NZ226361A

NZ226361A - Renin-inhibiting dipeptide and pharmaceutical compositions

Info

Publication number: NZ226361A
Application number: NZ226361A
Authority: NZ
Inventors: Adalbert Wagner; Heinz-Werner Kleemann; Dieter Ruppert; Bernward Scholkens; Hansjorg Urbach
Original assignee: Hoechst Ag
Priority date: 1987-09-30
Filing date: 1988-09-28
Publication date: 1991-12-23
Also published as: DK543788A; ZA887264B; HUT48278A; DE3732971A1; KR890005146A; NO884324L; PT88622B; HU203118B; FI884455A0; NO884324D0; PT88622A; AU2295988A; EP0310015A2; EP0310015A3; JPH01121258A; DK543788D0; IL87912A0; AU624579B2; FI884455A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £26361 22 1 Priority Pat^s): :....30. rr.q.r.fiq. Specification FHad: Cfsssi .C-OlTH. k.5./ O.Co r.. .^.Q . PubiicaSion Dai®: ?.APfr£;?.?.?.) P.O. Journal Ho: NO DRAWINGS N.Z. NO NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION RENIN-INHIBITING DIPEPTIPES, A PROCESS FOR THE PREPARATION THEREOF, AGENTS CONTAINING THEM, AND THEIR USE We, HOECHST AKTIENGESELLSCHAFT, a corporation organized under the laws of the Federal Republic of Germany of D-6230 Frankfurt am Main 80, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (Followed by 1A) I t r~ \ -iA~ 4ioccust Airncncgpshfag6ii^rt hoc 87/r atn phwi/jbIm 226361 Specification Renin-inhibiting dipeptides, a process for the preparation thereof, agents containing then, 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. 10 15 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 R5 R1-A-B-HN-CH-CH-CH-R4 / . ^ V 10 OCT 199! (I) i i n wh i c h 1 R a-j) is absent or denotes hydrogen, 20 a2) denotes (C-j-C2Q)-alkyl which is optionally substituted by one, two or three identical or different radicals from the series comprising hydroxyl, (C1-C7)-alkoxy, carboxyl, (C•j-C7)-alkoxycarbonyI, (C^-Cg)-alkanoyloxy, CI, Br, amino, (C-j-CyJ-alkylamino, Di-25 (Ci-C7)-alkylamino, (Ci-C5)-alkoxycarbonylamino and (C7-C 1 )-ar a I ky loxycarbony I am i no, or denotes (Cj-Cg)-cycloalkyl, (Cj-CgJ-cycloalkyl-CCi-C-jQi-alkyl or (C^-C-j4>-aryl-(C-)-Cg)-alkyl which is optionally substituted in the aryl moiety by one or two identical or 30 different radicals from the series comprising F, CI, Br, hydroxyl, (C-j-C7)-alkoxy, ( C •)-C7)-a I ky I , (C1-C7)-alkoxycarbonyl, ami no and trifluoromethyl, or 83) denotes a radical of the formula II 35 Ra-W- (11) o c. - 2 - in which W represents -CO-, -0-C0-, -SOj- or -NH-CO-, and Ra represents hydrogen, (C -pC ig)-alkyl which is optionally singly or doubly unsaturated and is optionally substituted by up to 3 identical or different 5 radicals from the series comprising hydroxyl, (C-j — C7) — alkoxy, ( C i~C 7)-a I k anoy lo xy , carboxyl, ( C 1-C7)-a I koxy-carbonyl, Cl, Br, amino, ( C -j-C7)-a I ky I am i no, Di — (C-j — C7) — alkylamino, (Cy-C5)-a Ikoxycarbony I amino, (C7-C 15)-ara I-koxycarbonylamino and 9-f I uorenyI methyIoxycarbonyI amino, 10 or represents (C3-C8)-cyc I oaIkyI, (C3-C8)-cycIoaIkyI-(C1-C^)-alkyl, (C$-C14 )-ary I which is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C1-C7)-a Ikoxy, (C1-C7)- alkyl, (Ci-C7>-alkoxycarbonyl, amino and tri- .fv- 15 fIuoromethyI, or represents (Cg-Ci4)-aryl-(Ci-C$)-alkyl, y in which the aryl moiety is optionally substituted by one2 or two identical or different radicals from the series \ ^ comprising F, Cl, Br, I, hydroxyl, (C'i-C7>-alkoxy, (C1 - C7>-alkyl, (C-| — C7) — al koxycarbonyl , amino, (Ci~C7)-alkyl- 20 amino, d i - ( C -j — C 7)-a I ky I am i no, carboxyl, carboxymethoxy, - amino-(Ci-C7)-alkyl, (Ci-C7)-alkylamino-(Ci~C7)-alkyl, di- <Ci-C7)-alkyl-amino-(Ci-C7)-alkyl, (Ci~C7)-alkoxycarbonyl- methoxy, carbamoyl, sulfamoyl, (C 1-C7)-alkoxysulfonyI, sulfo- and guanidinomethyl, or represents the radical of a 25 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaromatic compound which has at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members too and which is optionally mono-, di- or trisubstituted as (C$-C14)-aryI defined under aj), 30 A b.) denotes a radical of the formula III or Ilia, 0 0 0 c I 1 H " r-(ch0) -ch-c- r1 - s - ch~ - ch - c - <- n H c- !l 0 I (0h,)„ 35 2'm r6 r5 (III) ( 11 la ) - 3 - 226361 in which R^ is defined as above, n and m are identical or different and denote 0, 1, 2, 3 or 4; and are identical or different and denote phenyl, 2- or 3-thienyl, 2-, 3- or 4-5 pyridyl, 1-, 2- or 4-imidazoIy I , 1- or 2-naphthyl, 2- or 3-benzoCbDthienyl, OH or hydrogen, or b2) denotes a radical, which is linked N-terminal with 1 R and C-terminal with B, of an amino acid from the series comprising phenylalanine, histidine, tyrosine, tryptophan, 10 methionine, leucine, isoleucine, asparagine, aspartic acid, B-2-thienylalanine, B-3-thienylalanine, 8-2-furyI a I anine, B-3-fury I a I anine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2-pyridyI a I anine, 15 3-py r i dy I a I an i ne, c y c I ohe xy I a I an i ne, cy c I ohexy I g I y c i ne , i in-met hy I h i s t i d i ne, 0-methyltyrosine, O-benzyI tyrosine, 0-tert.-butyItyrosine, phenylglycine, 1-naphthyI a I anine, 2-naphthyI a I anine, 4-nitrophenylalanine, norvaline, B-2-ben-zoCb]thienyI a I anine, B-3-benzoCb]thienyI a I anine, 2-fluoro-20 phenylalanine, 3-fluorophenylalanine, 4-fIuorophenyI- alanine, norleucine, cysteine, S-methylcysteine, 1,2,3,4-tetrahydroisoquinoline-3-carboxyIic acid, homophenyI a Ia-nine, DOPA, O-dimethyl-DOPA, 2-amino-4-(2-thienyI)-butyric acid, benzodioxoI-5-y1 a I anine, N-methy I-histidine, 2-25 amino-4-(3-thienyI)butyric acid, 3-(2-thienyl)-serine, (Z)-dehydrophenylalanine and (E)-dehydrophenyI a I anine, B denotes a radical of an amino acid as defined under <b2>, 2 R denotes hydrogen, ( C <|-C iq )-a I ky I , (C^CyJ-cycloalkyl, 30 ( C 4-C7)-c y c I oa I ky I - ( C 1 - C4)-a I k y I, ( C^-C-j^J-ary I or (C$-Ci4>-aryl-(C<|-C4>-alkyl, R^ denotes hydrogen, CC1 — C^q) — aLkyl, (C$- Ci4>-aryl or C C^-C 14)-a r y I - ( C <|-C4 )-al ky I , 4 R denotes a radical of the formula IV - (CH2)p - X - (CH2)q - R7 (IV) 10 22(>3(n - 4 - g with X representing - C F 2 - , -CO- or -CHR - , p and q denoting, independently of one another, 0, 1, 2, 3 or 4, and R® denoting ( C -j - C 7 )-a I k y I , ( C 1 - C 5 ) - a I k 0 x y , ( C 1 -C5 ) - a I k y I -thio, (Cf — C 5)-a IkyI amino, -OH, -N3, -F, -Cl, -Br or -I, R^ denotes hydrogen, -OH, -NH2, (C$-C 14)-aryI or heteroaryl, which can also be partially or completely hydrogenated, and 9 R can be -OH or -F, wjth the proviso that compounds of the formula I wherein X = CHR8, p = = OH or NH2 and R8 = (C,-C7)-alkyl are excluded , J ^ ' o, and to the physiologically tolerated salts thereof. 