AU624579B2 - Renin-inhibiting dipeptides, a process for the preparation thereof, agents containing them, and their use - Google Patents

Description

~ss~~ 624579 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 Form COMPLETE SPECIFICATION

(ORIGINAL)

Class Application Number: Lodged: Int. Class Complete Specification Lodged: Accepted: Published: Priority Related Art: 99 9 t Name of Applicant: Address of Applicant: Abtdal Inventor: rI Addves' for Service 99 HOECHST AKTIENGESELLSCHAFT 45 Bruningstrasse, D-6230 Frankfurt/Main Federal Republic of Germany.

ADALBERT WAGNER, HEINZ-WERNER KLEEMANN, DIETER RUPPERT and BERNWARD SCHOLKENS and HANSJORG URBACH.

EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: RENIN-INHIBITING DIPEPTIDES, A PROCESS FOR THE PREPARATION THEREOF, AGENTS CONTAINING THEM, AND THEIR USE.

us The following statement is a full description of this invention, including the best method of performing it known to i-i -e ;rr. -i i la HOECHST AKTIENGESELLSCHAFT HOE 87/F 291 Dr.WI/sch Specification Renin-inhibiting dipeptides, a process for the preparation thereof, agents containing them, and their use.

EP-A 189,203, EP-A 230,266, EP-A 172,346, EP-A 172,347 and EP-A 229,667 disclose dipeptide derivatives and the use thereof as renin inhibitors.

New peptide derivatives which highly effectively inhibit the enzyme renin in vitro and in vivo have been found.

The invention relates to compounds of the formula I _R2 R9 R3 (I) R -A-B-HN-CH-CH-CH-R 4 in which

R

1 al) is absent or denotes hydrogen, L0 a 2 denotes (C 1

-C

2 0 )-alkyl which is optionally substituted by one, two or three identical or different radicals from the series comprising hydroxyl, (C 1

-C

7 alkoxy, carboxyl, (C 1

-C

7 )-alkoxycarbonyL, (C 1

-C

8 alkanoyloxy, Cl, Br, amino, (C 1

-C

7 )-alkyLamino, Di- 25 (C 1

-C

7 )-alkylamino, (C 1

-C

5 )-alkoxycarbonylamino or (C 7

-C

11 )-aralkyloxycarbonyLamino, or denotes (C 3

-C

8 cycLoalkyL, (C 3

-C

8 )-cycloalkyl-(C1-C 10 )-alkyL or

(C

6

-C

14 )-aryl-(C 1

-C

8 )-alkyL which is optionally substituted in the aryl moiety by one or two identical or I 3P different radicals from the series comprising F, CL, Br, hydroxyl, (C 1

-C

7 )-alkoxy, (C 1

-C

7 )-alkyl, (C 1

-C

7 alkoxycarbonyl, amino or trifluoromethyl, or a3) denotes a radical of the formula II Rf-W_ (II) i; -2in which W represents or -NH-GO-, and R a represents hydrogen, (Cl-G 10 ))-aLkyL which is optionally singly or doubly unsaturated and is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyL, (Cl-C 7 aLkoxy, G 1

-C

7 )-aLkanoyLoxy, carboxyL, (Cl-G 7 )-aLkoxycarbonyL, CL, Br, amino, (Cl-C 7 )-aLkyLamino, Di-(Cl-C 7 alkyLamino, (Cl-C5)-aLkoxycarbonyLamino, C C 7 -G 15 )-araLkoxycarbonyLamino and 9-fLuorenyLmethyLoxycarbonyLamino, or represents (C 3

-G

8 )-cycLoaLkyL, (C 3 -G8)-cycLoaLkyL-L(Cj-

C

6 )-aLkyL, (G 6

-C

14 )-aryL which is optionaLly substituted by one or two identicaL or different radicals from the series comprising F, CL, Br, I, hydroxyL, (G 1

-G

7 -aLkoxy,

(G

1

-G

7 aLkyL, (G 1

-C

7 )-aLkoxycarbonyL, amino and trifLuoromethyL, or represents CG 6

-G

14 )-aryL-(G 1

-G

6 )-aLkyL, in which the aryL moiety is optionaLly substituted by one or two identical or different radicaLs from the series comprising F, CL, Br, I, hydroxyL, (CG-G 7 )-aLkoxy, (Cl-

G

7 )-aLkyL, (CG 1 -W-aLkox~'carbonyL, amino, (G 1

-G

7 )-aLkyLamino, di-(C 1 -r.

7 )-aLkyLamino, carboxyL, carboxymethoxy, amino-(Cl-G 7 )-aLkyL (CG -C 7 )-aLkyLamino-( G 1

-G

7 )-aLkyL di- (C 1

-C

7 )-aLkyL-amino-(G 1

-G

7 )-aLkyL (C 1

-G

7 )-aL koxycarbonyLmethoxy, carbamoyL, suLfamoyL, (C 1

-G

7 )-aLkoxysuLfonyL, suLfo- and guanidinomethyL, or represent the radicaL of a 5- or 6-membered monocycLic or 9- or lO-membered bicycLic heteroaromatic compound which has at Least 1 carbon atom, 1 4 nitrogen atoms and/or 1 sulfur or oxygen atom as 0 ring members too and which is optionalLy mono-, di- or trisubstituted as (C 6

-C

14 )-aryL defined under a 2 A bi) denotes a radical of the formula III or TIIa, 0 0 0 C 1 1 1 i R C 2 n- CH-C- R S CH 2 -CH C (CH 2 )m 2 )n

R

6

R

I I I I I I b -3in wh ic h Ris defined as above, n and m are identicaL or different and denote 0, 1, 2, 3 or 4; R 5and R6 are identicaL or different and denote phenyL, 2- or 3-thienyL, 3- or 4pyridyL, 2- or 4-imidazoLyL, 1- or 2-naphthyL, 2- or 3benzolblthienyL, OH or hydrogen, or b 2 denotes a radlicaL, which is Linked N-terminaL with R 1and C-terminaL with B, of an amino acid from the series comprising phenyLaLanine, histidline, tyrosine, tryptophan, methionine, Leucine, isoLeucine, asparagine, aspartic acid, -2-th ienyLaLanine, B-3-th ienyLaLanine, -2-furyLaLanime, B-3-furyLaLanine, Lysine, ornithine, vaLine, aLanine, 2,4diaminobutyric acid, arginine, 4-chiorophenyLaLanine, methionine suLfone, methionine suLfoxide, 2-pyridyLaLanine, 3-pyridyLaLanine, cycLohexyLaLanine, cycLohexyLgLycine, immethyLhistidine, 0-methyL tyrosime, O-benzyLtyrosine, 0tert.-butyLtyrosime, phenyigLycime, 1-naphthyLaLanine, 2naphthyLaLanine, 4-nitrophenyLaLanine, norvaLime, B-2-ben- 4 zo~blth ienyLaLanine, a-3-benzolblthienyLaLanine, 2-fLuoro- 'P0 phenyLalanine, 3-fLuorophenyLaL anine, 4-f LuorophenyLaLanine, norleucine, cysteine, S-methyLcysteine, 1,2,3,4tetrahydroisoqusinoL ine-3-carboxyL ic acid, homophenyLaL anine, DOPA, 0-dimethyL-DOPA, 2-amino-4-(2-thienyL )-butyric acid, benzodioxoL-5-yLaLanine, N-methyL-h ist idine, 2amino-4-C3-thienyL)butyric acid, 3-(2-thienyL )-serine, (Z)-dehydrophenyLaanime and (E)-dehydrophenyLaLanime, 0 00 B denotes a radlical of an amino acid as defined under 4 44 Rdenotes hydrogen, (Cl-Cl 0 )-aLkyL, (C 4

-C

7 )-cycLoaLkyL, .03 (C 4

-C

7 )-cycLoaLk.,L-(Cl-C 4 )-aLkyL, (C 6 -C l4)-aryL or C C 6 -Cl 4 aryL-(C C-C 4 )-aL kyL, Rdenotes hydrogen, (CC-Cl 0 )-aikyL, (C 6 C14-ay or (C 6 -C14 )-aryL-(C 1

-C

4 )-aL kyL, Rdenotes a radical of the formula IV (CH 2 )p X (CH 2 )q R7(IV) -4- 8with X representing -CF 2 -CO- or -CHR p and q denoting, independently of one another, 0, 1, 2, 3 or 4, and

R

8 denoting (C 1

-C

7 )-alky, (C 1

-C

5 )-akoxy, (C 1

-C

5 )-alkylthio, (C 1

-C

5 )-aLkylamino, -OH, -N 3 -CL, -Br or -I,

R

7 denotes hydrogen, -OH, -NH 2

(C

6

-C

14 )-aryL or heteroaryl, which can also be partiaLLy or compLetely hydrogenated, and R9 can be -OH or -F, and to the physioLogically tolerated salts thereof.

The carbon atoms substituted by R, R3, R and R can each have the R, S or R,S configuration.

Alkyl can be straight-chain or branched. A corresponding statement applies to radicals derived therefrom such as, for example, alkoxy, alkylthio, aLkyLamino, dialkylamino, alkanoyL and aralkyl.

CycloalkyL is to be understood to include alkyl-substituted radicaLs such as, for exampLe, 4-methyLcycohexy or 2,3-dimethylcyclopentyL.

