ipropanesulf onamide N- [2S-isopropyl-4S-.hydroxy-5S- (6-BOC-amino-hexanoyl-Mal- His-amino) -6-cyclohexyihexyl ]propanesulfonam Lde N- 2S-isopropyl-4S-hydroxy-5S- (4-BOC-amino-piperidinocarbonyl-Mal-His -amino) -6 -cyc lohexyihexyl Ipropanesul fonamide [2S-isopropyl-4S-hydroxy-5S-( 6-methoxycarbonyl-hexanoyl- 28 Mal-E-is-amino) -6 -cyclohexyl-hexyl) -propanesulfonamide N-L-2s-isopropyl-4S-hydroxy-5S-(N-(3-dimethylaminopropyl)carbamoyl-Mal-His- amino) -6-cyclohexyl-hexyl-propanesulf onamide N-/2S-isopropyl-4S-hydroxy-5S- (N-(C5-dimethylaminopentyl) carbamoyl-Mal-His-amino )-6-cyclohexyl-hexyl]-propanesulfonamide C4-BOC-aminopiperidinocarbonyl-Phe-Hisamino) -G-cyclohexyl-hexylJ-propanesulfonamide N-/4S-hydroxy--5S-(C4-BOC-aminopiperidinocarbonyl-Mal-Hisamino) -6-cyclohexylj -propanesulfonamide N-f2S-methyl-4S-hydroxy-5S-C4-BOC-aminopiperidinocarbonyl- Phe-His-amino )-6-cyclohexyl-hexyli7-propanesulfonamide N-L-2S-methyl-4S--hydroxy-5S-C4-BOC-aminopiperidinocarbonyl- Mal-His-amino -6-cyclohexyl-he-xvlj-propanesulfonamide N-[2S-isobutyl-4S--hydroxy-5S-C4-BOC-aminopiperidinocarbonyl-Phe-His-amino) -6-cyclohexyl-hexyl]7-methanesulfonamide N-/-2S-isobutyl-4S-hydroxy--5S-(4-BOC-aminopiperidinocarbonyl-Mal-His-amino)-6-cyclohexyl-hexyl]7-methanesulfonamide (2-Cl -naphthylmethyl (4-BOG-aminopiperidinocarbonyl )-propionyl-His-amino) -6-cyclohexylhexyl7-oropanesulfonamide N-/2S-methyl-4S-hydroxy-5s-C2-Cl-naphthylmethyl)-3-C4- BOC-aminopiperidinocarbonyl) -propionyl-His-amino) -6- ,fit cyclohexyl-hexylj-propanesulfonamide N-L 2S-isopropyl-4S-hydroxy-5S- (2-Cl -naphthyimethyi 1 25 (4-BOC-aminopiperidinocarbonyl)-propionyl-His-amino)-6cyclohexyl-hexyl7-propanesulfonamide N-,C4S-hydroxy-5S-(2-benzyl-3-tert.-butylsuifonyl-propionyl- His-amino) -6-cyclohexyl-hexyl]-propanesulfonamide N-f 2S-methyl-4S-hydroxy-5S-(2-benzy-3-tert.-butylsulfonylpropionyl-His-amino)-6-'byclohexyl-hexyl7- propanesulfonamide If R 8 0 3 S-C mH 2- CO-Z-NH-CHR 3_CHOH-CH 2-CHR mgR CH T Mm s C nH L(R -C H H -CO-Z-NH- CHR -CHOH-CH 2 -CHR 2p rr -29 N- [2S-isopropyl-4S-hydroxy-5S- (BDC-Phe-His-amino)-6cyclohexyihexyl]-2-methyipropanesulfonamide N-[l2S-i sopropyl-4S-hydroxy-5S- (BOC-Cal-His-amino) -6cyclohexyihexyl] -2-methyipropanesulfonamide N-[2S-isopropyl-4S-hydroxy-5S-(BOC-caNal-His-amino)-6cyclohexyihexyl I-2-methyipropanesulfonamide N-[2S-isopropyl-4S-hydroxy-5S- (BOC-2-Tia-His-amino) -6cyclohexyihexyl] -2 -methylpropanesulfonanide N- [2S-isopropyl-4S-hydroxy-5S- (BOC-Trp-His-amino) -6cyclohexyihexyl ]-2-methyipropanesulfonanide N-[2S-isopropyl-4S-hydroxy-5S-(BOC-Pro-His-amino)-6cyclohexyihexyl]3-2-methyipropanesulfonamide N-[2S-isopropyl-4S-hydroxy-5S-(3,3-dimethyibutyryl-Pro- Phe-N-Me-His-amino) -6-cyclohexyihexyl] -2-methyipropanesulfonamide 1 4 N-[2S-isopropyl-4S-hydroxy-5S-(4-CBZ-amino-piperidinoc 'carbonyl -Phe -His -amino) 6-cyc lohexylhexyl ]propane sul fonainide.

Example 2 j 4- 20 1 g of N-[2S-isopropyl-4S-hydroxy-5S-(3-(N-3- 4 dimethylaminopropyl-carbamoyl)-2-(l-naphthylmethyl)propionyl- (ilni-BOM-His )-amino) -6-cyclohexyihexyll propanesulfonamide [mixture of stereoisomers; obtainable by condensation of N-(2S-isopropyl-4S-hydroxy-5S-amino-6cyclohexylhexyl)-propanesulfonamide with BOC-(imi-B14- His)-OH. to give N-[2S-isopropyl-4S-hydroxy-5S-BOC-(imi- BOM-His )-amino-6-cyclohexylhexyl) -propanesulfonamide, j elimination of the BOC group and condensation with DL-3- (N-3-dimethylaxninopropyl-carbamoyl) l-naphthyliethyl) propionic acid, m.p. l22-123o] is dissolved in 25 ml of ethanol and hydrogenated on 0.5 g of 10% Pd-C at 200 and 1 bar until H 2 uptake ceases, and the mixture is filtered and evaporated, and purification by chromatography results in N- [2S-isopropyl-4S-hydroxy-5S- (N-3-dinethylaminopropyl-carbamoyl)-2- (l-naphthylmethyl) -propionyl- His-amino )-6-cyc lohexyl hexyl 3-propanesuifonamide, 2 epimers, m.p. 1020 (hydrochloride, m.p. 1190) and oil (hydrochloride, m.p. 117').