2 3 8 9 V\ 30 OCT 1991 /£ The carbon atoms substituted by R , R , R and R "a //' can each have the R , S or R , S configuration. ! Alkyl can be straight-chain or branched. A c o tyre so o n d i n 15 statement applies to radicals derived therefrom such as, for example, alkoxy, alkylthio, alkylamino, dialkylamino, alkanoyl and aralkyl. Cycloalkyl is to be understood to include a I ky I-substi-20 tuted radicals such as, for example, 4-methyIcycIohexyI or 2,3-dimethylcyclopentyl. Examples of (C^-C14)-aryI are phenyl, naphthyl, bi-phenylyl or fluorenyl; phenyl is preferred. A corre-25 spending statement applies to radicals derived therefrom such as, for example, aryloxy, aroyl, aralkyl and aral-kyloxy. Aralkyl is to be understood to be an unsubsti-* tuted or substitued ( C^-C-j 4 )-a r y I radical which is linked to ( C-| - C ^ )-a I k y I , such as, for example, benzyl, 30 a- and 0-naphthyI methy I , halobenzyl and alkoxybenzyl, with, however, aralkyl not being restricted to the said radicals. « A radical of a 5- or 6-membered monocyclic or 9- or 10-35 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 5 226361 in, for example, Katritzky, Lagowski, Chemistry of Heterocyclic Compounds, BerIin, Heidelberg 1968. The heteroaromatic radical can be substituted by one, two or three, preferably one or two, identical or different 5 radicals from the series comprising F, Cl, Br, hydroxyl, C C-C7)-a I koxy , ( C -j-C7)-a I ky I , (C 1-C7 )-a I koxy c a r bony I , amino or trifIuoromethyI. Examples of monocyclic heteroaromatic compounds are thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyri.jnidine, 10 pyridazine, 1,2,3,A-1riazoIe, thiazole, tetrazole, isothiazole, oxazole and isoxazole. Examples of bicyclic heteroaromatic compounds are benzothiophene, benzofuran, indole, isoindole, indazole, benzimidazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline and 15 cinnoline. A corresponding statement applies to radicals derived from heteroaryl compounds such as, for example, partially or completely hydrogenated heteroaryl, hetero-aryloxy, heteroary11hi0 and heteroarylalkyl. 20 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, 0 or D,L configuration, preferably of the L configuration. 25 Salts of compounds of the formula I are to be understood to be, in particular, pharmaceutically utilizable or nontoxic salts. Salts of these types are formed, for example, by compounds 30 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, triethyl-amine and tri(2-hydroxyethyI)amine. 35 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, 226361' - 6 - hydrochloric 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-to IuenesuIfonic 5 acid. Preferred compounds of the formula I are those in which the radicals are defined as follows: 1 R is preferably absent, denotes hydrogen or represents 10 CC-j — Ciq> — alkyl , cyclopentyl, cyclohexyl, cycI opentyI-(C1-Cig)-alkyl, cycIohexyI-(C1-C1g )-a IkyI, optionally substituted pheny I - ( C-j-Cg )-a I ky I , H2 N-( C -j-C 1 q )-a I k y I , H0 — ( C ^ — C<|g)-alkyl, ( C 1-C4 )-a I koxy-( C 1-C 10)-a I ky I , ( C ^-C^-alkoxy-c a r bony I - ( C-j-C ig)-a I ky I , carboxy-(C1-Cig)-a IkyI such as 15 2-hydroxyprop i ony I or 2-hydroxy-3-methylbutyryl, (C<|-Cg)-a I kanoy I oxy-( C 1-C ig )-a I ky I , ( C-|-C 11 )-alkanoy I such as n-decanoyl, formyl, acetyl, pivaloyl, isovaleryl or isobuty-ryl, optionally protected amino-(C1-C11)-aIkanoyI such as 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyI, 4-N-20 tert.-butoxycarbony I aminobutyry 1, 5-N-tert.-butoxycar-bonylaminopentanoyl or 6-N-tert.-butoxycarbony I amino-hexanoyl; d i - ( C 1-C7 )-al ky I am i no-( Cj-C <] 1)-a I k anoy I , such as dimethylaminoacetyl,* (C4~C9)-cycloalkylcarbonyl, such as eye I op ropy IcarbonyI, cycIobuty I carbony I, cycI opentyIcar-25 bonyl or cycIohexyIcarbonyI; (C^-C^g)-aryl-<Cj-C^)-aIka-noyl, such as phenylacetyl, phenylpropanoyI or phenyl-butanoyl; benzoyl which is optionally substituted by halogen, (C1-C7)-aIkyI, (Ci-C7>-alkoxy or (C1-C7)-a Ikoxy-carbonyl, such as 4-chlorobenzoyl, 4-methylbenzoyl, 2-30 methoxycarbonyLbenzoyl or 4-methxoybenzoyI; pyrrolyl-2-carbonyl; pyridyl-3-carbonyi; benzenesulfonyl/ (Ci~C-|g)-aIkoxycarbony I such as methoxycarbonyI, ethoxycarbonyl or tert .-butoxycarbony I / ( C1 -C <|g)-a I koxy c arbony I which is substituted by halogen, such as 2,2,2-trichloroethoxy-35 carbonyl or 1, 1-d i me t hy 1-2,2 ,2-t r i c h I oroe t hoxy c a r bony I *, (C6~C14)-aryI-<C1-C6)-a IkoxyearbonyI, such as benzyloxy-carbonyl or 9-fIuorenyI methoxycarbony I, is preferably isobutyl, benzyl or cycI ohexyI methy I , 10 - 7 - 226361 R is preferably hydrogen, isopropyl or isobutyl, 4 8 9 R , R and R are preferably as defined above, R^ and R^ are identical or different and preferably represent phenyl, 2-thienyl, 2-pyridyl, 1-naphthyl, 2- benzoCb]thienyl, 3-benzoCb]thienyI, 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 1 R represents isobutyIcarbony I, A denotes Phe or a radical of the formula Ilia in which i 15 R is ( C -j-C$)-a I k y I which can optionally be sub stituted by -NH2 or -C00H; n denotes 1 and R^ is phenyl, 2- or 3-thienyl B denotes histidine, 2 R is eyelohexylmethyI, 20 R^ is hydrogen, 4 R represents a radical of the formula IV in which q is Q 0, p denotes 1 or 2, X is -CF2-CO- or -CHR - and Q R denotes OH, F, Cl, Br, (C <|-C4 )-a I koxy or (C1-C4)- alkyl, especially F, and 9 25 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, B-2-thienylalanine, B-3-1hienyI a I anine, B~2 — furyI a I anine, lysine, ornithine, 2,4-diaminobutyric acid, arginine, norvaline, 4-chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2-pyridyI a I anine, 3-pyridyI a I anine, 35 cyclohexylalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O-benzyltyrosine, O-tert.-butyltyrosine, phenylglycine, 1-naphthy I a I anine, 2-naphthyI a I anine, 4-nitrophenyI a I anine, norleucine, valine, alanine, cysteine, 226361 S-methylcysteine, N-methyLhistidine, benzodioxol-5-yl-alanine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, homophenyI a I anine, 2-amino-4-(2-1hienyL)butyric acid, (Z) — dehydrophenyLa I anine or (E )-dehydrophenyIaIanine. Moreover, 5 A preferably denotes a radical of the formula III as described under (b <|). The invention also relates to a process for the preparation of compounds of the formula I, which comprises coupling 10 a fragment having a terminal carboxyl group, or its reactive derivative, to a corresponding fragment having a free amino group, where appropriate eliminating (a) protective group(s) which has (have) been temporarily introduced to protect other functional groups, and con-15 verting the resulting compound, where appropriate, into its physiologically tolerated salt. Fragments of a compound of the formula I having a terminal carboxyl group have the formulae Va - Vc which follow: 20 r1 -oh 25 . r1-a-0h r1-a-b-0h 30 Fragments of a compound of the formula I having a terminal amino group have the formulae Via - Vic which follow: (Vb) (Vc ) 35 r2 r9 r5 h2n-a-b-nh-ch-ch-ch-r4 (Via) - 9 - R2 R9 R- 226361 fit /i (VIb) h2n-b-nh-ch-ch-ch-r4 r2 r9 r5 5 ill a (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; 10 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 preferably employed: the active ester method using N-hydroxysuccinimide as ester component, 15 coupling with a carbodiimide such as dicycIohexyIcarbo-diimide or with propanephosphonic anhydride, and the mixed anhydride method with pivaloyl chloride. The optically active amines of the formula VII 20 r2 r3 h-n-ch-ch-ch-r4 (VII) 2 | q Ry 2 3 4 9 25 in which R , R , R and R are as defined above, which are used as starting compounds, are prepared start ing 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 o amino alcohols of the formula VII (R = OH). As an alternative to this, the epoxides are prepared from the 35 protected amino aldehydes via the allylamines in a manner known per se. These epoxides can either be directly reacted with the appropriate arylalkyl nucIeophiIes, or are first opened with trimethyIsiIyI chloride and Nal in 226361 - 10 - acetonitriIe, 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 nucIeophiIes. Synthesis 5 of arylalkyl-substituted amino alcohols extended by one CH2 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 10 group into a bromide, which can be reacted with arylalkyl nucleophiles under analogous conditions like the electro-philes already mentioned. Examples of suitable arylalkyl nucleophiles are acetylimines and acetylhydrazones. Further compounds of the arylalkyl-substituted amino alcohols 15 having (a) extended CH2 group(s) can be obtained by the generally customary methods of chain extension. If the chosen synthetic route results in diastereomers in respect 9 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 diastereo-meric purity is carried out by HPLC, and the enantiomeric purity can be examined in a known manner by conversion into Mosher derivatives (H.S. Mosher et al., J. org. Chem. 34, 2543 (1969)). 