Examples of (C 6

-C

14 )-aryl are phenyl, naphthyl, biphenylyl or fluorenyL; pheny is preferred. A corresponding statement applies to radicals derived therefrom such as, for example, aryLoxy, aroyL, aralkyl and araLkyLoxy. AraLkyl is to be understood to be an unsubstituted or substitued (C 6

-C

14 )-ary radicaL which is Linked to (C 1

-C

6 )-alkyL, such as, for example, benzyL, 03 c a- and 8-naphthyLmethyL, halobenzyl and aLkoxybenzyl, with, however, aralkyl not being restricted to the said radicals.

(F I A radical of a 5- or 6-membered monocyclic or 9- or membered bicyclic heteroaromatic compound which has at Least 1 carbon atom, 1-4 nitrogen atoms and/or 1 sulphur or oxygen atom as ring members is to be understood to include radicals of heteroaromatic compounds as defined in, for exampLe, Katritzky, Lagowski, Chemistry of Heterocyclic Compounds, BerLin, HeideLberg 1968. The heteroaromatic radicaL can be substituted by one, two or three, preferabLy one or two, identicaL or different radicaLs from the series comprising F, CL, Br, hydroxyl,

(C

1 -C7)-aLkoxy, (C 1

-C

7 )-akyL, (C 1

-C

7 )-aLkoxycarbonyL, amino or trifLuoromethyL. Examples of monocyclic heteroaromatic compounds are thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyri midine, pyridazine, 1,2,3,4-triazoLe, thiazoLe, tetrazole, isothiazoLe, oxazoLe and isoxazoLe. Exa"'lIs of bicyclic heteroaromatic compounds are benzothiophene, benzofuran, indoLe, isoindole, indazole, benzimidazole, quinoline, isoquinoLine, phthaLazine, quinoxaLine, quinazoLine and cinnoLine. A corresponding statement appLies to radicaLs derived from heteroaryl compounds such as, for exampLe, partiaLLy or completely hydrogenated heteroaryl, heteroaryloxy, heteroarylthio and heteroaryLaLkyl.

cat The amino acids A and B in formula I are Linked together by an amide bond, and they take the form of naturaL or unnatural a-amino acids of the L, D or D,L configuration, preferabLy of the L configuration.

Salts of compounds of the formula I are to be understood to be, in particular, pharmaceutically utilizable or nona* toxic salts.

S0 Salts of these types are formed, for example, by compounds Lo, 03: of the formula I which contain acidic groups, for example carboxyl, with alkali metals or alkaline earth metals such as Na, K, Mg and Ca, as well as with physiologically tolerated organic amines such as, for example, triethylamine and tri(2-hydroxyethy)amine.

Compounds of the formula I which contain basic groups, for example an amino group or a guanidino group, form salts with inorganic acids such as, for example, -6hydrochLoric acid, suLfuric acid or phosphoric acid and with organic carboxyLic or suLfonic acids such as, for example, acetic acid, citric acid, benzoic acid, maLeic acid, fumaric acid, tartaric acid and p-toLuenesuLfonic ac id.

Preferred compounds of the formuLa I are those in which the radicals are defined as foLlows: R 1 s preferabLy absent, denotes hydrogen or represents (Cl-Cl 0 )-aLkyL. cycLopentyL, cyclohexyl, cycLopentyL-(Cl- Cl 0 )-aLkyL, cycLohexyL-(Cj-Cj 0 )-aLkyL, optionaLly substituted phenyL-( C -C 8 )-aLkyL, H 2 Cj-Cj 0 )-aLkyL, HO-(C Cl 0 )-aLkyL, (C i-C 4 )-aLkoxyCjCj~O)-aLkyL, (Cl-C 4 )-aLkoxycarbonyL-(C i-C 10 )-aLkyL carboxy-(C 1 -Cl 0 )-aLkyL such as 2-hydroxypropionyL or 2-hydroxy-3-methyLbutyryL, (Cl-C 8 aLkanoyLoxy-(Cj-Cj 0 )-aLkyL, (Cl-Cll)-aLkanoyL such as ndecanoyL, formyL, acetyL, pivaLoyL, isovaLeryL or isobutyryl, optionally protected amino-(Cl-Cll)-aLkanoyL such as 4-aminobutyryL, 5-aminopentanoyl, 6-aminohexanoyL, 4-Ntert.-butoxycarbonyL aminobutyryL, 5-N-tert butoxycarbonyLaminopentanoyL or 6-N-tert butoxycarbonyLaminohexanoyL; di-(Cl-Ci7)-aLkyLamino-(C2-Cll1)-ai~kanoyL, such as dimethyLaminoacetyL C C 4

-C

9 )-cycLoaLkyLcarbonyL, such as cycLopropyLcarbonyL, cycLobutyLcarbonyL, cyc LopentyLcarbonyL or cycLohexyLcarbonyL; (C 6 -Cj 0 )-aryL-CC 2 -Cjj)-aLkanoyL, such as phenyLacetyL, phenyLpropanoyL or phenyL- O*.6 butanoyL; benzoyl which is optionally substituted by KK:~halogen, (Cl-C 7 )-aLkyL. (CC-C 7 )-aLkoxy or (Cl-C 7 )-aLkoxycarbonyL, such as 4-chLorobenzoyL, 4-methylbenzoyl, 2- *.3DJ rethoxycarbonyLbenzoyL or 4-methxoybenzoyL; pyrroLyL-2carbonyL; pyridyL-3-carbonyL; benzenesuLfonyL' (CC-Cl 0 aLkoxycarbonyL such as methoxycarbonyL, ethoxycarbonyL or S tert.-butoxycarbonyL, (Cl-Cl 0 )-aLkoxycarbonyL which is S substituted by halogen, such as 2,2,2-trichLoroethoxycarbonyL or 1, 1-dimethyL-2,2,2-tr ichLoroethoxycarbonyL'

C

6 -C 14 C 1 6 )-aLkoxycarboniyL, such as benzyLoxycarbonyL or 9-fLuorenyLmethoxycarbonyL, Ris preferably isobutyL, benzyL or cycLohexyLmethyL, -7-

R

3 is preferabLy hydrogen, isopropyL or isobutyL, R R8 and R are preferably as defined above, R and R 6 are identical or different and preferabLy represent phenyL, 2-thienyL, 2-pyridyl, 1-naphthyL, 2benzolbjthieny, 3-benzoEb3thienyL, OH or hydrogen, and R preferably represents an optionaLly substituted heteroaryL which is as defined above and has 1 or 2 nitrogen atoms as ring members, and n, p and q preferably represent 0 or 1.

Particularly preferred compounds of the formula I are those in which R1 represents isobutylcarbonyl, A denotes Phe or a radical of the formula IIIa in which R1 is (C 1

-C

6 )-aky which can optionally be substituted by -NH 2 or -COOH; n denotes 1 and R5 is phenyl, 2- or 3-thieny B denotes histidine, R 2 is cyclohexylmethyl, 3 R is hydrogen, 4 R represents a radicaL of the formula IV in which q is 0, p denotes 1 or 2, X is -CF 2 -CO- or -CHR and R denotes OH, F, CL, Br, (C 1

-C

4 )-akoxy or (C1-4)alkyl, especially F, and R' represents OH, as well as the physiologically tolerated salts thereof.

Preferred amino acids suitable for the radicals A and B are phenylalanine, histidine, tyrosine, tryptophan, meth- :30 ionine, Leucine, isoleucine, asparagine, aspartic acid, S-2-thienylaLanine, B-3-thienyLaLanine, -2-furylalanine, Lysine, ornithine, 2,4-diaminobutyric acid, arginine, norvaline, 4-chlorophenylalanine, methionine sulfone, methionine suLfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cycLohexylglycine, im-methyhistidine, 0-methyltyrosine, -benzyLtyrosine, -tert.-butyLtyrosine, phenylgLycine, 1-naphthylalanine, 2-naphthylaLanine, 4nitrophenylaLanine, norleucine, valine, aLanine, cysteine, 1 8 8 S-methylcysteine, N-methylhistidine, aLanine, 1,2,3,4-tetrahydroisoquinoLine-3-carboxylic acid, homophenyLaLanine, 2-amino-4-(2-thienyl)butyric acid, dehydrophenyLaLanine or (E)-dehydrophenylalanine. Moreover, A preferably denotes a radical of the formula III as described under (bl).

The invention also relates to a process for the preparation of compounds of the formula I, which comprises coupling a fragment having a terminal carboxyl group, or its reactive derivative, to a corresponding fragment hiving a free amino group, where appropriate eliminating (a) protective group(s) which has (have) been temporarily introduced to protect other functional groups, and converting the resulting compound, where appropriate, into its phy. iologically tolerated salt.