The following are obtained analogously by hydro- The compounds ot the tormu.La i, 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 genolysis of the corresponding imi-BOM-His derivatives N-[2S-isopropyl-4S-hydroxy-5S-(2S-benzyl-3-tert.-butylsulfonyl-propionyl-His-amino) -6-cyclohexyihexyl ]-methanesulfonamide, m.p. 1030; hydrochloride, m.p. 104-1050 N-f 2S-isopropyl-4S-hydroxy-5S- (2S-benzyl-3-tert. -butylsulfonyl-propionyl-His-amino) -6-cyclohexylhexyl 1-propanesulfonamide, m.p. 1220; hydrochloride, m.p. 1220 N- [2S-isopropyl-4S-hydroxy-5S- (2S-benzyl-3-tert. -butylsulfonyl-propionyl-His-amino) -6-cyclohexylhexyl ]-butanesulfonamide, m.p. 970; hydrochloride, m.p. 1220 N-[2S-isopropyl-4S-hydroxy-5S-(2S-benzyl-3-tert. -butylsulfonyl-propionyl-His-amino) -6-cyclohexylhexyl] -2- 4 methyl-propanesulfonamide Nm-[2S-isopropyl-4S-hydroxy-5S-(2S-benzyl-3-tert. -butylsulfonyl-propionyl-His-amino) -6-cyclohexylhexyl]3-phenylmethane-sulfonamide 0 N-[2S-isopropyl-4S-hydroxy-5S-(2S-benzyl-3-tert.-butyl- .0 sulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-cyclohexylmethane-sul fonamide N-[2S-isopropyl-4S-hydroxy-5S-(2S-benzyl-3-tert.-butylsulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-N'o, propyl-urea N-[2S-isopropyl-4S-hydroxy-5S-(2S-benzyl-3-tert. -butylsulfonyl-propionyl-His-amino)-6-cyclohexylhexyl)-N'butyl-urea N- [2S-isopropyl-4S-hydroxy-5S- (2S-benzyl-3-tert. -butylsulfonyl-propionyl-His-amino) -6-cyclohexylhexyl]-N'o propyl-thiourea N-f 2S-isopropyl-4S-hydroxy-5S- 2S-benzyl-3-tert. -butylsulfonyl-propionyl-His-amino) -6-cyclohexylhexyl]-N'-(paminophenyl )-urea N- [2S-isopropyl-4S-hydroxy-5S- (2S-benzyl-3-tert. -butylsulfonyl-propionyl-His-amino) -6-cyclohexylhexyl 1-4methylpentanoamide.

Example 3 In analogy to Example 2, hydrogenolysis of 1-CBz- -6-cyclohexylhexane (obtainable by reaction of 1-CBZ-amino-4S-hydroxy- S-amino- 6-cyc lohexylhexane with BOC-Phe-Gly-OH) results in 4S-hydroxy-5S- (BOC-Phe-Gly-amino) -6-cyclohexylhexyl- -31amine.

The following are obtained analogously: 2S-methyl-4S-hydroxy-5S-(BOC-Phe-Gly-amino) -6-cyclohexylhexylamine 2S-ethyl-4S-hydroxy-5S- (BOC-Phe-Gly-amino) -6-cyclohexylhexylainine hexylhexylamine A 2S-isobutyl-4S-hydroxy-5S-(BOC-Phe-Gly-anino) -6-cyclohexylhexylanine.

Hydrogenolysis of N-[2S-isopropyl-4S-hydroxy-SS- (3-benzyloxysulfonyl-propionyl-Phe-His-amino) -7-methyloctyl ]-propane sul1f onamide analogously results in N-[2S- *is opropyl- 4 S-hydroxy- 5S- 3 -sul f opropionyl-Phe-His -amino) 7-methyl-octyl]-propanesulfonamide.

Example 4 1.01 g of N-methylmorpholine are added to a *solution of 4.33 g of N-[2S-isopropyl-4S-hydroxy-5S-(H- 4 ~pAla-amino) -6-cyclohexylhexyl] -propanesulfonamide [obtainable by condensation of BOC-PAla-OH with N-(2Sisopropyl-4S-hydroxy-5S-amino-6-cyclohexylhexyl) -propane- [1 02 sulfonamide to give N-[2S-isopropyl-4S-hydroxy-5S-(BOC- N pAla-amino) -6-cyclohexylhexyl]-propanesulfonamide and elimination of the BOC group with 4 N HCl in dioxane] in 26 60 ml of dichloromethane. While stirring, 3.19 g of 4and a solution of 2.06 g of DCCI in 50 ml of dichloromethane are 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-isopropyl-4S-hyd-koxy-5S-(4-dimethylamino-piperidinocarbonyl-Phe-pAla-amino) -6-cyclohexylhexyl ]-propanesulfonamide.

N- [2S-Isopropyl-4S-hydzoxy-5S- (4-BOC-axninopiperidinocarbonyl-Phe-PAla-amino) -6-cyclohexylhexyl ]-propanesulfonamide is obtained analogously with 4-BOC-aminopiperidinocarbonyl-Phe-OH.

The following are obtained analogously: N- [2S-isopropyl-4S-hydroxy-5S- (4-BOC-amino-piperidino-

I

32 carbonyl-Phe-2-Tia-amino) -6-cyclohexylhexyl]-propanesul fonainide N- [2S-isopropyl-4S-hydroxy-5S- (5-dixnethylaminopentyl) carbamoyl-Phe-pAla-afilo) -6 -cyclohexyihexyl] -propanesulfonamide N- £2S-isopropyl-4S-hydroxv-5S- (5-dimethylaminopentyl) carbaxnoyl-Phe-2-Tia-amfino) -6-cyclohexylhexyl]-propalesulfonamide N-[4S-hydroxy-5S-(BOC-Phe-Gly-amino)-7-Tmethyl-octyl1piperidine.

Example In analogy to Example 4, N-(2S-isopropyl-4Shydroxy-5S-BOC-Phe-Gly-amino-6-cyclohexylhexyl) -propanesulfonamide is obtained from BOC-Phe-Gly-OH and N-(2S- 0 J15 isopropyl-4S-hydroxy-5S-amino-6-cyclohexylhexyl) -propane- 6~ sulfonamide.

The following are obtained analogously N- (2S-isopropyl-4S-hydroxy-5S-BOC-Phe-Abu-amilo-6-cyclohexylhexyl) -propanesulfonamide N-(2S-isopropyl-4S-hydroxy-5S-BOC-Phe-Ala--milo-6-cyclo- 0 4 44 hexylhexyl)-propanesulfonamide N- (2S-isopropyl-4S-hydroxy-5S-BOC-Phe-Aa-amio-6cyclohexylhexyl) -propanesulfonamide N- (2S-isopropyl-4S-hydroxy-5S-BOC--Phe-Asn-amiflo-6-cyclohexylhexyl)-propanesulfonamide N-(2S-isopropyl-4S-hydroxy-5S-BOC-Phe-Gln-ami.,io-6-cyclohexylhexyl) -propanesulfonamide N- (2S-isopropyl-4S-hydroxy-5S-BOC-Phe-Nle-amino-6-cyc lohexylhexyl) -propanesulfonamide N-2-spoy-Shdoy5-O-h--y-~io6 cyclohexylhexyl) -propanesulfonamide N- [3S-hydroxy-4S- (4-ethoxycarbonyl-piperidino-carboflyl- Phe-Gly-amino) Example 6 In analogy to Example 4, N-[2S-isopropyl-4S- (pivaloyl-Phe-Gly-amino) -6-cyclohexylhexyl] propanesulfonamide is obtained from pivalic acid and -33 N-[2S-isopropyl-4S-hydroxy-5S-(H-Phe-Gly-amino)-6-cyclohexyihexyl]3-propanesulfonanide.

Example 7 In analogy to Example 4, N-[2S-isopropyl-4Shydroxy-5S- (4-BOC-aminopiperidinocarbonyl-Phe-Gly-amino) 7-methyloctyl]--ethanesulfonamide is obtained from 4-BOCaminopiperidinocarbonyl-Phe-Ol and N- [2S-isopropyl-4S- (H-Gly-amino) -7-methyloctyl] -ethanesulfonamide.