25 The method of B. Castro et al. (Synthesis 1983, 676) is used to prepare aldehydes of N-protected amino acids. Addition of the arylalkyl nucleophiles onto the said 30 N-protected electrophiles (preferably N-tert.-butoxy-carbonyl and benzyloxycarbonyL protective groups) is carried out in a solvent which is inert towards bases, such as ether, THF, toluene, DMF, DMSO or dimethoxyethane . 35 Bases which can be used for the deprotonation of the heteroarylalkyl component are alkali metal alcoholates such as potassium 0-1ert.-butyI ate and sodium methylate, alkali metal hydrides such as sodium or potassium hydride, 226361 - 11 - organometalLic bases such as n-butyLIithium, s-butyl-lithium, methyl Iithium or pheny11ithium, or sodamide, as well as alkali metal salts of organic nitrogen bases, such as lithium diisopropyI amide. 5 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. 10 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 15 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. 20 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 25 stimuli (volume depletion, sodium deficiency, B_receptor stimulation) from the juxtaglomerular cells of the kidney into the blood circulation. There it eliminates the decapeptide angiotensin I from the angiotensinogen which is secreted from the liver. The former is converted by 30 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 35 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 226361 - 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 5 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 10 plasma, porcine renin). For this purpose, for example, human plasma, which contains both renin and angiotensin-ogen, is incubated at 37°C with the compound to be tested. The concentration of angiotensin I which has been formed during the incubation is then measured using 15 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 10"5 to 10~10 mol/l. 20 Renin inhibitors 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 sub-25 stantially homologous. Endogenous renin release is stimulated by i.v. injection of furosemide. The test compounds are then administered by continuous infusion, and their effect on blood pressure and heart rate is measured. The compounds of the present invention are effective in 30 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. 35 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 - 13 - to primates, especially to humans, 226361 is preferred. Pharmaceutical products contain an effective amount of reactive compound of the formula I together with an in-5 organic 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. 0 The pharmaceutical products of the present invention are prepared in solution, mixing, granulating or coating processes known per se. 15 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, 20 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 25 starch. In this connection, the formulation can be carried out both as dry and wet granules. Examples of oily vehicles or solvents are vegetable or animal oils such as sunflower oil and fish liver oil. 30 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 soIubiIizers, emulsifiers or other auxiliaries. 35 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 - 226361 solvents mentioned, List of abbreviations used: Ac Acetyl 5 ACHPA C3S,4S]-4-amino-3-hydroxy-5-cycI oh exyI pentanoic acid Boc tert.-ButoxycarbonyI BuLi Butyllithium DAST DiethyI aminosuIfur trifluoride TLC Thin-layer chromatography 10 DCC DicycIohexyIcarbodiimide DCI Desorption Chemical Ionization DIP Diisopropyl ether DNP 2,4-DinitrophenyI DMF Dimethylformamide 15 DMSO Dimethyl sulfoxide EA Ethyl acetate EI Electron Impact Etoc Ethoxycarbonyl FAB Fast atom bombardment 20 H Hexane HOBt 1-HydroxybenzotriazoIe Iva Isovaleryl M Molecular peak MeOH Methanol 25 MS Mass spectrum MTB Methyl tert.-butyl ether R.T. Room temperature m.p. Melting point Sta [3S,4S]-4-amino-3-hydroxy-6-methyI heptanoic acid 30 Thi B-2-ThienyI a I anine THF Tetrahydrofuran Z BenzyloxycarbonyL The other abbreviations used for amino acids correspond 35 to the three-letter code customary in peptide 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. 226361 - 15 - The examples which follow serve to illustrate the present invention without intending to restrict it to them. Example 1 5 Iva-Phe-His 1(S )-cycI ohexyI methyI-2(S)-hydroxy-6-oxo-6-phenylhexylamide 150 mg of Iva-Phe-His(DNP ) 1 (S )-cyc I ohexyI methyI-2(S ) -hydroxy-6-oxo-6-phenyIhexyI amide are stirred in 5 ml of 10 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^Clj/MeOH 12/1). Concentration of the product-containing fractions provides the product as a pale yellow powder. 15 Rf(CH2Cl2/Me0H 12/1) = 0.2; MS (FAB) = 672 (M+1) a) Iva-Phe-His(DNP) 1(S )-cycIohexyI methyI-2(S)-hydroxy-6-oxo-6-phenylhexylamide 20 70 pi of pivaloyl chloride are added at -5°C to 300 mg of Iva-Phe-His(DNP)-OH, 46 pi of pyridine and 80 pi of N-ethylpiperidine in 5 ml of CH2C12- The mixture is stirred at +5°C to +10°C for 30 minutes are then cooled to -10°C, and 165 mg of 1(S)-cycIohexyImethyI-2(S)-hy-25 droxy-6-oxo-6-phenylhexylamine in 5 ml of CH2CI2 are added dropwise. The mixture is stirred without cooling for 16 h, concentrated in vacuo, and the residue is taken up in 100 ml of EA. The solution is washed 3 times with aqueous K 2 C 0 3 solution and once with H2O, 30 dried over Na2S04 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) 35 b) Iva-Phe-His(DNP)-OH was prepared by the procedure described in J.Am.Chem.Soc. 86, 1839 (1964). 226361 - 16 - c) 1(S)-Cyclohexylmethyl-2(S)-hydroxy-6-oxo-6-phenyl-hexyL am i ne 200 mg of 3-Boc-4(S)-cycLohexyI methyI-2,2-dimethyI-5 5-(4-dimethylhydrazono-4-phenylbutyl)oxazolidine are dissolved in 10 ml of dimethoxyethane and, while cooling (T - 10°C), 10 ml of dimethoxyethane saturated with HCl are added dropwise, and the mixture is stirred for 3 h. It is now concentrated, and the residue is taken 10 up in H2O, and the solution is adjusted to pH 9-10 with saturated Na2C0j solution and extracted 3 times with EA. Drying results in the title compound, which is used without further purification in the next reaction step. 15 d) 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-(4-dimethyl-hydrazono-4-phenylbutyl)oxazolidine 0.8 ml of n-butylIithium (1.5 M in hexane) is added 20 dropwise at -78°C under an argon atmosphere to 203 mg of acetophenone dimethyIhydrazone (prepared by the procedure indicated in J.Org.Chem. 3J, 677 (1966)) in 10 ml of dry THF. After 15 minutes, 303 mg of 3-Boc-4(S)-cycIo-hexylmethyl-2,2-dimethyl-5-(2-bromoethyl)oxazolidine in 25 3 ml of THF are added, and the mixture is then stirred without cooling for 2 h. H2O is then added, and the mixture is extracted 3 times with EA. Drying over Na2S04 is followed by concentration and chromatography on silica gel (mobile phase: EA/hexane 1/5). 