Fragments of a compound of the formula I having a terminal carboxyl group have the formulae Va Vc which follow: Vuoa 3o R1 (Va) o -OH R -A-OH RA-B-OH- Va) a 0 0 1 Fragments of a compound of the formula I having a terminal amino group have the formulae Via VIc which follow: H2N-A-B-NH-CH-CH-CH-R 9

R

2

R

9

R

3 H 1 I 4 (VIb)

H

2

N-B-NH-CH-CH-CH-R

R

2

R

9

R

3 I I 1 4 (Vic) H2N-CH-CH-CH-R Methods suitable for preparing an amide bond are described in, for example, Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), volume 15/2; Bodanszky et al., Peptide synthesis, 2nd ed. (Wiley Sons, New York 1976) or Gross, Meienhofer, The Peptides. Analysis, synthesis, biology (Academic Press, New York 1979). The following methods are preferaoly employed: the active ester method using N-hydroxysuccinimide as ester component, coupling with a carbodiimide such as dicyclohexylcarbodiimide or with propanephosphonic anhydride, and the mixed anhydride method with pivaloyl chloride.

o The optically active amines of the formula VII R 2

R

1I 4

H

2 N-CH-CH-CH-R

(VII)

2 2 9

R

in which R R R and R are as defined above, which are used as starting compounds, are prepared starting from optically active a-amino acids, with retention of the center of asymmetry thereof. For this purpose, an aldehyde of an N-protected amino acid is prepared in a 30 known manner and is coupled, in an aldol-analogous addition, to an appropriate heteroarylalkyl component and, after elimination of the N-protective group, yields amino alcohols of the formula VII (R 9 OH). As an alternative to this, the epoxides are prepared from the protected amino aldehydes via the allylamines in a manner known per se. These epoxides can either be directly reacted with the appropriate arylalkyl nucLeophiles, or are first opened with trimethylsilyl chloride and Nal in Lli~-~ 10 acetonitrile, and the silyl ether is cleaved with CsF, and the iodide is protected using 2,2-dimethoxypropane under acid catalysis as the oxazolidine. This iodide can be reacted with Less reactive nucleophiLes. Synthesis of arylalkyl-substituted amino alcohols extended by one

CH

2 group starts, for example, from Boc-ACHPA-OEt (prepared according to J.Med.Chem. 28, 1779 (1985)).

N, 0 protection is first carried out, then the reduction of the ester group and finally the conversion of the hydroxyl group into a bromide, which can be reacted with arylalkyl nucleophiles under analogous conditions like the electrophiles already mentioned. Examples of suitable arylalkyl nucleophiles are acetylimines and acetylhydrazones. Further compounds of the arylalkyl-substituted amino alcohols having extended CH 2 group(s) can be obtained by the generally customary methods of chain extension. If the chosen synthetic route results in diastereomers in respect of the center carrying R these can be separated in a manner known per se, for example by fractional crystalliza- 20 tion or by chromatography. Examination of the diastereot* meric purity is carried out by HPLC, and the enantiomeric purity can be examined in a known manner by conversion into Mosher derivatives Mosher et al., J. org. Chem.

34, 2543 (1969)).

The method of B. Castro et al. (Synthesis 1983, 676) is 4o used to prepare aldehydes of N-protected amino acids.

Addition of the arylalkyl nucleophiles onto the said N-protected electrophiles (preferably N-tert.-butoxycarbonyl and benzyloxycarbonyl protective groups) is carried out in a solvent which is inert towards bases, such as ether, THF, toluene, DMF, DMSO or dimethoxyethane.

Bases which can be used for the deprotonation of the heteroarylalkyl component are alkali metaL alcohoLates such as potassium O-tert.-butyLate and sodium methylate, alkali metal hydrides such as sodium or potassium hydride, ~I i i i i r 11 organometallic bases such as n-butyllithium, s-butyllithium, methyllithium or phenyllithium, or sodamide, as well as aLkali metal salts of organic nitrogen bases, such as Lithium diisopropylamide.

The operations which are necessary before and after the preparation of compounds of the formula I, such as introduction and elimination of protective groups, are known from the Literature and described, for example, in T.W.

Greene, "Protective Groups in Organic Synthesis". Salts of compounds of the formula I having salt-forming groups are prepared in a manner known per se by, for example, reacting a compound of the formula I having a basic group with a stoichiometric amount of a suitable acid. Mixtures of stereoisomers, in particular mixtures of diastereomers, produced when racemic amino acids A or B are used, can be separated in a manner known per se by fractional crystallization or by chromatography.

The compounds of the formula I, according to the invention, have enzyme-inhibiting properties; in particular, they inhibit the effect of the natural enzyme renin. Renin is a proteolytic enzyme which belongs to the class of aspartyl proteases and is secreted following various stimuli (volume depletion, sodium deficiency, B-receptor stimulation) from the juxtaglomerular cells of the kidney S into the blood circulation. There it eliminates the S decapeptide angiotensin I from the angiotensinogen which is secreted from the liver. The former is converted by 3;0 angiotensin converting enzyme (ACE) into angiotensin II.

Angiotensin II has considerable importance in regulating the blood pressure because it directly increases blood pressure due to vasoconstriction. In addition, it stimulates the secretion of aldosterone from the adrenal and, in this way, it increases, via inhibition of sodium excretion, the extracellular fluid volume, which in turn contributes to increasing the blood pressure. Inhibitors of the enzymatic activity of renin bring about a reduction 12 in the formation of angiotensin I, which results in a reduction in the formation of angiotensin II. The reduction in the concentration of this active peptide hormone is the direct cause of the action of renin inhibitors to Lower blood pressure.

The activity of renin inhibitors can be checked by in vitro assays. These entail measurements of the reduction in the formation of angiotensin I in various systems (human plasma, porcine renin). For this purpose, for example, human plasma, which contains both renin and angiotensinogen, is incubated at 370C with the compound to be tested. The concentration of angiotensin I which has been formed during the incubation is then measured using a radioimmunoassay. The compounds of the general formula I described in the present invention show, in the in vitro assays used, inhibitory effects at concentrations of about 5 to 10 10 mol/l.

20 Renin i-hibitors lower the blood pressure of salt-restricted animals. Since human renin differs from the renin from other species, the in vivo assay of renin inhibitors makes use of primates (marmosets, rhesus monkeys).

The sequences of primate renin and human renin are substantially homologous. Endogenous renin release is stimulated by i.v. injection of furosemide. The test com- S pounds are then administered by continuous infusion, and S*o their effect on blood pressure and heart rate is measured.

o os The compounds of the present invention are effective in 3$0 these tests in a dose range of about 0.1 5 mg/kg i.v.

The compounds of the general formula I described in the present invention can be used as antihypertensives and for the treatment of cardiac insufficiency.

Hence the invention also relates to the use of compounds of the formula I as medicines, and to pharmaceutical compositions which contain these compounds, as well as to a process for the preparation thereof. Administration 1 13 to primates, especially to humans, is preferred.

PharmaceuticaL products contain an effective amount of reactive compound of the formula I together with an inorganic or organic vehicle which can be used in pharmacy.

Administration can be intranasal, intravenous, subcutaneous or oral. The dosage of the active compound depends on the warm-blooded species, the body weight, age and mode of administration.

The pharmaceutical products of the present invention are prepared in solution, mixing, granulating or coating processes known per se.

For a form for oral administration, the active compounds are mixed with the additives customary for this purpose, such as vehicles, stabilizers or inert diluents, and converted by customary methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions, Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, in particular corn starch. In this connection, the formulation can be carried out both as dry and wet granules. Examples of S oily vehicles or solvents are vegetable or animal oils Ssuch as sunflower oil and fish liver oil.

o *3 0 For subcutaneous or intravenous administration, the active compounds or their physiologically tolerated salts are converted into solutions, suspensions or emulsions, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries.

Examples of suitable solvents are: water, physiological saline solutions or aLcohols, for example ethanoL, propane dioL or glycerol, as well as sugar solutions such as gLucose or mannitol solutions, or a mixture of the various 14 soLvents mentioned.

List of abbreviations used: A c

ACHFA

TLC

DC C

DNP

DMF

DMS0 E A E I E to c F AB n2~ H HOBt I v a

M

MeCH M S

MTB

R.T.

4 99 M 1* 9S t

THF

Z

AcetyL E3S,4SJ-4-amino-3-hydroxy-5-cycLohexyLpentanoic acid tert.-ButoxycarbonyL ButyL lithium D jethyLaminosuLfur tnifluoridle Thin-Layer chromatography DicycLohexyLcarbodiimide Desorption ChemicaL Ionization DiisopropyL ether 2,4-DinitrophenyL Di methyl formam ide D imethyL suLfoxidle Ethyl acetate ELectron Impact EthoxycarbonyL Fast atom bombardment Hex ane 1-Hydroxybenzot r iazoL e Is oval ery I MolecuLar peak Methanol Mass spectrum Methyl tert.-butyL ether Room temperature Melting point E3S,4S]-4-amino-3-hydroxy-6-methyLheptanoic acid B-2-Th ieny Ialan ine Tetrahydrofuran BenzyL oxyc arbonyL 1. The other abbreviations used for amino acids correspond to the three-Letter code customary in peptidle chemistry, as is described in, for example, Europ. J. Biochem. 138, 9-37 (1984). Unless expressLy indicated otherwise, the amino acids always have the L configuration.

15 The exampLes which folLow serve to illustrate the present invention without intending to restrict it to them.

Example 1 Iva-Phe-His 1(S)-cycLohexylmethyL-2(S)-hydroxy-6-oxo-6phenyihexylamide 150 mg of Iva-Phe-Ris(DNP) 1(S)-cycLohexyLmethyL-2(S)hydroxy-6-oxo-6-phenyLhexyLamide are stirred in 5 mL of acetonitrile and 0.1 mL of thiophenoL at R.T. for 10 h.

Concentration in vacuo is foLLowed by chromatography on siLica gel (mobile phase CH 2

CL

2 /MeOH 12/1). Concentration of the product-containing fractions provides the product as a pale yellow powder.