Example 8 A solution of 1.25 g of cyclohexyl isocyanate in ml of THF is added dropwise at 200 to a stirred solution of 5.6 g of 2S-isopropyl-4S-hydroxy-5S-(BOC-Phe- Gly- amino) 6-cvc lohexylhexylamine in 60 ml of THF. The mixture is then stirred at 20' for 3 h, and the usual working up results in N-[2S-isopropyl-4S-hydroxy-5S-(BOC- Phe-Glyamino--cyclohexvihexvl-N' -cyclohexylurea.

Example 9 A solution of 1 g of N-[2S-isopropyl-4S-hydroxy- 0 20 5S-(4-BOC-aminopiperidinocarbonyl-Phe-His-amino)-6cycl1ohexylhexylj]-propane s ulf onamide in 20 ml of 4 N IiCl o in dioxane is stirred at 200 for 30 min and then evaporated. N-[2S-Isopropyl-4S-hydroxy-5S-(4--aminopiperidinocarbonyl-Phe-His-amino )-6-cyclohexylhexyl I-propanesulfonamide, dihydrochioride, n.p. 161-162', is obtained.

The following are obtained analogously by cleavage of the corresponding BOC derivatives: N-[2S-isopropyl-4S-hydroxy-5S-(2-benzyl-3-(4-aminopiperidinocarbonyl) -propionyl-His-amino) -6 -cyc lohexylhexyl Ipropanesulfonamide N- [2S-isopropyl-4S-hydroxy-5S- (l-naphthylmethyl) (4aminopiperidinocarbonyl) -propionyl-His-amino) -6-cyc lohexylhexyl] -propanesulfonamide N- [2S-isopropyl-4S-hydroxy-5S- (4-aminopiperidinocarbonyl- Phe-pAla-amino) -6-cyclohexylhexyl]-propanesulfonamide N- [2S-isopropyl-4S-hydroxy-5S- (4-aminopiperidinocarbonyl- Phe-2-Tia-amino )-6-cyclohexylhexyl]3-propanesulfonamide 2S-isopropyl-4S-hydroxy-5S-( 4-aminopiperidinocarbonyl- Phe-His-amino )-6-cyclohexylhexyl]I-propanesulfonamide as dichioromethane, an ether such as THF or dioxane, an amide such as DMP or dimethylacetanide, or a nitrile such as acetonitrile, at temperatures between about -10 and preferably between 0 and 300.

-34 N- [2S-isopropyl-4s-hyiroxy-5S- (4-axinopiperidinocarbonyl- Mal-His-amino) -6-cyclohexyihexyl I-propanesulfonamide N- [2S-isopropyl-4S-hydroxy-5S- (2-amino-2-methyl-propionyl-Phe-,His-amino) -6-cyclohexyihexyl] -propanesulfonamide N-[2S-isopropyl-4S-hydroxy-5S-( 2-amino-2-methyl-propionyl-Mal-His-amino) -6-cyclohex'ylhexyl] -propanesulfonamide N- [2S-isopropyl-4S-hydroxy-5S- (6-aiinohexanoyl-Phe-Hisamino) -6-cyclohexvihexyl] -propanesulfonanide 4 N- [2S-isopropyl-4S-hvdroxy-5S- (6-aminohexanoyl-Mal-Hisamino) -6-cyclohexylhexyl3-propanesulfonamide N- [4S-hydroxy-5S- (4 -aminopiveridinoc arbonyl-Phe-His-amno)- 6fccohx exi-propanesulfonamnide, dihydrochioride, m.p. 1 25' (dec.) N-[4S-hydroxy-5S-(4-aminopi~eridinocarbonvl-Mal-Hisamnino) -6-cyclohexylhexyl] -propanesulfonamide 7tt4 15 N-[2S-methyl-4S-hydroxy-5S-(4-aminopiperidinocarbonyl- Phe-Hls-anino) -6-cyclohexylhexyl]-propanesuifonanide N-[2S-methyl-4S-hydroxy-5S-(4-aminopiperidinocarbonyl- Mal-His-aiino) -6-cyclohexylhexyl ]-propanesuifonamide N-[2S-isobutyl-4S-hydroxy-5S- (4-aminopiperidinocarbonyl Phe-His-amino) -6-cyclohexyihexyl] -methanesulfonanide 4 N-[2S-isobutyl-4S-hydroxy-5S-(4-aninopiperidinocarbonyl- Mal-His-anino) -6-cyclohexyihexyl] -methanesulfonanide L2'~ N- [4S-hydroxy-5S- -naphthylmethyl) (4-aminopiperidinocarbonyl) -propionyl-His-amino) -6-cyclohexylhexyl] propanesulfonamide N-[2S-methyl-4S-hydroxy-5S- -naphthylmethyl) (4- 30aiinopiperidinocarbonyl)-propionyl-His-amino)-6-cyc loaminopiperidinocarbonyl)-propionyl-His-aM4 no)-6-cyclohexyihexyl ]-propanesulfonamide.

Example A mixture of 1 g of N-[3S-hydroxy-4S-(4-ethoxycarbonylpiperidinocarbonyl-Phe-Gly-amino) pentyl]-propanesulfonanide, 50 ml of dioxane, and 20 ml of 2 N NaOH (aqueous) is stirred at 200 for 3 h. The usual working up results in N-I3S-hydroxy-4S-(4-carboxypiperidinocarbonyl-Phe-Gly-amino) -5-cyclohexylpentyl) -propanesulfonam 4 .de.

35 The following are obtained analogously by hydrolysis of the corresponding methyl esters: 2S-isopropyl-4S-hydroxy-5S- (6-carboxyhexanoyl-Phe-Hisamino) -6-cyc lohexyihexyl ]-propanesulfonamide 2S-isopropyl-4S-hydroxy-5S-(6-carboxyhexanoyl-Mal-Hisamino) -6-cyclohexyihexyl I-propanesulfonamide.

Example 11 1.01 g of triethylamine are added, followed by a solution of 1.15 g of methanesulfonyl chloride in 10 ml of THF dro-pwise while stirring at 00, to a solution of 5.18 g of 4S-hydroxy-5S- (BOC -Phe -Gly- amino) -6-cyclohexyl- 4 hexylamine in 250 ml of THF. The mixture is then stirred for 1 h, during which the temperature is allowed to rise to 200, and the usual working up results in N-[4S-hydroxv- 5S-(BOC-Phe-Gly-ainino)-6-cyclohexylhexyl]-methanesul- Example 12 0 In analogy to Example 3, N-[2S-isopropyl-4Sh0 ycoeyhxlprpnsloai, m.p. 161-1620, is ~o obtained from N- 2S-isopropyl-4S-hydroxy-5S- (4 -CBZ -aminoo 00piperidinocarnonyl-Phe-His-amino) -6-cyclohexyihexyl]propanesulfonamide by hydrogenolysis.