30 Rf (hexane/EA 8/1) = 0.5; MS (DCI) = 487 (M+1) e) 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-(2-bromo-ethyl)oxazolidine 35 1.6 ml of diethyl azodicarboxylate are added dropwise at 20°C to 690 mg of 3-Boc-4(S)-cycIohexyI methyI-2,2-dimethyI-5-(2-hydroxyethyI)0xazo I idine, 2.6 g of triphenyl-phosphine and 1.6 g of pyridinium hydrobromide in 15 ml 10 30 226361 - 17 - of CH2CL2 under argon. After 16 h at R.T., H2O is added, and the mixture is diluted with 100 ml of CH2CI2-The organic phase is washed twice with saturated NaHCOj solution and once with saturated NaCl solution. The organic phase is dried with N a 2 S 0 4 and concentrated, and the residue is taken up in a little EA and filtered to remove PPhj. 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-hydroxy-methyl)oxazolidine 10 g of Boc-ACHPA-OEt (J.Med.Chem. 28, 1179 (1985)), 500 mg 15 of p-toluenesuIfonic acid and 7.2 ml of dimethoxypropane in 160 ml of toluene are heated at 80°C 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 LiAlH4 in 200 ml of THF. After 2.5 h at 0°C, 100 ml of 5 % strength NaHSO^ 20 solution are added, and the mixture is extracted 3 times with EA. The combined organic phases are washed once with saturated NaHCOj solution. Drying with Na2S04 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) 35 a) Iva-Phe-His(DNP) 1(S)-cycIohexyI methyI-2-(S)-hydroxy-6-oxo-6-(2-pyridyl)hexylamide 22636! - 18 - 270 mg of 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-[4-(2-pyridyl)-4-oxobutyl]oxazolidine are dissolved in 5 ml of dimethoxyethane and, while cooling, (T 10°C), 5 ml of dimethoxyethane saturated with HCl are added drop-5 wise, and the mixture is stirred for 3 h. The hydrochloride is obtained by concentration at R.T. For the coupling, 68 pi of pivaloyl chloride are added at -5°C to 335 mg of Iva-Phe-His(DNP)-OH, 45 y I of pyridine and 230 y I of N-e t hy I p i pe r i d i ne in 5 ml of After 10 minutes 10 at +10°C, the mixture is cooled to 0°C, and the hydrochloride described above is added dropwise in 2 ml of CH2Cl2-After 2 h at 0°C, the mixture is stirred for a further 16 h at R.T. Working up and purification are carried out in analogy to Example 1a). 15 Rf (EA) = 0.1; MS (FAB) = 839 (M+1) b) 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-C4-(2-pyridyl)-4-oxobutyl]oxazolidine. 20 0.8 ml of n-butyllithium (1.5 M in n-hexane) is added at -60°C under an argon atmosphere to 160 pi of diisopropyl-amine in 10 ml of THF. After 1 h at -50°C, 225 mg of N-[1-(2-pyridyl)ethylidene]cyclohexylamine in 3 ml of THF are added. The mixture is left to stir at 0°C for 1 h, during 25 which an intense red coloration appears. 300 mg of 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-(2-bromoethyl)oxazo-lidine in 2 ml of THF are now added, and the reaction is stopped after 1 h by addition of H2O. Extraction with EA, drying over Na2S04 and concentration are followed by 30 chromatography on silica gel (mobile phase: hexane/EA 4/1). Rf (hexane/EA 4/1) = 0.3; MS (DCI) = 444 (M) c) N-C1-(2-pyridyl)ethylideneDcyclohexylamine 35 20 g of 2-acetyIpyridine, 30 g of cyclohexylamine and 0.5 g of p-101uenesuIfonic 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°C 226361 Example 3 Iva-Phe-His 1(S)-cyclohexylmethyl-2(S),6(R,S)-dihydroxy-5 6-(2-pyridyI)hexyI amide The title compound was synthesized in analogy to Example 1 from Iva-Phe-His(DNP ) 1(S)-cycI ohexyI methyI-2(S),6(R,S ) dihydroxy-6-(2-pyridyl)hexylamide. 10 Rf (EA/MeOH 3/1) = 0.6; MS (FAB) = 675 (M+1) a) Iva-Phe-H i s(DNP ) 1(S)-cycIohexyI methyI-2(S),6(R , S)-dihydroxy-6-(2-pyridyl)hexylamide 15 The title compound was obtained from 300 mg of 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-[4(R,S)-hydroxy-4-(2-pyridyI)butyI]oxazoIidine in analogy to Example 2a). Rf (EA/MeOH 10/1) = 0.25 MS (FAB) = 841 (M+1) 20 b) 3-Boc-4(S)-cycIohexyI methyI-2,2-dimethyI-5-C4(R,S)-hydroxy-4-(2-pyr idyl)butyl]oxazolidine 130 mg of 3-Boc-4(S)-cycIohexyI methy1-2,2-dimethyI-5-[4-(2-pyridyI)-4-oxobutyIDoxazolidine and 40 mg of sodium 25 borohydride in 5 ml of ethanol are stirred at R.T. for 90 minutes. Addition of 15 ml of H2O is followed by extraction 3 times with EA, drying over NagSO^ and concentration. Chromatography on silica gel (mobile phase EA/hexane 1/1) provides the title compound. 30 Rf (EA/hexane 1/1) = 0.4; MS (EI) = 446 (M) The compounds of Examples 4 and 5 are prepared in analogy to Example 3. 35 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) 226361 Example 5 Iva-Phe-His 1(S)-cyclohexylmethyl-2(R),6(R,,S)-dihydroxy-6-(4-pyridyl)hexylamide Rf (EA/hexane 3/1) = 0.2; MS (FAB) = 675 (M+1) 5 Example 6 Iva-Phe-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-6(R,S)-methoxy-6-(2-pyridyl)hexylamide 10 The title compound was obtained from 3-Boc-4(S)-eyelo- hexylmethyl-2,2-dimethyl-5-[4(R,S)-methoxy-4-(2-pyridyl)-buty I ]oxazoIidine in analogy to Example 2, 2a). Rf (EA/MeOH 5/1) = 0.15; MS (FAB) = 689 (M+1) 15 a) 3-Boc-1(S)-cyclohexyImethyI — 5 — C 4(R,S)-methoxy-4-(2-pyridyl)butyl]oxazolidine. The title compound was obtained from 3-Boc-4(S)-cycIohexyI methyl-2,2-dimethyl-5-[4(R,S)-hydroxy-4-(2-pyridyl)-butyl] 20 oxazolidine in analogy to Acta Chem. Scand. 2_6, 1 ( 1972). Rf (DIP) = 0.25; MS (FAB) = 461 (M+1) Example 7 Iva-Phe-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-6(R,S)-25 ethoxy-6-(2-pyridyl)hexylamide was obtained in analogy to Example 6. Rf (EA/MeOH 5/1) = 0.15; MS (FAB) = 703 (M+1) Example 8 30 Iva-Phe-His 1(S)-cycIohexyI methyI-2(S)-hydroxy-6(R,S)-fluoro-6-(4-pyridyl)hexylamide The title compound was obtained from 3-Boc-4(S)-cycIo-hexylmethyl-2,2-dimethyl-5-C4(R,S)-fluoro-4-(4-pyridyl)-35 butyl]oxazolidine in analogy to Example 2, 2a). Rf (EA/MeOH 4/1) = 0.3; MS (FAB) = 677 (M+1) a) 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-[4-(R,S)- - 21 - fluoro-4-(4-pyridyl)butyl ]ox a z oIidine 226361 160 mg of 3-Boc-4(S)-cycIohexyI methyI-2,2-dimethyI-5-C4(R,S)-hydroxy-4-(4-pyridyl)butyl3oxazolidine in 2 ml 5 of CH2CI2 are added dropwise to a solution of 50 ul of diethylaminosulfur trifluoride (OAST) at -35°C under an argon atmosphere. After 75 minutes, 10 ml of saturated Na2C03 solution are added, and the mixture is extracted 3 times with EA. Drying over Na2S(>4 and 10 concentration are followed by chromatography on silica gel (mobile phase hexane/EA 1/1). Rf (hexane/EA 1/1) = 0.3; MS (FAB) = 449 (M+1) Exanple 9 15 Iva-Phe-His 1(S)-cycIohexyI methyI-2(S),5(R,S)-dihydr0xy-5-(2-pyridyl)pentylamide The title compound was synthesized from 4(S)-cycIohexyI-methyl-5-C3(R,S)-hydroxy-3-(2-pyridyl)propyl]oxazolidin-20 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-C3(R,S)-hydroxy-3-(2-pyridyl)-propyl]oxazolidin-2-one 25 The title compound is synthesized from 4(S)-cyclohexyl-methyl-5-C3-(2-pyridyl)-3-oxopropyl]oxazolidin-2-one in analogy to Example 3b). Rf (EA) = 0.4; MS (FAB) = 319 (M+1) 30 b) 4(S)-cyclohexylmethyl-5-[3-(2-pyridyl)-3-oxopropyl3-oxazolid in-2-one 3 ml of n-buty11ithium (1.5 M in hexane) are added drop-35 wise at -60°C under an argon atmosphere to 0.6 ml of diisop ropy I amine in 20 ml of THF, and the mixture is stirred at 0°C for 45 minutes. Now 850 mg of N-C1-(2-pyridy I) ethyIidene]cycIohexyI amine in 3 ml of THF are 226361 - 22 - added at -50°C, and the mixture is then stirred at 0°C for 1 h (red coloration). Then 380 mg of Boc-2-cycI ohexyI-1 (S)-oxiran-2(S)-yIethyI amine in 5 ml of THF are added dropwise. After 60 minutes at 0°C, H2O is added, and the 5 mixture is extracted 3 times with EA. Drying over Na2S04 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) 10 c) Boc-2-cycIohexyI methyI-1(S)-oxiran-2(S)-yIethyI amine 2.6 g of Boc-1(S)-cycIohexyImethyI-2-propen-1-yI amine are dissolved in 50 ml of CH2CI2, and 1.9 g of m-chloro-perbenzoic acid in 50 ml of CH2CI2 are added dropwise 15 at 0°C. The reaction solution is stirred at R.T. for 36 h and then extracted first with 100 ml of 5 % strength aqueous Na2S03 solution and then with 100 ml of saturated aqueous Na2S03 solution. Drying over Na2S04 and concentration in vacuo are followed by chromato-20 graphy on silica gel (mobile phase: MTB/eye Iohexane 1/5), 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)-cycIohexyI methyI-2-propen-1-yI amine 5.A g of methyltriphenyIphosphonium bromide are suspended in 100 ml of THF and, at R.T., 1.7 g of potassium t-butylate are added under argon. The mixture is stirred 30 at R.T. for 2 h, cooled to 0°C and 3.9 g of Boc-cyclo-hexylalaninal in 50 ml of THF are added dropwise. The mixture is then stirred at 0°C for 30 minutes, 100 ml of H2O are added dropwise, and the THF is removed in vacuo. 