Rf(CH 2

CL

2 /MeOH 12/1) 0.2; MS (FAB) 672 (M+1) a) Iva-Phe-His(DNP) 1(S)-cyclohexylmethyl-2(S)-hydroxy- 6-oxo-6-phenylhexyLamide 70 pL of pivaloyl chloride are added at -5 C to 300 mg of Iva-Phe-His(DNP)-OH, 46 p1 of pyridine and 80 p1 of .0 N-ethyLpiperidine in 5 mL of CH 2

CL

2 The mixture is S stirred at +5oC to +100C for 30 minutes are then cooled S to -10 0 C, and 165 mg of 1(S)-cyclohexylmethyl-2(S)-hy- 5 droxy-6-oxo-6-phenylhexylamine in 5 mL of CH 2

CL

2 are added dropwise. The mixture is stirred without cooling for 16 h, concentrated in vacuo, and the residue is a~ taken up in 100 ml of EA. The solution is washed 3 .a times with aqueous K 2 C0 3 soLution and once with H 2 0, dried over Na 2

SO

4 and concentrated in vacuo. Chromatography on silica gel (mobile phase EA) results in the title compound as a pale yellow powder.

Rf (EA) 0.3; MS (FAB) 838 (M+1) 6 35 b) Iva-Phe-His(DNP)-OH was prepared by the procedure described in J.Am.Chem.Soc. 86, 1839 (1964).

-16 C) 1 CS)-CycLohexyLmethyL-2(S)-hydroxy-6-oxo-6-phenyLhexy lam ine 200 mg of 3-Boc-4( S)-cyc LohexyLmethyL-2,2-d imethyL- 5-(4-dimethyLhydrazono-4-phenyLbutyL )oxazoL idine are dissoLved in 10 ml of dlimethoxyethane and, while cooling (T -10 0 10 ml of dlimethoxyethane saturated with HCI are added dropwise, and the mixture is stirred for 3 h. it is now concentrated, and the residue is tLaken up in H 2 0, and the soLution is adjusted to pH 9-10 with saturated Na 2 C0 3 solution and extracted 3 times with EA. Drying results in the title compound, which is used without further purification in the ne'xt reaction step.d) 3-Boc-4(S )-cycLohexyLmethyL-2,2-dimethyL-5-C4-dimethyLhydrazono-4-phenyLbutyL)oxazoLidine 0.8 mL of n-butyLLithium (1.5 M in hexane) is added dropwise at 78 o C under an argon atmosphere to 203 mg of acetophenone dimethyLhydrazone (prepared by the procedure indicated in J.Org.Chem. 31, 677 (1966)) in 10 mL of dry THF. After 15 minutes, 303 mg of 3-Boc-4(S)-cycLo- 0:hexyLmethyL-2,2-dimethyL-5-(2-bromoethyL)oxazoLidine in a .5 3 ml of THF are added, and the mixture is then stirred 0 00 without cooling for 2 h. HZ0 is then added, and the mixture is extracted 3 tLimes with EA. Drying over Na 2 S0 4 is foLlowed by concentration and chromatography on silica 00 gel (mobile phase: EA/hexane 0 1.30 Rf (hexane/EA 8/1) 0.5; MS (DCI) 487 (M+1) o0: e) 3-Boc--4(S)-cycLohexyLmethyL-2,2-dimethyL-5-(2-bromoethyl )oxazoLidine 1.6 ml cf dliethyl azodicarboxyLate are added dropwise at 200C to 690 mg of 3-Boc-4(S)-cycLohexyLmethyL-2,2dimethyL-5-(2-hydroxyethyL)oxazoLidine, 2.6 g of triphenyLphosphine and 1.6 g of pyridlinium hydrobromidle in 15 mL 17 of CH 2

CI

2 under argon. After 16 h at H 2 0 is added, and the mixture is diluted with 100 ml of CH 2

CL

2 The organic phase is washed twice witn saturated NaHCO 3 solution and once with saturated NaCL solution. The organic phase is dried with Na 2

SO

4 and concentrated, and the residue is taken up in a Little EA and filtered to remove PPh 3 Purification on silica gel provides the title compound (mobile phase: H/EA 15/1).

Rf (H/EA 15/1) 0.3; MS (EI) 404 (M) f) 3-Boc-4(S)-cyclohexylmethyL-2,2-dimethyl-5-(2-hydroxymethyl)oxazolidine g of Boc-ACHPA-OEt (J.Med.Chem. 28, 1179 (1985)), 500 mg of p-toluenesulfonic acid and 7.2 ml of dimethoxypropane in 160 ml of toluene are heated at 800C under argon for 2 h.

The mixture is then concentrated. The residue is added dropwise at 0°C to a suspension of 2 g of LiALH 4 in 200 ml of THF. After 2.5 h at 00C, 100 ml of 5 strength NaHS04 solution are added, and the mixture is extracted 3 times with EA. The combined organic phases are washed once with saturated NaHCO 3 solution. Drying with Na 2

SO

4 is followed by concentration and chromatography (mobile phase: H/EA 2/1).

25 Rf (H/EA 4/1) 0.1; MS (EI) 342 (M+1) Example 2 Iva-Phe-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-6-oxo-6- (2 -pyridyl)hexylamide The title compound was prepared from Iva-Phe-His(DNP) 1- (S)-cyclohexylmethyL-2(S)-hydroxy-6-oxo-6-(2-pyridyL)hexylamide in analogy to Example 1.

Rf (EA/MeOH 5/1) 0.25; MS (FAB) 673 (M+1) S a) Iva-Phe-His(DNP) 1(S)-cyclohexylmethyl-2-(S)-hydroxy- 6-oxo-6-(2-pyridyL)hexylamide 1_ I 18 270 mg of 3-Boc-4(S)-cyclohexyLmethyL-2,2-dimethy-5- [4-(2-pyridy)-4-oxobutyLtoxazoLidine are dissoLved in mL of dimethoxyethane and, while cooLing, (T 10 0

C),

mL of dimethoxyethane saturated with HCL are added dropwise, and the mixture is stirred for 3 h. The hydrochloride is obtained by concentration at R.T. For the coupling, 68 p1 of pivaloyl chloride are added at -50C to 335 mg of Iva-Phe-His(DNP)-OH, 45 p1 of pyridine and 230 p1 of N-ethyLpiperidine in 5 mL of CH 2

CL

2 After 10 minutes at +10 0 C, the mixture is cooled to 0 0 C, and the hydrochloride described above is added dropwise in 2 ml of CH 2 CL2 After 2 h at 00C, the mixture is stirred for a further 16 h at R.T. Working up and purification are carried out in analogy to Example la).

Rf (EA) 0.1; MS (FAB) 839 (M+1) b) 3-Boc-4(S)-cycLohexyLmethyL-2,2-dimethyL-5-C4-(2pyridyl)-4-oxobutyL]oxazolidine.

0.8 mL of n-butyllithium (1.5 M in n-hexane) is added at a -60 0 C under an argon atmosphere to 160 p1 of diisonropyLt amine in 10 mL of THF. After 1 h at -50 C, 225 mg of N- [1-(2-pyridyL)ethyLidenecycLohexyamine in 3 mL of THF are ai. added. The mixture is Left to stir at 00 C for 1 h, during which an intense red coloration appears. 300 mg of 3-Boc- 4(S)-cyclohexylmethyL-2,2-dimethyl-5-(2-bromoethyL)oxazolidine in 2 mL of THF are now added, and the reaction is stopped after 1 h by addition of H 2 0. Extraction with EA, drying over Na 2

SO

4 and concentration are followed by chromatography on silica gel (mobiLe phase: hexane/EA 4/1).

S.

Rf (hexane/EA 4/1) 0.3; MS (DCI) 444 (M) 'a g( tt c) N-E1-(2-pyridy)ethyidenelcycohexyLamine 20 g of 2-acetylpyridine, 30 g of cyclohexylamine and 0.5 g of p-toluenesulfonic acid in 250 ml of toluene are heated to boiling with use of a water trap for 24 h. The mixture is then distilled in vacuo.

19 BoiLing point (0.05 torr) =102 0

C

Example 3 lva-Phe-His 1 (S)-cycLohexyLmethyL--2(S ),6(R,S)-dihydroxy- 6-(2-pyr idyL )hexylamide The title compound was synthesized in anaLogy to ExampLe 1 from Iva-Phe-His (DNP) 1 (S )-cycLohexyLmethyL-2(S) ,6(R,S dihydroxy-6-(2-pyridyL)hexyLamide.

Rf (EA/MeOH 3/1) 0.6; MS (FAB) =675 (M+1) a) Iva-Phe-His(DNP) 1 (S)-cycLohexyLmethyL-2(S),6(R,S)dihydroxy-6-(2-pyridyL)hexyLamide The title compound was obtained fromr 300 mg of 3-Boc-4(S)cycLohexyLmethyL-2,2--dimethyL-5--E4(R,S)-hydroxy-4-(2pyridyL)butyL]oxazoLidine in analogy to Example 2a).

Rf (EA/MeOH 10/1) 0.25 MS (FAB) 841 (M+l) b) 3-Boc-4(S)-cyc LohexyLmethyL-2,2-dimethyL-5-E4(R,S hydroxy-4-C2-pyridyL)butyL~oxazoL idine 130 mg of 3-Boc-4(S)-cycLohexyLmethyL-2,2-dimethyL-5- [4-(2-pyridyL)-4-oxobutyL]oxazoLidine and 40 mg of sodium 2, 5 borohydridle in 5 ml of ethanol are stirred at R.T. for minutes. Addition of 15 ml of H 2 0 is followed by extraction 3 times with EA, drying over Na 2

SO

4 and concentration. Chromatography on silica gel (mobiLe 4' phase EA/hexane 1/1) provides the title compound.