Example 13 a) In analogy to Example 4, N-[2S,-isopropyl-4-oxo-5S- (4 -dime thyl1aminobutyryl -Phe -Gly- amino 6-cyc lohexylhexyl ]-propane sul fonamide is obtained from 4-dimethylaminobutyryl-Phe-Gly-OK and N- (2S-isopropyl- 4-oxo-5S-amino-6-cyclohexylhex- yl) -propanesulfonamide.

b) A solution of 1 g of the abovementioned keto amide in 25 ml of CHi 3 OH is hydrogenated on 0. 1 g of Pd-c at 20' and 1 bar until H 2 uptake ceases. Filtration and evaporation result in a mixture of N-[2Sisopropyl-4R- and -4S-hydroxy-5S- (4-dimethylaminobutyryl-Phe-Gly-amino) -6-cyclohexylhexyl]-propanesulfonamide.

Example 14 mg of hydroxylamine hydrochloride are adde$ to acia, iactic acia, tartaric acda, miu±.u aCU3., L.U-L acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisul fonic acid, 2 -hydroxyethanesul fonic acid, q0 benzenesulfonic acid, p-toluenesulfonic acid, naphtha- -36 a solution of 627 mg of the keto amnide obtainable as in Example 13a) and 1.43 g of Na 2

CO

3 10 H120 in1 5 Ml Of methanol and 5 ml of water, and the mixture is stirred at 200 for 14 h. The precipitated oxime is filtered off, dried, dissolved in 10 ml of methanol and hydrogenated on g of Raney Ni at 200 and 5 bar. The catalyst is filtered off, the filtrate is evaporated, the resulting mixture is separated on silica gel, and N-[2S-iSopropyl- 4-djrethylaminobutyrylPheGly-amino) -6cyclohexylhexyl]-propanesulfonamide is obtained; the 4Ramino epimer is also obtained.