100 ml of saturated aqueous NaHC03 solution are added, 35 and the mixture is extracted 3 times with 100 ml of CH2CI2' Drying over Na2S04 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 226361 oil. Rf (MTB/cyclohexane 1/3 = 0.4; MS (DCI) = 254 (M+1) e) Boc-cycIohexyI a I aninaI was obtained by the method 5 described in J.Med.Chem. 2_8, 1 179 ( 1985). Example 10 Iva-Phe-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-5(R,S)-fluoro-5-(2-pyridyl)pentylamide 10 The title compound was obtained in analogy to Example 2, 2a) from 3-Boc-4(S)-cycIohexyI methyI-2,2-dimethyI-5-C3(R , S ) -fluoro-3-(2-pyridyl )propyl3oxazolidine. Rf (EA/MeOH 5/1) = 0.3; MS (FAB = 663 (M+1) 15 a) 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-[3(R,S)-fluoro-3-(2-pyridyl)propyl]oxazolidine The title compound was obtained in analogy to Example 3 20 b) and 8 a) from 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-C3-(2-pyridyl)-3-oxopropyl]oxazolidine. Rf (EA/hexane 1/1) = 0.7; MS (DCI) = 435 (M+1) b) 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-[3-(2-25 pyridyl)-3-oxopropyl]oxazolidine The title compound was prepared in analogy to Example 9 b) from 3-Boc-4(S)-cycIohexyI methyI-2,2-dimethyI-5(S)-iodomethyloxazolidine. 30 Rf (DIP) = 0.7; MS (EI) = 430 (M) c) 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5(S)-iodo-methyloxazolidine 35 2.4 g of Boc-2-cycIohexyI-1(S )-oxiran-2(S)-yIethyI amine, 1.3 g of Nal and 1.1 ml of trimethylsi lyl chloride are dissolved in 100 ml of acetonitrile and stirred at R.T. for 1.5 h. Then 1 equivalent of cesium fluoride in THF - 24 - and 5.3 ml of dimethoxyethane are injected. is stirred at R.T. for 2.5 h and then 200 ml of saturated aqueous NaHCOj solution are added, and the mixture is extracted 3 times with 200 ml of MTB. Drying over Na2S04 5 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-CH3) 10 Example 11 Iva-Phe-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-6(R,S)-fluoro-6-(2-pyridyl)hexylamide The title compound was obtained from 3-Boc-4(S)-cyc10-15 hexylmethyl-2,2-dimethyl-5-[4(R,.S)-fluoro-4-(2-pyridyl ) -butylDoxazolidine in analogy to Example 2, 2 a). Rf (EA/MeOH 5/1) = 0.2; MS (FAB) = 677 (M+1) a) 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-C4(R,S)-20 fIuoro-4-(2-pyridyI)butyI]oxazoIidine was obtained in analogy to Example 8 a). Rf (H/EA 1/1) = 0.6; MS (FAB) = 449 (M+1) Example 12 25 Iva-Phe-His 1(S)-cycIohexyI methy1-2(S)-hydroxy-6,6-difluoro-6-(4-pyridyl)hexylamide The title compound was obtained in analogy to Example 2, 2 a) from 3-Boc-4(S)-cyclohexylmethyl-2^2-dimethyl-5-[4,4-30 difluoro-4-(4-pyridyl)butyl]oxazolidine. Rf (EA/MeOH) = 0.2; MS (FAB) = 695 (M+1) a) 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-[4,4-difluoro-4-(4-pyridyl)butyl]oxazolidine 35 1 ml of DAST is added at 0°C to 200 mg of 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-C4-(4-pyridyl)-4-oxobutyl]-oxazolidine in 2 ml of CH2CI2- After 2 days at R.T., 226361 - 25 - 10 ml of saturated Na2C03 solution are added, and the mixture is extracted 3 times with EA. Drying with N a 2 S 0 4 and concentration in vacuo are followed by chromatography on silica gel (eluent H/DIP 1.5/1), resulting in the 5 title compound as an oil. Rf (H/EA 1/1) = 0.45; MS = 467 (M + 1) Example 13 Iva-Phe-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-5,5-difluoro-10 5-(2-pyridyI)pentyI amide The title compound was obtained from 3-Boc-4(S)-cycIo-hexylmethyl-2,2-dimethyl-5-C3,3-difluoro-3-(2-pyridyl)-propyI]oxazolidine in analogy to Example 12, 12 a). 15 Rf (EA/MeOH 5/1) = 0.3; MS (FAB) = 681 (M + 1) Example 14 Iva-Phe-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-5(R,S)-isopropyl-5-(2-pyridyl)pentylamide 20 The title compound was obtained from 3-Boc-4(S)-cyclo-hexylmethyl-2,2-dimethyl-5-C3(R,S)-isopropyl-3-(2-pyridyl)-propy I]oxazoIidine in analogy to Example 2, 2 a). Rf (EA/MeOH 5/1) = 0.2; MS (FAB) = 687 (M+1) 25 a) 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-C3(R,S)-isopropyl-3-(2-pyridyl)propyl]oxazolidine 1.3 ml of 1.5 M n-BuLi (solution in hexane) are added at 30 -60°C to 250 mg of 2-isobutyIpyridine in 10 ml of THF. The reaction temperature is then maintained at R.T. for 90 minutes and, after cooling once again to -60°C, 500 mg of 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-(2-bromo-ethyl)oxazolidine in 10 ml of THF are added dropwise. 35 After 2 h at -60°C, 20 ml of H2O 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) 226361' b) 2-IsobutyIpyridine 5 40 ml of 1.5 M n-BuLi (solution in hexane) are added dropwise at -60°C to 5 g of 2-picoline in 50 ml of diethyl ether. After 1.5 h at R.T., the mixture is cooled once again to -60°C, and 10 g of 2-iodoprop ane are added dropwise. After 30 minutes at -60°C, the mixture 10 is stirred at R.T. for 60 minutes. Then 50 ml of H2O are added, and the crude material is isolated by extraction 3 times with diethyl ether. It is then purified by distillation under reduced pressure. Boiling point (40 mm) = 85°C. 15 Example 15 Iva-Phe-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-4-iso-propyl-4-(2-pyridyl)butylamide 20 (Non-polar isomer) The title compound was obtained from 3-Boc-4(S)-cyc10-hexylmethyl-2,2-dimethyl-5(S)-iodomethyloxazolidine in analogy to Example 14. 25 Rf (EA/MeOH 5/1) = 0.2; MS (FAB) = 673 (M+1) Exaaple 16 Iva-Phe-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-4-isopropyl-4-(2-pyridyl)butylamide 30 (Polar isomer) The title compound was obtained in analogy to Example 14 and 15. Rf (EA/MeOH 5/1) = 0.15; MS (FAB) = 673 (M+1) 35 ExanpLe 17 Iva-Phe-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-6(R,S)-ethoxy-6-(4-pyridyl)hexylamide • 226361 - 27 - The title compound was obtained in analogy to Example 6. Rf (EA/MeOH 5/1) = 0.1; MS (FAB) = 703 (M + 1) Example 18 5 Iva-Phe-His 1 ( S )-cycIohexyI methyI-2(S)-hydroxy-6(R,S)-n-propoxy-6-(4-pyr idyl)hexylamide The title compound was obtained in analogy to Example 2, 2a from 3-Boc-4(S)-cycI ohexyI methyI-2,2-dimethyI-5-C4(R,S)-10 n-propoxy-4-(4-pyridyl)butyl3oxazolidine. Rf (EA/MeOH 5/1) = 0.15; MS (FAB) = 717 (M + 1) a) 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-[4(R,S)-n-propyl-4-(4-pyridyl)butyl]oxazolidine 15 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) 20 Example 19 a) 3-t-Butylsulfonyl-2(R)-phenylmethylpropionyl-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-5(R,S)-fluoro-5-(2-pyridyl)pentylamide and B) 3-t-Butylsulfonyl-2(S)-phenylmethylpropionyl-His 25 1(S)-cyclohexylmethyl-2(S)-hydroxy-5(R,S)-fluoro- 5-(2-pyridyl)pentylamide The two title compounds were obtained from 3-t-butyIsuI-fonyl-2(R,S)-phenylmethylpropionyl-His(DNP) 1(S)-cyclo-30 hexylmethyl-2(S)-hydroxy-5(R,S)-fluoro-5-(2-pyridyl)pen-tylamide in analogy to Example 1 with subsequent separation of the diastereomers (a,B) on silica gel (eluent: EA/MeOH 5/1). a) Rf (EA/MeOH 5/1) = 0.25; MS (FAB) = 698 (M + 1) 35 8) Rf (EA/MeOH 5/1) = 0.15; MS (FAB) = 698 (M + 1) a) 3-t-Butylsulfonyl-2(R,S)-phenylmethylpropionyl-His(DNP) 1(S)-cyclohexylmethyl-2(S)-hydroxy-5(R,S)-fluoro-5- - 28 - (2-pyridyl)pentylamide 22 6 361 200 mg of H-His(DNP) 1 (S )-cycLohexyI methyI-2(S)-hydroxy-5(R,S)-fLuoro-5-(2-pyridyI)pentyIamide in 5 ml of THF were added dropwise at 0°C to 95 mg of 3-t-butylsul-fonyI-2(R,S)-phenyI methyIpropionic acid (see Example 22), 84 mg of HOBt (85%) and 95 mg of DCC in 10 ml of THF. The mixture was then stirred at RT for 16 h. Addition of 20 ml of saturated N a 2 C 0 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)-cycIohexyI methyI-2(S)-hydroxy-5(R,S)-fluoro-5-(2-pyridyl)pentylamide The title compound was obtained in analogy to Example 1c from 300 mg of Boc-His(DNP) 1 (S )-cycIohexyI methyI-2(S)-hydroxy-5(R,S)-fluoro-5-(2-pyridyl)pentylamide and used without further purification. c) Boc-His(DNP) 1(S)-cyclohexyImethyI-2(S)-hydroxy-5(R,S)-fluoro-5-(2-pyridyl)pentylamide The title compound was obtained in analogy to Example 1a from Boc-His(DNP)-OH and N-Boc- 1(S)-cycIohexyI methyI-2(S)-hydroxy-5(R,S)-fluoro-5-(2-pyridyl)pentylamide after elimination of the Boc group (1c). Rf (EA/MeOH 10/1) = 0.5; MS (FAB) = 698 (M + 1) d) N-Boc-1(S)-cyclohexylmethyl-2(S)-hydroxy-5(R,S)-fluoro-5-(2-pyridyl)pentylamide The title compound was obtained in analogy to Tetrahedron Lett. 2_8, 4185, ( 1987) from 350 mg of 3-Boc-4(S)-cyclohexylmethyl-5(S)-[3(R,S)-fluoro-3-(2-pyridyl)propyl]-oxazolidin-2-one at 40 to 50°C. 226361 - 29 - Rf (EA) = 0.55; MS (DCI) = 395 (M + 1) e) 3-Boc-A(S)-cyclohexylmethyl-5(S)-[3(R,S)-fluoro-3-(2-pyridyl)propyl]oxazolidin-2-one 5 300 mg of A(S)-cycIohexyI methyI-5(S)-[3(R,S)-fIuoro-3-(2-pyridyI)propyI]oxazo I idin-2-one, 156 ul of triethyl-amine, 23 mg of dimethyI aminopyridine and 265 mg of di-t-butyl pyrocarbonate were stirred in 10 ml of 10 CH2CL2 at RT for 16 h. The mixture was then con centrated and chromatographed on silica gel. Rf (EA) = 0.55; MS (DCI) = A21 (M + H) f) A(S)-Cyclohexylmethyl-5(S)-[3(R,S)-fluoro-3-(2-pyr idyl)-15 propyl]oxazolidin-2-one The title compound was obtained from A(S )-cyclohexy I -methyl-5(S)-iodomethyloxazolidin-2-one in analogy to Example 8a, 3b and 2b. 20 Rf (EA) = 0.5; MS (DCI) = 321 (M + 1) g) A(S)-Cyclohexylmethyl-5(S)-iodomethyloxazolidin-2-one 137 g of ammonium cerium(IV) nitrate were added in 25 portions at RT to A5 g of 3-p-methoxybenzyI-A(S)-cyc10-hexyI methyI-5(S)-iodomethyIoxazolidin-2-one in 1500 ml of acetonitrile/H20 2/1. After 1 h the mixture was extracted 3 x with EA (500 ml), and the combined organic phases were dried (Na2S04) and concentrated. Chromato-30 graphy 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) = 32A (M + 1) h) 3-p-Methoxybenzyl-A(S)-cyclohexylmethyl-5(S)-iodomethyl-35 oxazolidin-2-one 60 g of N-p-methoxybenzyl-N-Z-1(S)-cyclohexylmethylprop-2-en-1-y I amine in 300 ml of CH2CI2 were added dropwise, 10 15 226361 - 30 - at -50°C under an argon atmosphere, to 150 g of in I I of CH2Cl2- After 4 1/2 h at this temperature, 1.5 I of 5% strength Na2SC>3 solution were added, and the mixture was shaken without cooling until the reaction solution was decolorized. It was washed once with saturated NaCl solution and then dried (Na2S04) and concentrated. Chromatography on silica gel (eluent: hexane/EA 4/1) followed by recrysta 11 ization 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-yI am i ne 9.4 g of sodium hydride were added in portions at 0°C, to 50 g of N-Z-1(S)-cyclohexyImethyIprop-2-en-1-yI amine in 500 ml of DMF. After 2 h at 0°C, 25 ml of p-methoxybenzyI chloride were added dropwise. After 20 16 h at RT, 100 ml of 5% NaHS04 solution were added, and the mixture was extracted 3 x with 300 ml of EA. The solution was dried with Na2S(>4 and then concentrated, and the residue was chromatographed on silica gel (eluent: hexane/EA 8/1). 25 Rf (hexane/EA 8/1) = 0.3; MS (DCI) = 408 (M + 1) j) N-Z-1(S)-cyclohexylmethylprop-2-en-1-ylamine II g of 1 (S )-cycIohexyI methyIprop-2-en-1-yI amine and 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) 35 k) 1(S)-CycIohexyI me thy Iprop-2-en-1-yI amine The title compound was obtained in analogy to 1c from Boc-1(S)-cyclohexylmethylprop-2-en-1-ylamine. 226361' 31 Examples 20a and 200 were prepared in analogy to Example 19. Example 20 a) 3-t-Butylsulfonyl-2(R)-(2-thienylmethyl)propionyl-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-5(R,S)-fluoro-5-(2-pyridyl)pentylamide Rf (EA/MeOH 5/1) = 0.25; MS (FAB) = 704 (M + 1) 0) 3-t-Butylsulfonyl-2(S)-(2-thienylmethyl)propionyl-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-5(R,S)-fluoro-5-(2-pyridyl)pentylamide Rf (EA/MeOH 5/1) = 0.15; MS (FAB) = 704 (M + 1) Example 21 3-t-Butylsulfonyl-2(R,S)-(2-thienylmethyl)propionic acid 4.4 g of methyl 3-1-butyIsuIfonyI-2(R,S)-(2-1hienyI methyI)-20 propionate are suspended in 50 ml of 5N HCl 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 Na2S0^, and the solvent is removed in vacuo. 4.0 g of the title compound are obtained as a pale yellow oil. Separation 25 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-butyIsuIfonyI-2(R,S)-(2-1hienyI methyI)prop-30 ionate 5 10 15 8.4 g of methyl 3-t-buty11hio-2(R,S)-(2-thienyI methyI)-propionate are dissolved in 100 ml of CH2Cl2, and 10.6 g of m-chloroperbenzoic acid are added in portions 35 while cooling in ice. The mixture is stirred at RT for 1 h and then washed first with 100 ml of 10% Na2S03 and then with 100 ml of NaHCOj. The solution is dried over Na2S04, and the solvent is removed in vacuo. 226361 - 32 - 7.2 g of the title compound are obtained as a colorless oil. Rf (MTB) = 0.56; MS (DCI): 305 (M + 1) 5 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-thienyImethyl)-10 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% NaHSO^, solution. The solution is dried over Na^SC^, and the solvent is 15 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 20 c) Methyl 2-(2-1hienyI methyI) acryI ate 11.8 g of monomethyl 2-thienylmethyImalonate, 5.8 ml of diethylamine and 5.0 ml of 36% aqueous formaldehyde solution are stirred under argon at RT for 1 h. The 25 water is subsequently removed in vacuo and the residue is chromatographed. 7.6 g of the title compound are obtained as a colorless liquid. Rp (MTB/H 1/5) = 0.49 30 d) Monomethyl 2-thienyImethyImalonate 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 35 removed in vacuo, and the residue is taken up in 100 ml of each of 5% Na2C03 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 226361 Na2S04, 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-thienylmethyImalonate 87.8 g of dimethyl malonate and 41.0 g of potassium t-butylate are dissolved in 1.1 I of THF (anhydrous) while cooling in ice and, under argon, 44.1 g of 2-thienyImethyl chloride in 500 ml of THF are added drop-wise. 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 (I) are obtained as a colorless oil in addition to 8.8 g of dimethyl bis(2-1hienyI methyI)ma Ionate (II) Rf (I) (Toluene/DIP 20:1) = 0.35 Rf (II) (Toluene/DIP 20:1) = 0.44 f) 2-Thienylmethyl chloride 252 g of thiophene are suspended in 128 ml of concentrated aqueous HCl and, at 0°C, gaseous HCl 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 0°C 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 CHgClj. The solution is then washed 2 x with 600 ml of saturated aqueous NajCOj and dried over NagSO^, 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 - 84°C Example 22 3-t-Butylsulfonyl-2(R,S)-phenylmethylpropionic acid </div>