30 Rf (EA/hexane 1/1) 0.4; MS (El) 446 WM The compounds of Examples 4 and 5 are prepared in analogy to Example 3.

Example 4 Iva-Phe-His 1 (S)-cycLohexyLmethyL-2(R),6(R,S)-dihydroxy- 6-(3-pyridyL)hexyLamide Rf (EA/MeOH 3/1) 0.4; MS (FAB) =675 (M+1) Example Iva-Phe-His 1 (S)-cycLohexyLmethyL-2(R),6(R,S)-dihydroxy- 6 -(4-pyridyL)hexyLamide Rf (EA/hexane 3/1) MS (FAB) 675 (M+1) Example 6 Iva-Phe-His 1 (S)-cycLohexyLmethyL-2(S)-hydroxy-6(R,S)methoxy-6-(2-pyridyL)hexyLamide The titLe compound was obtained from 3-Boc-4(S)-cycLohexyLmethyL-2,2-dimethyL-l-4(R,S)-methoxy-4(2pyidyL)butyijoxazoLidline in analogy to ExampLe 2, 2a).

Rf CEA/MeOH 5/1) =0.15; MS (FAB) =689 (M+1) a) 3-Boc-1 (S)-cyctohexyLmethyL-5-[4(R,S)-methoxy-4-(2pyridyL)butyLjoxazoLidine.

The titLe compound was obtained from 3-Boc-4CS)-cycLohexylrethyL-2,2-dimethyL-5-[4(R,S)-hydroxy-4-(2-pyridyL)-butyLjoxazoLidline in analogy to Acta Chem. Scand. 26, 1 (1972).

Rf (DIP) 0.25; MS (FAB) =461 (M+1) Example 7 00 Iva-Phe-His 1 (S)-cycLohexyLmethyL-2(S)-hydroxy-6(R,S)ethoxy-6-(2-pyridyL)hexyLamide was obtained in anaLogy to ExampLe 6.

Rf CEA/MeOH 5/1) 0.15; MS (FAB) 703 0 ExampLe 8 00 0 0 30 Iva-Phe-His l(S)-cyct~ohexyLmethyL-2(S)--hydroxy-6(R,S)fLuoro-6-(4-pyridyL)hexylamide The title compound was obtained from 3-Boc-4(S)-cycLo- O*:*hexyLmethyL-2,2-difnethyL-5-E4(R,S)-fLuoro-4-C4-pyridyL)- 0*3 butyiloxazoLidline in aiiaLogy to ExampLe 2, 2a).

0 Rf (EA/MeOH 4/1) 0.3; MS (FAB) 677 CM+1) a) 3-B~oc-4(S)-cycLohexyLmethyL-2,2-d imethyL-5-[4-(RS)- -21 fLuoro-4-(4-pyridyL )butyL]oxazoL idine 160 mg of 3-Boc-4CS )-cycLohexyLmethyL-2,2-d E4(R,S)-hydroxy-4--(4-pyri,'yL)butyL~oxazoLidine in 2 mL of CH 2

CI

2 are added dropwise to a soLution of 50 p1 of diethyLaminosuLfur trifLuoridle (DAST) at -35 0 C under an argon atmosphere. After 75 minutes, 10 mL of saturated Na 2

CO

3 solution are added, and the mixture is extracted 3 times with EA. Drying over Na 2

SO

4 and concentration are followed by chromatography on silica gel (mobile phase hexane/EA 1/1).

Rf (hexane/EA i/1) 0.3; MS (FAB) 449 (M+f1) ExampLe 9 Iva-Phe-His 1 5-(2-pyridyL)pentyLamide The title compound was synthesized from 4(S)-cycLohexyLme thyL-5--E3(CR, S)-hydroxy-3- (2-pyr idyL) propyL~oxazoL id in- 2-one in analogy to Example 2, 2a).

Rf (EA/MeOH 3/1) 0.2; MS (FAB) =661 (M+1) a) 4(S)-cycLohexyLmethyL-5-[3(R,S)-hydroxy-3-(2-pyridyL propyL~oxazoLidin-2-one The title compound is synthesized from 4(S)-cycLohexyLmethyL-5-E3-(2-pyridyL)-3-oxopropyL~oxazoL idin-2-one in analogy to Example 3b).

Rf (EA) 0.4; MS (FAB) 319 (M+1) b) 4(S)-cycohexyLmethyL-5-E3-(2-pyridYl )-3-oxopropyLJ- 3 mL of n-butyLLithium (1.5 M in hexaine) are added dropwise at 6 0 O 0C under an argon atmosphere to 0.6 mL of diisopropyLamine in 20 ml of THF, and the mixture is stirred at 0 0 C for 45 minutes. Now 850 mg of N-E1-(2pyridyL)ethyLidenelcycLohexyLamine in 3 mL of THF are 22 added at -50 0 C, and the mixture is then stirred at 0 0 C for 1 h (red coLoration). Then 380 mg of Boc-2-cycLohexyL- 1(S)-oxiran-2(S)-yLethyLamine in 5 mL of THF are added dropwise. After 60 minutes at 0 0 C, H 2 0 is added, and the mixture is extracted 3 times with EA. Drying over Na 2

SO

4 is foLLowed by chromatography on silica gel (mobile phase: hexane/EA 1/1).

Rf (hexane/EA 1/1) 0.3; MS (FAB) 317 (M+1) c) Boc-2-cycLohexylmethy-1(S)-oxiran-2(S)-yLethyLamine 2.6 g of Boc-I(S)-cycLohexymethyL-2-propen--yLamine are dissoLved in 50 ml of CH 2

CL

2 ana 1.9 g of m-chloroperbenzoic acid in 50 mL of CH 2

CL

2 are added dropwise at 00C. The reaction solution is stirred at R.T. for 36 h and then extracted first with 100 mL of 5 strength aqueous Na 2 S0 3 solution and then with 100 mL of saturated aqueous Na 2 SO3 solution. Drying over Na2S04 and concentration in vacuo are followed by chromatography on silica gel (mobile phase: MTB/cyclohexane resulting in the title compound as a colorless oil, in addition to the 2(R)isomer.

Rf (MTB/cyclohexane 1/1) 0.4; MS (FAB) 270 (M+1) 25 d) Boc-1(S)-cyclohexylmethy-2-propen-1-yLamine 5.4 g of methyltriphenylphosphonium bromide are suspended in 100 mL of THF and, at 1.7 g of potassium t- Sbutylate are added under argon. The mixture is stirred at R.T. for 2 h, cooled to 00 C and 3.9 g of Boc-cyclohexylalaninal in 50 mL of THF are added dropwise. The mixture is then stirred at 00 C for 30 minutes, 100 mL of

H

2 0 are added dropwise, and the THF is removed in vacuo.

100 mL of saturated aqueous NaHCO 3 solution are added, and the mixture is extracted 3 times with 100 mL of CH 2

CL

2 Drying over Na 2

SO

4 and concentration in vacuo are followed by chromatography on silica gel (mobile phase: MTB/cycLohexane 1/3) resulting in the title compound as a colorless -23 o iL.

Rf (MTB/cycLohexane 1/3 MS (Dci) 254 (M+1) e) Boc-cycLohexyLaLaninaL was obtained by the method described in J.Med.Chen. 28, 1179 (1985).

Example Iva-Phe-His 1 fLuoro-5-(2-pyridyL)pentyLamide The title compound was obtained in analogy to ExampLe 2, 2a from 3.Boc-4(S)-cycLohexyLmethyL-2,2-dimethyL-5-[ 3 R,S fLuoro-3-C2-pyridyL)propyloxazoLidine.

Rf (EA/MeOH 5/1) 0.3; MS (FAB =663 (M+1) a) 3-Boc-4(S )-cyc LohexyLmethyL-2,2-dimethyL-5C3( R,S fLuoro-3-C2-pyridyL)propyL~oxazoLidine The title compound was obtained in analogy to Example 3 b) and 8 a) from 3-Boc-4(S)-cycLohexyLmethyL-2,2-dimethyL- 5-[3-(2-pyridyL)-3-oxopropyL]oxazoL idine.

Rf (EA/hexane 1/1) 0.7; MS (DCI) 435 (M+1) b) 3-Boc-4 S )-cyc LohexyLmethyL-2,2-dimethyL-5-E3-( 2 225 pyridyL)-3-oxopropyL~oxazoL idinie The title compound was prepared in an,-Logy to Example 9 b) from 3-Boc-4(S )-cycLohexyLmethyL-2,2-dimethyL-5(S)- 4. iodomethyLoxazoLidine.

Rf (DIP) 0.7; MS (El) 430 WM I c) 3-.Boc-4(S)-cycLohexyLmethyL-2,2-dimfethyL-5(S )-iodomethyLoxazoLidine 2.4 g of Boc-2-cycLohexyL-1(S)-oxiran-2(S)-yLethyLamile, 1.3 g of NaI and 1.1 ml of trimethyLsiLyL chloride are dissolved in 100 ml of acetonitriLe and stirred at R.T.

for 1.5 h. Then 1 equivalent of cesium fluoridle in THF -24 and 5.3 ml of dlimethoxyethane are injected. The mixture is stirred at R.T. for 2.5 h and then 200 mL of saturated aqueous NaHCO 3 soLution are added, and the mixture is extracted 3 times with 200 ml of MTB. Drying over Na 2

SO

4 and concentration in vacuo are followed by chromatography on silica gel (mobile phase: MTB/diisopropyL ether 1/2) resulting in the title compound as a colorLess oil.