Example

A-

0~ 0400 0 0 00 0 *8 0 0 0 00 *0 0 9 0O 00 o o 0 o 0 0000 0 0 0 00 0 o 00 00 0 O 00 0 0000 Analogously to Example 2, the following are obtained from the corresponding imi-BOM derivatives: 15 N-[4S-Hvdroxy-5S-(2S-benzyi-3-tert.-butylsulfonyl-propionyl-His-amino )-6-cyclohexvl-hexyl] -propanesulfonic acid amide, M.P. 90-9l0 N-[4S-Hydroxy-5S-(2R-benzyl-3-tert.-butylsulfonyl-propionyl-His-arnino )-6-cyclohexyl-hiexylj -propanesulfonic acid amide, 20 m.p. 81-820 N- [4S-Hydroxy-5S- (4-BOC-amino-piperidinocarbonyl-Phe- His-amino )-6-cyclohexyilhexyl] -propanesulfonic acid amide, m.p. 18-1200 N- [4S-Hydroxy-5S- (4-BOC-amiino-piperidinocarbonyl-Mal- His-amino)-6-cyclohexyl-hexyl] -propanesulfonic acid amide, m.p. 123-1250 N- [2R-Methyl-4S-hydroxy-5S- (4-BOC-amino-piperidinocarbonyl-Phe-His-amino )-6-cyclohexyl-hexyl] -propanesulfonic acid amide, M.p. 1640 (dec.) N-[2S-Methyl-4S-hydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Phe-His-amino )-6-cyclohexyl-hexyl] -propanesulfonic acid amide, m.p. 1400 (dec.) N-[2R-Methyl-4S-hydroxy-5S- (4-BOC-amino-piperidinocarbonyl-Mal-His-amino )-6-cyclohexyl-hexyl] -prope'nesulfonic acid amide, m.p. 1330 (dec.) compounds 'can also be freeze-dried and the resulting lyophilisates used, for example, to prepare products for injection. The stated compositions can be sterilized 37 0 0 00 0 0O 0 0 0 0 00 0 0 0 00 0 00 0 00069 0 0 4 .00 t N-[2R-Methyl-4S-hydroxy-5S-(2R-benzyl-3-tert. -butvlsulfonyl-propionyvl-His-amino )-6-cvcl ohexyl-hexyl] -propanesulfonic acid amide, hydrochloride, m.p. 1240 (dec.) N-[2R-Methyl-4S-hydroxv-5S-(2S-benzyl-3-tert.-butylsulfonyl-propionyl-His-amino )-6-cvclohexyl-hexyll -propanesulfonic acid amide, hydrochloride, m.p. 1160 (dec.) N- [4S-Hydroxy (4-BOC-amino-piperidinocarbonyl-Phe-Hisamino )-6-cyclohexyl-hexyl] -1-methyl-ethanesulfonic acid amide, N-[4S-Hydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Mal-Hisamino )-6-cyclohexyl-hexyl] -1-methyl-ethanesulfonic acid amide, m.p. 107-1090 N-[4S-Hydroxy-5S- (2S-I" -2zyl-3-tert. -butvlsulfonyl-propionyl- His-amino)-6-cyclohexyl-hexyl] -1-methyl-ethanesulfonic acid 15 amide, hydrocnloride, m.p. 122-1230 N- t4S-Hydroxy-SS- (2R-benzyl-3-tert. -butylsulfonyl-propionyl- His-amino )-6-cyclohexyl-hexyl]-l-methyl-ethanesulfonic acid amide, hydrochloride, 97-980 N-[4S-Hydroxy-SS- (3-BOC-amino-3-methylbutyryl-Mal-His-amino 20 6-cyclohexyl-hexyl]-propanesulfonic acid amide, m.p. 132-1340 N-[4S-Hydroxy-5S-(2S-benzyl-3-tert.-butylsuifonyl-propionyl- His-amino)-6-cyc.Lohexyl-hexyl] -isopropyl-urea, hydrochloride, m.p. 170-1710 N-[4S-Hydroxy-5S-(2R-benzyl-3-tert. -butylsulfonyl-propionyl- His-amino )-6-cyclohexyl-hexyl] -isopropyl-urea, hydrochloride, m.p. 1760 (dec.) (4-BOC-aminaopiperidinocarbonyl-Mal-Hisamino)-6-cyclohexyl-hexyl] -isopropyl-urea, hydrochloride, m.p. 185-1860 N- [4S-Hydroxy-5S- (4-BOC-aminopipe ridinocarbonyl-Phe-Hisamino )-6-cyclohexyl-hexyl] -isopropyl-urea, hydrochloride, m.p. 186-1870 N- [2R-Methyl-4S-hydroxy-5S-(3-BOC-amiflo-3-methylbutyryl- Phe-His-amino )-6-cyclohexyl-hexyl] -propanesulfonic acid amide N- [2R-Methyl4Shydroxy-5S(3BOC-amino-3methylbutyryl- Mal-His-amino)-6-cyclohexyl-hexyl1 -propanesulfonic acid amide -38- N- f2R-Methyl-4S-hyd-roxy-5S- (3-BOC-amino-3-methylbutyryl- Phe-N-Me-His-amino )-6-cyclohexyl-hexylj -propanesulfonic acid amide N- f2R-Methyl-4S-hydraxy-5S- (3-BOC-amino-3-methylbutyryl- Phe-His-amino)-6-cvclohexyl-hexyl] -l-methylethanesulfonic acid amide N-f 2R-Methvl-4S-hydroxy-5S-(3-BOC-amino-3-methylbutyryl- Mal-His-amino)-6-cyclohexyl-hexyl3 -l-methylethanesulfonic acid amide N- f2R-Methyl-4S-hydroxv-S-(3-BOC-amino-3-methylbutyryl- Phe-N-Mve-His-amino )-6-cyclohexyll-hexyl] -1-methylethanesulfonic acid amide N-f 2R-Methvl-4S-hydroxy-5S-(3-BOC-amino-3-methylbutvryl- Phe-His-amino) -6-cvclohexyli-hexvl] -cyclohexanesulfonic no 15 acid amide N-f 2R-Methyl-4S-hvdroxy-5S-(3-BOC-amino-3-mrnehvlbuty7ryl- Phe-M'a1-amino )-6-cyclohexyl-hexylj -cyclohexanesuifonic acid amnide N-f 2R-Methvl-4S-hydroxy-5S-(3-BOC-amino-3-enyibutyry- Phe-His-amino)-6-cyclohexyl-hexyil-N--etnyl-urea N-f 2R-Methyi-4S-hydroxy-5S- (3-BOC-amino-3-rnezhyibutyryi- Phe-Mal-amino)-6-cyclohexyl-hexyl -ethyw-urea 0 N- f2R-Jvethy-4S-hydroxy-5S- (3-BOC-arnaino-3-nethiylbutyryl- Phe-N-Me-His-amino)-6-cyclohexyilhexylJ -isopropyl- S25 urea coot L N- f2R-Methyl-4S-hydroxy-5S- (4-BOC-amino-piperidinocarbonyl-Phe-His-amino )-6-cyclohiexyl-hiexyl] -1-methylethanesulfonic acid amnide 0 N-[2R-Methyl-4S-hydroxy-5S-(4-BOC-amino-piperidinocarbonyl-Nal-His-amino )-6-cyclohiexvl-hexyij -1-methylethanesulfonic acid amide N-f 2R-Methyl-4S-hvdroxy-5S- (4-BOC-amino-piperidinocarbonyl-Phe-His-aminio)-6-cyclohexyl-hiexyl] -cyclohexanesulfonic acid amnide N-f 2R-Methyl-4S-hydroxy-5S- (4-BOC-amino-piperidinocarbonyl-Mal-His-amino)-6--7yclohexyl-hiexyll -cyclohexanesulfonic acid amide PAT LOG 9 240289 -39- N-f 2R-Methyi-4S-hydroxy-5S- (4-BOC-amino-piperidinacarbonyl-Phe-His-amino)-6-cyclohexyl-hexyl] -ethyl-urea N-[2R-Met'-hyl-4S-hydroxy-5S- (4-BOC-amino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexyl-hexyl] -ethyl-urea N- [2R-Methyl-4S-hyvdroxy-5S- (4-BOC-amino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexyl-hexyl] -isopropyvlurea