Claims

<div class="application article clearfix printTableText" id="claims"> » 226361 - 34 - The title compound was prepared in analogy to EP 236,734. The separation into the R and S isomers was likewise carried out as in EP 236,734. Melting point 99 - 101 °C; Rf(EE/H 1/1) = 0.16. 5 Example 23 Iva-Phe-His 1(S)-cyclohexylmethyl-2(S)-hydroxy-5(R,S)-ethoxy-5-(2-pyridyl)pentylamide The title compound was obtained from Iva-Phe-His(DNP)-OH 10 and 1(S)-cycIohexyI methy I-2(S )-hydroxy-5(R,S)-ethoxy-5-(2-pyridyI) pentyI amine in analogy to Example 1, 1a and Example 10. Rf (EA/MeOH 5/1) = 0.15; MS (FAB) = 689 (M + 1) ? 2 6 3 6 1 - 35 - WHAT WE CLAIM IS:

1. A compound of the formula I

K2R9R' (i>

R1-A-B-HN-CH-CH-OH-R4

in which a-j) is absent or denotes hydrogen,

a2) denotes C C-|-C20^~al-ky I which is optionally substituted by one, two or three identical or different radicals from the series comprising hydroxyl, ( C -j — C 7)-a I koxy ,

carboxyl, ( C -j — C 7)-a I koxyc a rbony I , ( C -j-Cg )-al kanoy loxy, Cl,

Br, amino, (C-j-CyJ-alkylamino, di-(Ci-C7)-alkylamino, (C<|-C5)-alkoxycarbonylamino and (C7-Ci-j)-aralkyloxycarbonyl-amino, or denotes (Cj-CgJ-cycloalkyl, (C3-Cg)-cycloalkyl-( C1 — C iQ)-alkyl or (C6-C-|4)-aryl-(Ci-Cg)-alkyl which is optionally substituted in the aryl moiety by one or two ^

identical or different radicals from the series compris-^

![ +

ing F, Cl, Br, hydroxyl, (C i-C7>-alkoxy, (C<j-C7)-alkyl, ! isj (C1-C7)-aIkoxycarbonyI, aminoand trifluoromethyl, or ¥ 10 OCT 1991 a-*) denotes a radical of the formula II ^ ,<-C

Ra-W- (II)

in which W represents -CO-, -0-C0-, -S02- or -NH-CO-, and Ra represents hydrogen, (Ci-C-jQ)-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, (C-j-C7)-alkoxy, <C^ — C75 —

alkanoyloxy, carboxyl, (C1-C7)-aIkoxycarbonyI, Cl, Br,

amino, (Ci-C7)-alkylamino, di-(Ci-C7)-alkylamino, (C-p C5)-a IkoxycarbonyI amino, (C7-C 15 )-ara IkoxycarbonyI amino and 9-fluorenyI methyI oxycarbony I amino, or represents (C3-Cg)-cycloalkyl , ( C3-C g )-c y c I oa I ky I - ( C ]-C$ ) - a I ky I , (C^-C^)-aryl which is optionally substituted by one or two identical or different radicals from the series comprising F,