Rf (MTB/DIP 1/2) 0.5; MS 422 (M-CH 3 Example 11 Iva-Phe-His 1 (S)-cycLohexyLmethyL-2(S)-hydroxy-6(R, fLuoro-6--C2-pyridyL)hexyLanide The title compound was obtained from 3-Boc-4(S)-cycLohexyLmethyL-2,2-dimethyL-5-[4(R,S)-fLuoro-4-(2-pyridyL butyLjoxazoLidine in analogy to Example 2, 2 a).

Rf (EA/MeOH 5/1) 0.2; MS (FAB) =677 (M+1) a) 3-Boc-4(S)-cyc LohexyLmethyL-2,2-dimethyL-5-E4(R,S fLuoro-4-(2-pyridyL)butyL]oxazoLidine was obtained in analogy to Example 8 a).

Rf (H/EA 1/1) 0.6; MS (FAB) 449 CM+1) Example 12 Iva-Phe-His 1 (S)-cycLohexyLmethyL-2(S)-hydroxy-6,6difLuoro-6-(4-pyridyL )hexyLamide The title compound was obtained in anaLogy to ExampLe 2, 4t~t 2 a) from 3-Boc-4(S)-cycLohexyLmethyL-2,2-dimethyL-5-[4,4difLuoro-4-(4-pyridyL)butyL~oxazolidine.

Rf (EA/MeOH) 0.2; MS (FAB) 695 (M+1) a) 3-Boc-4(S )-cyc LohexyLmethyL-2,2-dimethyL-5-C4,4difLuoro-4-(4-pyridyL)butyL~oxazoLidine 1 ml of DAST is added at Co C to 200 mg of 3-Boc-4CS)cycLohexyLmethyL-2,2-dimethyL-5-E4-(4-pyridyL)-4-oxobutyLJoxazoLidline in 2 ml of CH 2

CL

2 After 2 days at R.T., 25 mL of saturated Na 2 C0-3 solution are added, and the mixture is extracted 3 times with EA. Drying with Na 2

SO

4 and concentration in vacuo are followed by chromatography on silica gel (eLuent H/DIP resulting in the titLe compound as an oiL.

Rf (H/EA 1/1) =0.45; MS 467 CM 1) C m ry Le 13 Iva-Phe-His 1 CS)-cycLohexyLmethyL--2(S)-hydroxy-5,5-difLuoro- 5-(2-pyridyL )pentylamide The title compound was obtained from 3-Boc--4CS)-cycLohexyLmethyL-2,2-dimethyL-5-[3,3-difLuoro-3-(2-pyridyL)propyloxazoLidine in analogy to Example 12, 12 a).

Rf (EA/MeOH 5/1) 0.3; MS (FAB) 681 (M 1) Example 14 Iva-Phe-His 1 isop ropy 1-5- 2 -p yr idy L )p eii ty Iam ide The title compound was obtained from 3-Boc-4(S)-cycLohexyLmethyL-2,2-dimethyL-5-[3(R,,S)-isopropyL-3-(2-pyridyL)propyloxazoLidline in analogy to Example 2, 2 a).

Rf (EA/MeOH 5/1) MS (FAB) 687 (M+1) a) 3-Boc-4(S)-cycLohexyLmethyL-2,2-dimethyL-5-E3(R,S isopropyL-3-(2-pyridyL)propyLloxazoLidine 144 1.3 ml of 1.5 M n-BuLi (soLution in hexane) are added at 4:1 30 -60o0. to 250 mg of 2-isobutyipyridine in 10 ml of THF.

The reaction temperature is then maintained at R.T. for minutes and, after cooling once again to -600C, 500 mg of 3-Boc-4( S)-cyc LohexyLmethyL-2,2-dimethyL-5-(2-bromoethyL)oxazoLidine in 10 ml of THF are added dropwise.

After 2 h at -600 C, 20 mL of H 2 0 are added, and the crude product is isolated by extraction 3 times with EA.

Chromatography on silica gel (DIP/H 2/1) provides the product as an oil.

26 Rf (DIP) 0.6; MS (FAB) 459 (M+1) b) 2-IsobutyLpyr idine 4C ml of 1.5 M n-BuLi (solution in hexane) are added dropwise at -600 C to 5 g of 2-picoline in 50 ml of diethyl ether. After 1.5 h at the mixture is cooled once again to -60 0 C, and 10 g of 2-iodlopropane are added dropwise. After 30 minutes at 60 O C, the mixture is stirred at R.T. for 60 minutes. Then 50 ml of H 2 0 are added, and the crude materiaL is isolated by extraction 3 times with diethyL ether. It is then purified by dlistillation under reduced pressure. Boiling point mm) 85 0 C.

Example Iva-Phe-His 1 (S)-cycLohexyLmethyL-2(S)-hydroxy-4-isopropyL-4-C2-pyridyL)butyLamide (Non-polar isomer) The title compound was obtained from 3-Boc-4(S)-cycLohexyLmethyL-2,2-dimethyL-5(S)-iodomethyLoxazoL idine in anaLogy to Example 14.

Rf (EA!MeOH 5/1) 0.2; MS (FAB) 673 (M+1) 0 4 Example 16 Iva-Phe-His 1 (S)-cyc LohexyLmethyL-2(S)-hydroxy-4-isopropyL- 4-(2-pyridyL)butyLamide (Polar isomer) It The title compound was obtained in analogy to Example 14 and Rf (EA/MeOH 5/1) 0.15; MS (FAB) 673 (M+1) ExampLe 17 Iva-Phe-His 1 (S)-cycLohexyLmethyL-2(S)-hydroxy-6(R,S ethoxy-6-(4-pyridyL)hexyLamide -27 The title compound was obtained in anaLogy to ExampLe 6.

Rf CEA/MeOH 5/1) MS (FAB) =703 (M 1) ExampLe 18 Iva-Phe-His 1 (S)-cyclohexyLmethyL-2(S)-hydroxy-6(R,S)n-propoxy-6-(4-pyridyL)hexyLamide The title compound was obtained in analogy to Example 2, 2a from 3-Boc-4(S)-cycLohexyLrnethyL-2,2-dimethyL-5-[4(R,S n-propoxy-4-(4-pyridyL )butyL]oxazoLidine.

Rf (EA/MeOH 5/1) 0.15; MS (FAB) 717 (M 1) a) 3-Boc-4(S)-cycLohexyLmethyL-2,2-dimethyL-5-E4(CR,S n-propyL-4-(4-pyridyL)butyLloxazoLidine The titLe compound was obtained in analogy to ExampLe 6a using n-propyL bromide as alkyLidine reagent.

Rf (EA/hexane 1/2) 0.3; MS (DCI) 489 (M 1) ExampLe 19 a) 3-t-ButyLsuLfonyL-2(R )-phenyLmethyLpropionyL-His 1(S)-cycLohexyLmethyL-2CS)-hydroxy-5(R,S)-fLuoro- 5-C2-pyridyL )pentyLamide and B) 3-t-ButyLsuLfon\,L-2CS )-phenyLmethyLpropionyL-H is 5-(2-pyridyL)pentyLamide The two title compounds were obtained from 3-t-butyLsuLfonyL-2(R,S)-phenyLmethyLpropionyL-His(DNP) 1CS)-cycLohexylmethyL-2(S)-hydroxy-5(R,S)-fLuoro-5-(2-pyridyL)pentyLamide in anaLogy to Example 1 with subsequent separation of the dliastereomers (ct,8) on silica gel (eLuent: EA/MeOH 5/1).

at) Rf (EA/MeOH 5/1) 0.25; MS (FAB) 698 CM 1) 8)Rf (EA/MeOH 5/1) 0.15; MS (FAB) =698 CM 1) a) 3-t-ButyLsuLfonyL-2(R,S)-phenyLmethyLpropionyL-His (DNP) 1(S)-cycLohexyLmethyL-2(S)-hydroxy-5(R,S)-fLuoro-5- (2-pyridyL)pentyLamide -2 200 mg of H-His(DNP) l(S)-cycLohexyLmethyL-2(S)-hydroxy- 5(R,S)-fLuoro-5-C2-pyridyL)pentyLamide in 5 mL of THF were added dropwise at 0 0 C to 95 mg of 3-t-butyLsuLfonyL-2(R,S)-phenyLmethyLpropionic acid (see ExampLe 22), 84 mg of HO~t and 95 mg of DCC in 10 ml of THF. The mixture was then stirred at RT for 16 h.

Addit ion of 20 mL of saturated Na 2

CO

3 was foLLowed by extraction 3 x with 25 mL of EA, and the combined organic phases were dried with sodium sulfate and concentrated. The mixture was then used without further purification in the next reaction step.

b) H-His(DNP) 1(S)-cycLohexyLmethyL-2(S)-hydroxy-5(R,S)fLuoro-5-(2-pyridyL)pentyLamide The title compound was obtained in analogy to Example lc from 300 mg of Boc-His(DNP) 1(S)-cycLohexyLmethyL- 2(S)-hydroxy-5CR,S)-fLuoro-5-(2-pyridyL )pentyLamide and used without further purification.

c) Boc-His(DNP) 1 fLuoro-5-(2-pyridyL)pentyLamide 2 4 The title compound was obtained in analogy to Example la from Boc-His(DNP)-OH and N-Boc-1CS)-cycLohexyLmethyL- 2(S)-hydroxy-5(R,S)-fLuoro-5--C2-pyridyL)pentyLamide after elimination of the Boc group (1c).