N- [2R-Methyl-4S-hvdroxv-5S- (4-BOC-amino-piperidinocarbonyl-Mal-His-amino )-6-cyclohexyl-hexyli -isopropylurea N- [2R-Methyl-4S-hydroxv-5S- (4-BOC-amino-piperidinocarboj nvl-Phe-His-amino)-6-cyclohexyl-hexvll -phenyl-urea N-[2R-Methyl-4S-hydroxy-5S-(4S-benzyl-4-(4-BOC-alfliflopierdnolboy)-rpinl-His-amino)-6-cyclohexyi-ev]-'Denlue N-[2R-Methyl-4S-hydroxy-5S- (2-(lC-anhhlmethyl )-3-bo N-2-ehl4-yrx-S(4-BOC-arnino-piperidinocarbonl-rpoy-s-ni)cylal-hexyl] o)--propanexsulfoni aid arniethiu-rm N-[2R-Methyl-4S-hydroxy-5S-(2S-(lnaphthylmethyl-mn- )-propionyl-His-amino )-6-eli 3 ccly-hexyl]-propanesuifonic acid amide N- [2R-Mvethy-4S-hydroxy-SS- (2R-benzyi-5-N4-BOC--methyainoerdntcarnol-ryl-His-amino )6-cyclohexy-ey]prnhxlrpnsulfonic acid amide PAT LOG 9 2hyl4S-yrxy5-22(-ahtillety) N-f 2S-isopropy1-4S-hydrocy- 5 S- (2-benzyl-3- (4-BOC-amnopiperidinocarbolYl) -propionly-His-aliflo) -6-cyclohexyl1 hexyl] -propanesulfoflmide N-f 2R-Methvl-4S-hydroxy-5S- amino-pentanoyl--His-amino )-6-cvclohexyl-hexyl] -propanesulfonic acid amide N-[2R-Methvl-4S-I ,<oxv- 5S- amino-pentanovi-His-amino )-6-cyclohexyl-hexyl] -1-methylethanesulfonic acid amide N-f 2R-Methvl-4s-hvdroxv-SS- arino-pentanovi-His-amino )-6-cvclohexyl-hexyll -1-methylethanesulfonic acid amnide N- [2R-Methyl-4S-hydroxy-SS- amino-pentanovi-His-amino ).-6-cyclohexyl-hexvl] -ethylurea N-[2R-fMethvi-4S-hvdroxv-5S-(2S-benzyl-5-N-BOC-N-methyl- 00 is1 urea ainoi-entaino-i-am.ino)6coexyl-hexyli -ohxN' ethyl-n N -[4S-Hyd~roxy--)S- 2--benzyi-3-tert. -butyisuifonyi-pro- 200 pionyi-His-aiinlo )-o-cyciliexyl-h-exyli -cyclohiexanesulfonic 0 a acid amidie 0 N-[4S-Hyciroxy-5S-(2R-benzyI-3--tert. -butyisulfonyi-propionyl-His-cuniino)-a-cycioh-exyi-liexyl] -cycioexanesufoli N-f4S-Hydroxy-5S-k2R-benzyl-3-tert. -bu-tylsulfonyl-pro- 2S pionyl-His-amino)-6-cycoflexyl-hexyI] -isopropyi-urea pi ropio-mno -6--yciohex-ylhexyi-' isroy-ueal N-f 2R-Methyl-4S-hydroxy-5S(2R-benzyl-3-tert. -butylsul- )-6-cyclohexyl-hexyl] -1-methylethanesulfonic acid amide PAT LOG 9 240289 K -41 N- [2R-Methvl-4S-hydroxy-5S (2R-benzyl-3-tert. -butylsulfanyl-propionyl-His-amino )-6-cyclohexyl-hexyl] -cyclohexanesulfonic acid amide N-f 2R-Methyl-4S-hydroxy-5S(2S-benzyl-3-tert. -butylsulfonyl-propionyl-His-amino)-6-cyclohexyl-hexyl] -cyclohexane- Isulfonic acid amide N- [2R-Methvi.-4S-hydroxy-5S (2R-benzvl-3-tert. -but-rlsulfonyl-propionyl-His-amino )-6-cyclohexyl-hexyl] -ethylurea N-f 2R-Methyl-4S-hydroxy-5S(2S-benzyl-3-tert. -butylsulfonyl-propionyl-His-amino )-6-cyclohexyl-hexyl] -ethylw~i urea N-[2R-Methvl-4S-hydroxv-5S(2R-benzyl-3-tert. -butylsulfov-propionyil-His-amino)-6-cyclohexyl-hexyl] -iso- 0 t 15 propyl-urea propyl-urea 4 4 4S-Hydroxy-5S-(2R-benzyl-3-tert.-uysloypri- 20 nyl-His-arnino)-6-cyclohexyl-hexanoic acid nitrile A 4f 43-Hvdroxy-5S-(2S--benzyl-3-tert. -butylsuifonyl-propio- 4 :a nyl-His-amino)-6-cyclohexyl-hexanoic acid nitrile 2R-Methyl-4S--hydroxy-5S-(2R-benzyl-3-tert.-butylsulfo- 1y-propionyl-His-anino )-6-cyclohexyl-hexanoic acid nitrile 2R-Methyl-4S-hydroxy-5S-(2S-benzyl-3-tert.-butylsulfonyl-propionyl-His-amino)-6-cyclohexyl-hexanoic acid nitrile 2S-Wethyl-4S-hydroxy-5S-(2S-benzyl-3-tert. -butylsulfoyl-propionyl-His-amino )-6-cyclohexyl-hexanoic acid ni tr iie PAT LOG 9 240289 42 N-[2R-Methyl-4S-hydroxy-5S-(2R-benzyl-heptanoyl-Hisamino)-6--cyclohexyl-hexyl] -propanesulfonic acid amide N- [2R-Methyl-4S-hvdroxv-5S- (2S-benzyl-heptanoyl-Hi-s- VI amino )-6-cyclohexvl-hexyl] -propanesulfonic acid amide 5 N-[2R-Methvl-4S-hvdroxy-5S-(2R-(l-naphthylmethy'l)-3morphnlinocarbonyl-propionyl-His-amino )-6-cyclohexvlhexyl]-propanesulfonic acid amide N- [2R-Hethvi-4S-hvdroxv-5S- (2S- (1-naphthylmethvl morpholinocarbonyl-propionyl-His-amino )-6-cyclohexylhexyl]-propansulfonic acid amide N-[2R-Methvl-4S-hydrox-5S.-(2R-benzvl-3-tert. -butyithiapropionvi-His-amino )-6-cvclohexvl-hexyl I-pro-oanesulfonic acid amide 15 N-I 2 R-Eethvl-4S-lcIvroxv-bS-(2S-benzvl-3-tert.-nziho Proplinvi-H4is-amino )-b-cvciohexvl-hexyi -propanesuifonic acid amice N-12R-Aethvi-4S-hivcroxy-3S- 4,2R-benzy±.-.- rerr. -,ou-visuLf invl -propiony±L-i s amino cyclohexyi -hexyi]j -prop anesulifonic acict amide N-t2R-Mercnyi-4S-nivclroxy-SS-(2S-benzyi-3-t-err.-Duc-yisulfinyl-proplinyi-niis-amiiio )-6o-cyciohexyl-hexyij -propanesulfonic acid amicie N-[2R-Methyl-4S-),-wrdroxy-5S-(2R-.benzyl-4-oxo-5, hexanoyl-His-amino )-6-cyclohexyl-hexyl] -propanesulfonic acid amide N-[2R-Methyl-4S-hydroxy-5S-(2S-benzyl-4-oxo-5, hexanoyl-His-amino )-6-cyclohexyl-hiexyi I-propanesulfonic acid amide N- [2R-Methyl-4S-hydroxy-5S- (2R-benzyl-4-hydroxy-5, dimethyl-hexanoyl-His-anino )-6-cyclohexyl-hexyll-propanesulfonic acid amide PAT LOG 9 240289 -43 N-f 2R-Methvl-4S-hydroxy-5S-(2S-benzyl-4-hydroxy-5, dimethyl-hexanoyl-His-amino )-6-cyclohexvl-hexyl] -propanesulfonic acid amide N-f 2R-Methyl-4S-hydroxy-5S- (4-dimethylamino-piperidinocarbonyl-Phe-His-amino )-6-cyclohexyl-hexyl] -propanesulfonic acid amide N- f2R-Methyl-4S-hydroxy-5S- (4-dimethylamino-pipoeridinocarbonyl-Mal-His-amino )-6-cyclohexyl-hexyi] -propanesulfonic N-[2R--Methyl-4S-hydroxy-5S- 5-dimethvlaminopentyl carbonvl-Phe-His-amino )-6-cyclohexyl-hexyl] -propanesulfonic acid acid amide.

4 t 4 Example 16 14 4 Analogously to Example 4, there is obtained N-[4S-Hydroxy- 444*445S-(4-BOC-amino-piperidinocarbonyl-Phe-13Aia-aminio)-6-cyclohexyl-hexylJ-propanesulfonic acid amide, m.p. 96-97'.

Example 17 Analogously to Example 9, there are obtained from the corresponding BOC derivatives: N-f 2R-Methyl-4S-hydroxy-5S- (4-amino-piperidinocarbonyl- Phe-His-amino)-6-cyclohexyl-hexyll -propanesulfonic acid amide, hydrochloride, m.p. 173' (dec.) N-2-ehl4-yrx-S(-mn-ieiioabnl Phe-His-amino)-6-cyclohexyl-hexyll -propanesulfonic acid amide, N-f 2R-Methyl-4S-hydroxy-5S- (4-amino-piperidinocarbonyl- Mal-His-amino)-6-.cyclohexyl-hexyl] -propanesulfonic acid amide, dihydrochloride, m.p. 136 0 (dec.) PAT LOG 9 240289 (BOC-Phe-Gly-amino) -6-cyclohexylhexane (obtainable by reaction of 1-CBZ-aniino-4S-hydroxy- 5S-amino-6-cyclohexylhexane with BOC-Phe-Gly-OH) results in 4S-hydroxy-5S- (BOC-Phe-Gly-amfino) -6-cyclohexyihexyl- -44- N-[4S-Hvdroxy-S-(4-amino-piperidinocarbonvl-phe-His- I amino)-6-cyclohexyl-hexvl]l -methvl-ethanesulfonic acid amide, dihydrochioride, m.p. 1450 (dec.) S N-[4S-Hydroxy-5S-(4-amino-piperidinocarbonvl-Mal-Hisamino)-6-cyclohexyl-hexyl] -1-methvl-ethanesulfonic acid amide, dihydrochioride, rn.p. 1730 (dec.) N-[4S-Hydroxv-5S-(3-amino-3-methvlbutvrvl-Mal-His-amino)- 6-cyclohexvl-hexvll-propanesulfonic acid amidie dihydrochioride, m.p. 1770 (dec.) N-[4S-Hydroxy-5S-(4-amino-piperidinocarbonvl-Mal-Hisamino)-6-cvclohexvl-hexvl f-N'-isourooyl-urea, ii dihvctrochloride, m.D. :0i9-210o N-I14S-Hvdroxv-5S-(4q-amino-roierlcinocarbonvi-Phe-Hisii-mno) )-t-cvcIonexvLi-1Cxvi I -N I-isooropyvi-urea, dihvrocloricte, m.o. L~~(alec.) N-1 2R- (der lvi S- yaroxv-,)S (3 -amino 3 -ethyibutyryl -Phea 0 His-amino) )--c-ycLonexyL-fexyl I -pro-panesulfonic acid amide N1- 2R-i.ethiV.L-'S-nVaroxy-,)S- (3-amino-3-methylbutyryl-Mal- 4 His-alnino)-o-cvcioilexv±-lexyi-propanesulfonic acid amide N- I2R-idlecny±--'±5-iwivroxy- (3 -amino 3-methylbutyryl -Phe N-Me-His-amiino )-o-cycioniexvi-hexyl] -propanesulfonic acid amide N-f 2R-Methyl-4S-hyaroxy-SS- (3-amino-3-methylbutyryl-Phe- His-amino )-6-cycilhexyilhexylJ -1-methyl-ethanesulfonic acid amide N- [2R-Methyl-4S-hydroxy-5S- (3-amino-3-methylbutyryl-Mal- His-amino)-6-cyclohexyl-hiexvl-1-methvl-ethanesulfonic acid amide N- [2R-Methyl-4S-hydroxy-5S- (3-amino-3-inethylbutvryl-Phe- N-Me-His-amino)-6-cyclolhexyl-hexyl] -1-methyl-ethianesulfonic acici amide N-f 2R-Methyl-4S-hydroxy-5S- (3-amino-3-rneth-ylbutyryl-Phe- His-amino)-6-cyclohexyl-hexyl] -cyclohexanesulfonic acid amide PAT LOG 9 240289 -4 N- f2R-Methyl-4S-hydroxy-5S- (3-amino-3-methvlbutvryl-Phe- Mal-amino)-6-cyclohexyl-hexyl] -cyclohexanesulfonic acid I amide N-f 2R-Methyl-4S-hydroxy-5S-(3-amno-3-methylbutyryl-Phe- His-amino )-6-cyclohexyl-hexyll -ethyl-urea N- f2R-Methyl-4S-hydroxy-5S-(3-amino-3-methylbutyryl-Phe- Mal-amino)-6-cyclohexyl-hexyl] -ethyl-urea N-f 2R-Methyl-4S-hvdroxy-5S- (3-amino-3-methylbutyryl-Phe- N-Me-His-amino)-6-cyclohexyl-hexyll -isopropylurea N-f 2R-Methyl-4S-hydroxy-5S- (4-amino-piperidinocarbonyl- Phe-His-amino )-6-cyclahexyl-hexyl] -1-methylethanesulfonic acid amide N-f 2R-Methvl-4S-hydroxy-5S-(4-amino-pieridiocarboflYl- P/al-His-amino)-6-cyclohexyl-hexyiI -1-me-thylethanesulfonic o 15 acid amide N-f 2R-N4ethyl-4S-hydroxy-5S-(4-ainfo-piperidilocarboflvl- *1 Phe-His-amino)-6-cyclohexyilhexyl j-cyclohexanesulfonic acid amide 4 N-[2R-Miethyl-4S-hydroxy-5S-(4-amilo-piperidilocarbolyl- Mal-His-amino)-6-cyclohex±-hexyl-cycioflexaesulfoflic acid amide N-[2R-Methyl-4S-hydroxy-5S-(4-amilo-piperidilocarbonl- Phe-His-amino) -6-cyclohexyl-hexylJ -ethyl-urea N-f 2R-Methyl-4S-hydroxy-5S-(4-amilo-piperidilocarbonl- Mal-His-amino)-6-cyclohexyl-hexyl] -ethyl-urea N-[2R-Methyl-4S-hydroxy-5S-(4-amilo-piperidilocarbofl- Phe-His-amino)-6-cyclohexyl-hexylj -isopropyl-urea N-[2R-Methyl-4S-hydroxy-5S-(4-amino-piperidilocarbonl- Mal-His-amino)-6-cyclohexyl-hexyll -isopropyl-urea Phe-His-amino )-6-cyclohexyl-hexyl] -phenyl-urea N-f 2R-Methyl-4S-hydroxy-5S- (4-arnino-piperidiflocarboflyl- Nal-His-amino )-6-cyclohexyl-lhexyl] -phenyl-urea PAT LOG 9 240289 Example 6 In analogy to Example 4, N-[2S-isopropyl-4S- (pivaloyl-Phe-Gly-amino) -6-cyclohexylhexyl) propanesulfonamide is obtained from pivalic acid and -46- N-f 2R-Methyl-4S-hydroxy-SS- (4-amino-piperidinocarbonyl- Phe-His-amino )-6-c-vclohexvl-hexylj -3-methvlbutyramide N-[2R-Methyi-4S-hydroxv-5S-(4-amino-piperidinocarbonyl- Mal-His-amino)-6-cvclohexvl-hexvlJ -3-methylbutvramide N-[22--Methvl-4S-hvdroxy-5S-(2R-benzvl-3-(L1-amino-piperidinocarbonvl )-propionvl-His-amino)-6-cvciohexyl-hexlprc-anesulfonic acid amide N- [2R-Methvl-4S-hvdroxv-5S- (2S-benzyl-3- (4-amino-piperidinocarbonvl)-propionyl-His-amino )-6-cyclohexvl-hexyl] propanesulfonic acid amide N- [2R-Methvl-4S-hydroxv-5S.- (2R- (l-na.Dhthvlmethyl (4amio-iperidinocarbonvi )-proplonvl-His-nno--clj hexyl-hexyli -propanesulfonic acid arnice N -[2R-Methvl-4S-hvdroxv-5S-(2S-(i-naunimernyi)-3-(4amino-piperidinocar-nonyl )-proplonv,,L-his-ainlno)-o-cvc-Lohexyl-hexyl]-propanesuifonic acia amnicie pentanoyl-His-amino)-6-cvciohaexv±-niexyi f-propaniesuiloniic acid amide 04 20 N-[2R-rMethyl-4S-hvdroxv-5S-(2S-benzyi-5.-N4-inieunIy±-amlno- 4641pentanoyl-His-amin )-6-cyclohexy.i-hexyi J-pro~aie-suitoflic 1101 acid amnide N-[2R-Methyl-4Shydroxy5S-(2R-belzy--N-flethyi-ahilopentanoyl-His-amino )-6-cyclohexyl-Ihexyl] -1-methylethanesulfonic acid amide N- [2R-Methyl-4S-hydroxy-5S- pentnoy-His-mn )-6-cyciohexyl-hiexylJ -1-methylethanesulfonic acid amide N-f 2R-Me'thyl-4S-hydroxy-5S-(2R-benzyl-5-N-iethyl-amniopentanoyl-His-amino )-6-cyclohexyl-hexyl] -ethyl-urea N-[2R-Methyl-4S-hydroxy-5S-(2S-bezyl-5-N-iethyl-aiflopentanoyl-His-amino )-6-cyclohexyl-hexyl] -ethyl-urea.

PAT LOG 9 240289 -47- Example 18 A mixture of 730 mg of N-[2R-methyl-4S-hydroxy-5S-(4amino-piperidino-carbonyl-Phe-His-amino -cyclohexylhexyl]-propanesulfonic acid amide, 90 mg of S-methylisothiourea, 5 ml of ethanol and 5 ml of water is stirred for 2 hours at 50 O. After the usual working up there is obtained N- [2R-methyl-4S-hydroxy-5S- (4-guanidinopiperidinocarbonyl-Phe-His-amino )-6-cyclohexyl-hexyl] propanesulfonic acid amide.

Analogously, there is obtained N-f 2R-methvl-4S.-hydroxy-5S- (4-guanidino-piperidinocarbonyl-Mal-His-amino)y-6-cvclohexvlhexvl]-propansulfonic acid amide.