0~ 30 Rf (EA/MeOH 10/1) MS (FAB) =698 (M 1) dl) N-Boc-1 5-C2-pyridyL)pentyLamide The title compound was obtained in analogy to Tetrahedron Lett. 28, 4185, (1987) from 350 mg of 3-Boc-4(S)cycLohexyLmethyL-5(S)-3(R,S)-fLuoro-3(2-pyridyL)propyL]> oxazoLidin-2-oie at 40 to 50 0

C.

29 -0.55; MS (DCI) 395 (M 1) Rf EA) e) 3-Boc-4(S)-cycLohexyLmethyL-5(S)-E3(R,S )-fLuoro-3- C2-pyridyL)propyL~oxazoLidin-2-one 300 mg of 4(5 )-cyc LohexyLmethyL-5(S )-fLuoro-3- (2-pyridyL)propyL~oxazoLidin-2-one, 156 iIL of triethyLamine, 23 mg of dlimethyLaminopyridline and 265 mg of dli-t-butyL pyrocarbonate were stirred in 10 ml of

CH

2

CL

2 at RT for 16 h. The mixture was then concentrated and chromatographed on silica gel.

Rf (EA) 0.55; MS (DCI) 421 (M H) f) 4(S)-CycLohexyLmethyL-5(S)-E3(R,S)-fLuoro-3-(2-pyridyL propyL~oxazoL idin-2-one The titLe compound was obtained from 4(S)-cycLohexyLidin-2-one in analogy to Example 8a, 3b and 2b.

Rf (EA) 0.5; MS (DCI) 321 CM 1) g) 4CS)-CycLohexyLmethyL-5(S)-iodomethyLoxazoL idin-2-one 137 g of ammonium cerium(IV) nitrate were added in portions at RT to 45 g of 3-p-methoxybenzyL-4(S)-cycLohexyLmethyL-5(S)-iodomethyLoxazoLidin-2-one in 1500 ml of acetonitriLe/H 2 0 2/1. After 1 h the mixture was extracted 3 x with EA (500 ml), and the combined organic phases were dried (Na 2

SO

4 and concentrated. Chromatography on silica gel (eLuent: hexane/EA 2/1) followed by crystallization from DIP provided the title compound.

Rf (hexane/EA 2/1) 0.25; MS (DCI) 324 CM 1) h) 3-p-MethoxybenzyL-4(S oxazoLidin-2-one g of N-p-methoxybenzyL-N-Z-1 (S)-cycLohexyLmethyLprop- 2-en-1-yLamine in 300 ml of CH 2

CL

2 were added dropwise, 30 at -50 0 C under an argon atmosphere, to 150 g of 12 in 1 L of CH 2

CL

2 After 4 1/2 h at this temperature, L of 5% strength Na 2 S5 3 solution were added, and the mixture was shaken without cooling until the reaction solution was decolorized. It was washed once with saturated NaC solution and then dried (Na 2

SO

4 and concentrated. Chromatography on silica gel (eluent: hexane/EA 4/1) followed by recrystallization from DIP provided the title compound.

Rf (hexane/EA 4/1) 0.3; MS (DCI) 444 (M 1) i) N-p-MethoxybenzyL-N-Z-1(S)-cyclohexylmethyLprop-2-en- 1-y am i ne 9.4 g of sodium hydride were added in portions at 0 C, to 50 g of N-Z-1(S)-cyclohexylmethylprop-2-en-1-ylamine in 500 ml of DMF. After 2 h at 0°C, 25 ml of pmethoxybenzyl chloride were added dropwise. After 16 h at RT, 100 ml of 5% NaHSO 4 solution were added, and the mixture was extracted 3 x with 300 ml of EA.

The solution was dried with Na 2

SO

4 and then concentrated, and the residue was chromatographed on silica gel (eluent: hexane/EA 8/1).

Rf (hexane/EA 8/1) 0.3; MS (DCI) 408 (M 1) j) N-Z-1(S)-cyclohexylmethylprop-2-en-l-ylamine 11 g of 1(S)-cyclohexylmethylprop-2-en-1-ylamine and S 30 12 g of N-Z-succinimide were stirred in 200 ml of DMF at RT for 16 h. The mixture was then concentrated, and the residue was chromatographed on silica gel (eluent: hexane/EA 4/1) Rf (hexane/EA 2/1) 0.55; MS (DCI) 288 (M 1) k) 1(S)-CycLohexylmethyLprop-2-en-1-yl amine The title compound was obtained in analogy to Ic from Boc-1(S)-cyclohexylmethylprop-2-en-l-ylamine.

31 Examples 20a~ and 205 were prepared in anaLogy to Example 19.

ExampLe ca) 3 -t-ButyLsuLfonyL-2(R)-(2-thienyLmethyL )propionyL-His l(S)-cycLohexyLmethyL-2(S)-hydroxy--5(R,S)-f'Luoro-5- (2-pyr idyl )pentyl amide Rf (EA/MeOH 5/1) 0.25; MS (FAB) =704 (M 1) 3 -t-ButyLsuLfonyL-2(S)-(2-thienyLmethyL )propionyL-His l(S)-cycLohexyLmethyL-2(S)-hydroxy-5(R,S)-fLuoro-5- (2-pyridyL)pentyLamide Rf (EA/Me0H 5/1) =0.15; MS (FAB) 704 (M 1) Example 21 3 -tButyLsuLfonyL-2(R,S)-(2-thienyLmethyL )propionic acid 4.4 g of methyl 3 -t-butyLsuLfonyL-2(R,S)-(2--thienyLmethyL)propionate are suspended in 50 mL of 5N HCI and refLuxed for 2 h. After the mixture has been cooled it is extracted 3 x with 50 ml EA, the soLution is dried over Na 2

SO

4 and the solvent is removed in vacuo. 4.0 g of the title compound are obtained as a pale yellow oil. Separation into the R and S isomers can be carried out, if required, in analogy to EP 236,734.

Rf (MTB) 0.15 0.25; MS (DCI): 291 (M 1) a) Methyl 3 -t-butyLsuLfonyL-2(R,S)-c2-thienyLmethyL )propi on a te 8.4 g of methyl 3 -t-butyLthio-2(R,S)-(2-thienyLmethyL)propionate are dlissolved in 100 ml of CH 2

CI

2 and 10.6 g of m-chLoroperbenzoic acid are added in portions while cooling in ice. The mixture is stirred at RT for 1 h and then washed first with 100 ml of 10% Na 2 S0 3 and then with 100 ml of NaHCO 3 The solution is dried over Na 2

SO

4 and the solvent is removed in vacuo.

I C 32 7.2 g of the title compound are obtained as a colorless oil.

Rf (MTB) 0.56; MS (DCI): 305 (M 1) b) Methyl 3-t-butyLthio-2(R,S)-(2-thienyLmethyL)propionate 6.1 ml of t-butyL mercaptan are dissolved in 100 ml of MeOH (anhydrous) and, under argon, 130 mg of NaH are added. Then 7.6 g of methyl 2-(2-thienylmethyl)acrylate are added dropwise, and the mixture is stirred at RT for 4 h. The solvent is removed in vacuo, the residue is taken up in 100 ml of MTB, and the solution is washed with 100 mL of 5% NaHS04 solution. The solution is dried over Na 2 S04, and the solvent is removed in vacuo. 10.4 g of the title compound are obtained as a pale yellow liquid which is used further without purification and characterization.

Rf (DIP/H 1/5) 0.31 0 a0 20 c) Methyl 2-(2-thicnylmethyl)acrylate 11.8 g of monomethyl 2-thienylmethylmalonate, 5.8 ml of diethylamine and 5.0 ml of 36% aqueous formaldehyde solution are stirred under argon at RT for 1 h. The water is subsequently removed in vacuo and the residue 1* is chromatographed. 7.6 g of the title compound are obtained as a colorless liquid.

RF (MTB/H 1/5) 0.49 d) Monomethyl 2-thienylmethylmalonate 20.1 g of dimethyl 2-thienylmethylmalonate are dissolved in 300 ml of MeOH, and 5.0 g of KOH are added.

The mixture is stirred at RT for 7 h, the solvent is removed in vacuo, and the residue is taken up in 100 ml of each of 5% Na 2

CO

3 solution and EA. The aqueous phase is then acidified to pH 2 and extracted 3 x with 100 ml of EA each time. The solution is dried over i I 33 Na 2 S0 4 and the solvent is removed in vaccuo. 16.0 g of the title compound are obtaine as a paLe yeLLow oil.

Rf (EA/MeOH 6/1) 0.3 0.4 e) Dimethyl 2-thienylmethylmalonate 87.8 g of dimethyl malonate and 41.0 g of potassium t-butyLate are dissolved in 1.1 L of THF (anhydrous) while cooling in ice and, under argon, 44.1 g of 2thienylmethyl chloride in 500 ml of THF are added dropwise. The mixture is stirred at RT for 3 h, the KCL is filtered off, the solvent is removed in vacuo and the residue is chromatographed. 33.8 g of the title compound are obtained as a colorless oil in addition to 8.8 g of dimethyl bis(2-thienyLmethyl)malonate

(II)

Rf (Toluene/DIP 20:1) 0.35 Rf (II) (Toluene/DIP 20:1) 0.44 0 6 0 f) 2-Thienylmethyl chloride 0 i 252 g of thiophene are suspended in 128 ml of concentrated aqueous HCL and, at 0°C, gaseous HCI is passed in for 1 h. Then, without interrupting the stream of HCL, 255 ml of 35% aqueous formaldehyde solution are added dropwise, and the mixture is stirred at 00C for a further 15 minutes. The organic phase is separated off, and then the aqueous phase is extracted 2 x more with 600 ml of CH 2

CL

2 The solution is then washed 2 x with 600 ml of saturated aqueous Na 2

CO

3 and dried over Na 2

SO

4 the solvent is removed in vacuo, and the residue is distilled. 174 g of the title compound are obtained as a colorless liquid.

Boiling point (22) 81 840C Example 22 3-t-Butylsulfonyl-2(R,S)-phenylmethylpropionic acid 34 The titLe compound was prepared in anaLogy to EP 2')6,734.

The separation into the R and S isomers was Likewise carried out as in EP 236,734. MeLting point 99 101 OC; Rf(EE/H 1/1) 0.16.

ExampLe 23 Iva-Phe-His 1 ethoxy-5-(2-pyridyL)pentyLamide The titLe compound was obtained from Iva-Phe--His(DNP)-0H and 1 (S)-cycLohexyLmethyL-2(S)-hydroxy-5(R,S)-ethoxy-5- (2-pyridyL)pentyLamine in anaLogy to ExampLe 1, la and ExampLe Rf (EA/MeOH 5/1) 0.15; MS (FAB) 689 (M 1) 0 a 4

Claims (8)

1. A compound of the formula I R 2 R 9 R 3 1 1 1 I) R 1 -A-B-HN-CH-C H-OH R 4 in which RI is absent or denotes hydrogen, a 2 denotes (0 1 -0 20 )-alkyl, or a 3 denotes a radical of the formula 11 in hic RaW_ (I inwihW represents -0-00, -SO 2 or -NH-CO-, and f represents hydrogen, (0 1 -0 10 )-alkyl which is option-ally substituted by up to 3 identical or different radicals selected from the group consisting of hydroxyl, (01 -0C7)- alkoxy, (0- 7 -alkanoyloxy, carboxyl, (C- 7 -alkoxycarbonyl, CI, Br, amino, (C 1 -C 7 )-alkylamino, di-(C 1 -C 7 )-alkylamino, (C 1 -0 5 )-alkoxycarbonylamino, or represents (C 6 -C 14 )-aryl-(Cj-0 6 )-alkyl, A bl) denotes a radical of the formula III or lila, 0 0 0 11 I1 1 R 5 -(CH 2 R 1 S OH 2 OH -C- Ii I H' (III) (111[a) in which RI' is defined as above, n and m are identical or different and denote 0, 1, 2, 3, or 4, R and R 6 are identical or different and denote phenyl, 2- or 3-thienyl, 3- or

4-pyridyl, 2- or 4-imidazolyl, 1- or 2-naphthyl, 2- or 3-benzo[b]thienyl, OH or hydrogen, or b 2 denotes a radical, which is linked N-terminal with Ri' and C-terminal with B, of an amino acid selected from the group consisting of phenylalanine, histidline, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, f3-2-thienylalanine, 0-3-thienylalanine, f3-2-furylalanine, P-3-furylalanine, lysine, ~-...4ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chiorophenylalanine, 36 methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methyihistidine, 0-methyltyrosine, O-benzyltyro sine, O-tert.-butyltyrosine, phenylglycine, 1 -naphthylala-nine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, f-2-benzo[b]thienylalanine, P-3-benzo[b]thienylalanine, 2-fluorophenylalanine, 3-fluoroph enylalanine, 4-fluorophenylalanine, norleucine, cysteine, S-methylcysteine, 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, homophenylalanine, DOPA, 0-dimethyl- DOPA, 2-ami no-4-(2-thilenyl)-butyric acid, benzodioxol1-5-yl alanine, N-methylhistidine, 2-amino-4-(3-thienyl)butyric acid, 3-(2-thienyi)-serine, (Z)-dehydrophenylalanine and (E)-dehydrophenylalanine, B denotes a radical of an amino acid which is linked N-terminal with A and C- terminal with NH, of an amino acid selected from the group consisting of phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic Sacid, P-2-thienylalanine, fP-3-thienylalanine, f-2-furylalanine, 0-3-furylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, melhionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, 0 -methyltyrosirie, 0-benzyltyrosine, 0-tert-butyltyrosine, phenylglycine, 1-naphthylalanine, 2-naphth lalanine, 4-nitrophenylalanine, norvaline, f3-2- benzo[b]-thienylalanine, Ojbenzo[blthienylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, norleucine, cysteine, S-methylcysteine, S9: 1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, homophenylalanine, DOPA, 0- dimethyl-DOPA, 2-amino-4-(2-thienyl)-butyric acid, benzodioxol-5-ylalanine, N- metiylhistidine, 2-amino-4-(3-thienyl)butyric acid, 3-(2-thienyl)-serine, -7Z/-dehydrophenylalanine and (E)-dehydrophenylalanine, R 2 denotes hydrogen, (Ci -C 1 )-alkyl, (04 -C 7 )-cycloalkyl, (04-07) -cycloalkyl- (C 1 -C41-alkyl, (C 6 -C 14 )-aryl or (C 6 -C 14 )-aryl-(Cj -)-alkyl, R 3 denotes hydrogen, R 4 denotes a radical of the formula IV (CH 2 )p X (CH2)q R7 UV) with X representing, -OF 2 -00- or -CHR 8 p denotes 1, 2 or 3, q denotes 0, 1 or 2, >1I~ AV R 8 denotes (Ci-C 7 )-alkyl, (C -Cs)-alkoxy, (C -C 5 )-alkylthio, (C -Cs)-alkylamino, -OH, -N 3 -CI, -Br or -I, R 7 denotes GHt r- heteroaryl, which can also be partially or completely hydrogenated, and R 9 denotes -OH or -F, and the physiologically tolerated salts thereof. 2. A compound of the formula I as claimed in claim 1, in which R 2 denotes isobutyl, benzyl or cyclohexylmethyl, and the physiologically tolerated salts thereof. 3. A compound of the formula I as claimed in one or more of claims 1-2, in which R 3 denotes hydrogen, isopropyl or isobutyl, and the physiologically tolerated salts Sthereof. 4. A compound of the formula I as claimed in one or more of claims 1-3, in which R 4 and R 8 are as defined in claim 1, and the physiologically tolerated salts thereof. A compound of the formula 1 as claimed in one or more of claims 1-4, in whih R 5 and R 6 are identical or different and denote phenyl, 2-thienyl, 2-pyridyl, 1-naphthyl, 2-benzo[b]thienyl, OH or hydrogen, and the physiologically tolerated salts thereof.

6. A compound of the formula I as claimed in one or more of claims 1-5, in which R 7 represents an optionally substituted heteroaryl which is defined as in claim 1, but contains 1 or 2 nitrogen atoms as ring members, and the physiologically tolerated salts thereof.

7. A compound of the formula 1 as claimed in one or more of claims 1-6, in which A and B are identical or different and denote phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, p-2- thienylalanine, p-3-thienylalanine, p-2-furylalanine, lysine, ornithine, 2,4- diaminobutyric acid, arginine, norvaline, 4-chlorophonylalanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, 0-methyltyrosine, 0-benzyltyrosine, 0-tert.- J -1 38 butyltyrosine, phenylglycine, 1-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norleucine, valine, alanine, cysteine, S-methylcysteine, N-methyl-histidine, benzodioxol-5-ylalanine, 1,2,3,4-tetrahydro-isoquinoline- 3-carboxylic acid, homophenylalanine, 2-amino-4-(2-thienyl)butyric acid, (Z)-dehydrophenylalanine or (E)-dehydrophenylalanine, and the physiologically tolerated salts thereof.

8. A compound of the formula I as claimed in one or more of claims 1-7, in which A denotes a radical of the formula I1I which is defined as in claim 1, and the physiologically tolerated salts thereof.

9. A compound of the formula I as claimed in one or more of claims 1-8 in which R 1 represents isobutylcarbonyl, A denotes Phe or a radical of the formula Illa in which R 1 is (C 1 -C 6 )-alkyl which can optionally be substituted by -NH 2 or -COOH; n denotes 1 and R 5 is phenyl, 2- or 3-thienyl B denotes histidine, R 2 is cyclohexylmethyl, R 3 is hydrogen, R 4 represents a radical of the formula IV in which q is 0, p denotes 1 or 2, X is -CF 2 -CO- or -CHR 8 and R 8 denotes OH, F, CI, Br, (C1-C4)-alkoxy or (C1-C 4 )-alkyl, especially, F, and R 9 represents OH, as well as the physiologically tolerated salts thereof. A process for the preparation of a compound of the formula I as claimed in one or more of claims 1 to 9, which comprises coupling a fragment having a terminal carboxyl group, or its reactive derivative, to a corresponding fragment having a free amino group, where appropriate eliminating protective group(s) which has (have) been temporarily introduced to protect other functional groups, and converting the resulting compound, where appropriate, into its physiologically tolerated salt. j A 39

11. A pharmaceutical composition comprising a compound as claimed in one or more of claims 1 to 9, or a physiologically tolerated salt thereof in adjunct with pharmaceutically acceptable carriers or excipients.

12. A process for the preparation of a pharmacQ'ltical composition as claimed in claim 10, which comprises converting a compound of the formula 1, or a physiologically tolerated salts thereof, into a suitable dosage form together with a physiologically acceptable vehicle and, where appropriate, further additives, auxiliaries and/or preservatives. DATED this 15th day of January, 1992. HOECHST AKTIENGESELLSCHAFT t, WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA i' 1