Example 19 A mixtuie of 730 mg of N-[2R-meu-hyl--4S-h-ydroxy-5S-(4amino-piperidinio-carbonyl-Phe-His-amino )-6-cyclohexylhexyl]-propanesulfonic acid amide, 115 mg of trimethylsilyl isocyanate and 10 ml of THF is stirred for 16 hours at 20 0. The mixture is stirred into water and worked up as usual. There is obtained N-[2R-methyl-4S-hydroxy- 5S-(4-ureido-piperidinocarbonyl-Phe-His-amino)-6-cyclohexyl-hexyl] -propanesulfonic acid amide.

Analogously, there is obtained N-[2R--methyi-4S-hyvdroxy- 5S-(4-ureido-piperidinocarbonyl-Nal-His-amino)-6-cyclohexyl-hexyl] -propanesulfonic acid amide, PAT LOG 9 240289 1 48 and with ethyl isocyanate: N-[2R-Methyl-4S-hydroxy-5S-(4-N'-ethylureido-piperidinocarbonyl-Phe-His-amino)-6-cyclohexyl-hexyl]-propanesulfonic acid amide N-[2R-Methyl-4S-hydroxy-5S-(4-N'-ethylureido-piperidinocarbonyl-Mal-His-amino)-6-cyclohexyl-hexyl]-propanesulfonic acid amide.

The examples which follow relate to pharmaceutical compositions.

i Example A: Tablets o 15 A mixture of 1 kg of 2S-isopropyl-4S-hydroxy-5S- (2-benzyl-4-oxo-5,5-dimethyl-hexanoyl-His-amino)-6cyclohexylhexylhexanonitrile, 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 So active compound.

s0 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-[2S-isopropyl-4S-hydroxy-5S-(2-benzyl- 3-tert.-butylsulfonyl-propionyl-His-amino)-6-cyclohexylhexyl]-butanesulfonamide hydrochloride 1090) 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-isopropyl-4Shydroxy-5S-(4-aminopiperidinocarbonyl-Phe-His-amino)-6cyclohexylhexyl]-propanesulfonamide dihydrochloride in 4 1 of double distilled water is adjusted to pH 6.5 with 2 N hydrochloric acid, filtered sterile and dispensed -i 49 into injection ampoules. These are lyophilized under sterile conditions and sealed sterile. Each injection ampoule contains 50 mg of active compound.

Example E: Suppositories A mixture of 50 g of N-[2S-isopropyl-4S-hydroxy- 5S-(2-benzyl-3-tert.-butylsulfonylpropionyl-His-amino)- 6-cyclohexylhexyl]-methanesulfonamide hydrochloride (m.p.

1120) with 10 g of soya lecithin and 140 g of cocoa butter is melted, poured into moulds and left to cool. Each suppository contains 250 mg of active compound.

gT-

Claims

7-14 C atoms, or bicycloalkyl'Ialkyl or tricycloalkylalkyl each having 8-18 C atoms, R1 is also RO-, RRN-, R'OOC- or AN' An, R ~is OH) NH 2 or =0, R 1 is H, A or CN, L is CHor N, P is 0, NH or NA, V is CHOH, CO, S, SO or S02, 8 8912 3 R RN and NR' 2 R 1 are also each a pyrrolidino, piperidino, morpholino or piperazino group which is unsubstituted or is substituted by A, OH, 7N2 NHA, NA 2 NHAC, NH-CO-C 1 ,H2.-O-R NH- CO-O-C. 2,-R' 5 hydroxyalkyl, COOH, COOA, CONH 2 aiinoalkyl, HAN-alkyl, A 2 N-alkyl, A 3 N~ alkyl An NH-CO-NH NH-CONHgainy or guanidinyl-alkyl, R' is A or Ar-alkyl, s and y are each 0or 1, mn, n, p, r and xare each 01 1, 2, 3,4, 5, 6,7,8, 9 or V Ar is phenyl which is unsubstituted or is substituted one or more times by A, OA, Li Hal, CF 3 ,OH, NO 2 hydroxyalkyl, NH 2 ,NA NA 2 NHA,7, SA, SO-A, SO 2 SO 2 NH 2 SO 2 NHA, COOH, COOA, CONH 2 CN, aininoalkyl, HAN- alkyl, A 2 N'-alkyl, A 3 N4) alkyl Ane and/or guanidinyl-alkyl, or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6- membered heterocyclic radical which has I- 4 N, 0 and/or S atoms and can be fused with a benzene ring and/or be substituted one or more times by A, OA, Hal, CF 3 OH, NO 2 carbonyl oxygen, NH 2 NRA, NA 2 NHAc, SA, SO-A, S0 2 S0 2 NH 2 SO 2 NHA, COOH, COOA, 2'I CN, NHI-SO Ar, rakl 272 A-lk i A 52 Hal Ac An e Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN- alkyl and/or A 2 N-alkyl, and/or whose N and/or S hetero atoms can also be oxid- ized, is F, Cl, Br or I, is A-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH- CO-, 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, is an alkylene group having 1-8 C atoms, t 4r IIr r s fr II 4 t i r L i i i i t -alkyl- 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, as we 2. ll as the salts thereof. a) N-[2-Isopropyl-4-hydroxy-5-(4-aminopiperidino- carbonyl-Phe-His-amino)-6-cyclohexylhexyl]- propanesulfonamide; b) N-[2-Isopropyl-4-hydroxy-5-(2-benzyl-3-tert.- butylsulfonyl-propionyl-His-amino) -6-cyclohexyl- hexyl]-methanesulfonamide. Process for preparation of an amino acid derivative of the formulr I,.accordinq to claim 1 and of the salts thereof, characterized in that it is liberated from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, or in that a carboxylic acid of the formula II R'-G -OH in which G' is absent, Z, Z 1 or one of the reactive derivatives thereof, is reacted with an amino compound of the formula III -53 H-G 2 -NR--CHR 3 CR 4 -CH-CRR6- I I in which G 2 is Z, absent, Z 2 and Z Z 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, R' OH) or NH 2 an amino keto acid derivative of the formula I, R 4 O, is reduced or reductively aminated, and/or a radical R is changed to another radical R and/or a compound of the formula I is converted by treatment with an acid into one of the salts thereof 4. Process for the preparation of pharmaceutical ii 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. Pharmaceutical composition characterized by containing at least one compound of the formula I and/or one of the physiologically acceptable salts thereof. 6. A method of treatment or prophylaxis of diseases of the heart, circulation and vessels, in an animal, including a human, comprising administering to said animal an effective amount of a compound or a physiologically acceptable salt thereof as defined in any one of claims 1 and 2. 7. A method according to claim 6 where said diseases are hypotension or cardiac insufficiency or hyperaldosteronism.
8. A method of treating renin/dependant hyposention or 1V,/ hyperaldostercnism, in an animal, including a human, I( comprising administering to said animal an effective amount of a compound defined in any one of claims I and 2. 1.- PAT LOG 9 240289 -54
9. An amino acid derivative of the formula 1 substantially as herein described with reference to any one of Examples 1-19. DATED this 25th day of September, 1991. MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG By Its Patent Attorneys ARTHUR S. CAVE CO. 4441 44 4i I 4t 4 74M/LFP