226361

- 36 -

Cl, Br, I, hydroxyl, ( C 1-C7 )-a I koxy, ( C -| — C 7 )-a I k y I , (C-j-C7)-alkoxycarbonyl, amino and trifIuoromethyI, or represents ( C^-C 14)-a r y I - ( C-j-C^)-a I ky I , 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, ( C 1-C7 )-a I koxy , ( C 1-C 7 )-a I k y I , (C-| — C7) — al koxycarbonyl , amino, ( C <| -C 7 )-a I k y I am i no, di — (C-j—C7) — alkylamino, carboxyl, carboxymethoxy, amino-(C1-C7)-a IkyI, (Ci-C7)-alkylamino-(Ci-C7)-alkyl, di-(C<|-C7)-alkylamino-(C1-C7)-a I ky I , (Ci-C7)-alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, ( C -j — C 7 )-a I koxy su I f ony I , sulfo- and guanidino-methyl, or represents the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaromatic compound which has at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members too and which is optionally mono-, di- or trisubstituted as (C^-C^J-aryl defined under a2),

A bi> denotes a radical of the formula III or Ilia,

0 0 0

c I 1

r -(ch_) -ch-c- ft

II 11

.2,n .. - s - ch2 - ch - c -

"Vm (™2>n

" (III) (Ilia) R5

in which

1

R is defined as above, n and m are identical or different and denote 0, 1, 2, 3 or 4, R^ and R^ are identical or different and denote phenyl, 2- or 3-thienyl, 2-, 3- or 4 -

pyridyl, 1-, 2- or 4-imidazoIy1, 1- or 2-naphthyl, 2- or 3-

benzoCb ] thieny I , OH or hydrogen, or b2) denotes a radical, which is linked N-terminal 1

with R and C-terminal with B, of an amino acid from the series comprising phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, B-2-thienylalanine, B-3-1hi_enyI a I anine, B-2-furyI a I anine, B-3-furyI a I anine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chI 0rophenyI a I anine, methionine sulfone, methionine

. . 37 . 22i;;ici sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexyl-alanine, cyclohexyIglycine, im-methy I histidine , O-methyl-tyrosine, 0-benzyItyrosine, 0-tert.-butyItyrosine, phenyl-glycine, 1-naphthylalanine, 2-naphthylalanine, 4-nitro-phenylalanine, norvaline, 8-2-benzoCb ] thienylalanine, 0-3-benzoCb]thienyI a I anine, 2-fluorophenylalanine, 3-fluoro-phenylalanine, 4-fIuorophenyI a I anine, norleucine, cysteine, S-methylcysteine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,, homophenylalanine, DOPA, 0-dimethyl-DOPA,

2-amino-4-<2-thienyI)-butyric acid, benzodioxol-5-ylala-nine, N-methylhistidine, 2-amino-4-(3-thienyI)butyric acid,

3-(2-thienyl)-serine, (Z)-dehydrophenylalanine and (E) -dehydrophenylalanine,

B denotes a radical of an amino acid as defined under Cb2>,

denotes hydrogen, (C -|-C iq )-a I ky I, (C4-C7)-cycloalkyl, (C4-C7)-cy c loa I ky I-(C-j-C 4)-a I ky I , (C^-C-^J-aryl or (C$-C-j4)-aryl-(Ci-C4)-alkyl,

R^ denotes hydrogen, (C -j-C -jq )-a I ky I , (C^-C 14)-ary I C14) - a r y I - (C -j - C 4) - a I k y I,

R^ denotes a radical of the formula IV ;| .

;7~; •

X,

- (ch2)p - x - (0h2)1 - r7

L

Q

with X representing -CF2-, -CO- or -CHR p and q denoting, independently of one another, 0, 1, 2, 3, or 4,

and

R® denoting ( C -j-C 7)-a I k y I , ( C 1-C5 )-a I koxy , ( C — C 5 )-a I ky l-

thio, ( C-J-C5)-a I ky I am i no , -OH, -N3, -F, -Cl, -Br or -I,

R^ denotes hydrogen, -OH, -NHg, (C$-C 14)~aryI or heteroaryl,

which can also be partially or completely hydrogenated,

and R9 can be -OH or -F, with the proviso that compounds of the formula I wherein

X = CHR8, p = 0,R7 = OH or NH2 and R8 = (CrC,)-allcyl are excluded,

and the physiologically tolerated salts thereof.

2. A compound of the formula I as claimed in claim

1, in which R1 is absent; denotes hydrogen or represents

226361

- 38 -

(C 1-C1Q )-31ky I ; cyclopentyl; cyclohexyl; cyclopentyl-(Ci-Cig)-alkyl; cyclohexyl-(Ci~CiQ)-alkyl; optionally substituted pheny l-( C i~Cg )-al kyl; H2N-( C -j-C -jq >_al ky I; H0-( C -|-Cio)-al kyl ; ( C 1 -C 4)-a I koxy-( C 1 -C iq)-a I ky I ; (C1-C4)-alkoxycarbonyl-(C<|-CiQ)-alkyl or c arboxy-( C pC iq)-a I ky I and the physiologically tolerated salts thereof.

3. A compound of the formula I as claimed in claim

1

1, in which R denotes (Ci~C 11 )-alkanoyI; optionally protected amino-(C-j-Cii)-alkanoyl; di-(Ci-C7)-alkylamino-(C2-C11)-alkanoy I; (C4-C9)-cycloalkylcarbonyl; (C$-Ciq)-aryI-(C2-C11)-a Ikanoy I; benzoyl which is optionally substituted by halogen, (C^ — C^)—alkyL, (Ci-C7>-alkoxy or (Ci~C7)-alkoxycarbonyI; pyrrolyl-2-carbonyl; pyridyl-3-carbonyl; benzenesulf ony I ; (Ci-Cig)-alkoxycarbonyl; ( c -j — CiQ)-alkoxycarbonyl which is substituted by halogen; or (C^-C14)-aryI-(C)-alkoxycarbonyI, and the physiologically tolerated salts thereof.

4. A compound of the formula I as claimed in any one claims 1-3, in which denotes isobutyl,

benzyl or cyclohexylmethyl, and the physiologically tol^

erated salts thereof. (W

If iooctwi j

V o //

5. A compound of the formula I as claimed in ^Ce,%i any one of claims 1-4, in which R denotes hydrogen,

isopropyl or isobutyl, and the physiologially tolerated salts thereof.

6. A compound of the formula I as claimed in any one of claims 1-5, in which R^ and R^ are identical or different and denote phenyl, 2-thienyl, 2-pyridyl, 1-naphthyl, 2-benzoCb]thieny I , OH or hydrogen, and the physiologically tolerated salts thereof.

226361

- 39 -

7. A compound of the formula I as claimed in any one of claims 1-6, in which R^ 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.

8. A compound of the formula I as claimed in any one of claims 1- 7, in which A and B are identical or different and denote phenylalanine, histidine, tyrosine,

tryptophan, methionine, leucine, isoleucine, asparagine,

aspartic acid, 8-2-1hienyI a I anine, S-3-thienyI a I anine,

B-2-furyI a I anine, lysine, ornithine, 2,4-diaminobutyric acid, arginine, norvaline, 4-chI orophenyI a I anine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyri-dylalanine, cyclohexyIalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O-benzyltyrosine, Cite^ .-butyl tyros ine, phenylglycine, 1-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norleucine,

valine, alanine, cysteine, S-methy Icysteine, N-methyl-histidine, benzodioxol-5-ylalanine, 1,2,3,4-tetrahydro-isoquinoline-3-carboxyIic acid, homophenyI a I anine, 2-am i no-4-(2-th i eny I) buty r i c acid, (Z)-dehydr opheny I a I an i ne or (E)-dehydrophenylalanine, and the physiologically c.

toleratedsaltsthereof.

'flsj oft fio OCT 1991""'

9. A compound of the formula I as claimed in ^ , any one- of claims 1-7, in which A denotes a radical of the formula III which is defined as in claim 1, and the physiologically tolerated salts thereof.

10. A compound of the formula I as claimed in an?

one of claims 1 to 9, in which i

R represents isobutylcarbonyl,

A denotes Phe or a radical of the formula Ilia in which R is (C)-a Iky I which can optionally be substituted by -NH2 or -C00H; n denotes 1 and R denotes histidine,

n denotes 1 and R** is phenyl, 2- or 3-thienyl

, " 40 " 22fj.'i(Jl

R is cyclohexyI methyI,

R"* is hydrogen,

R^ represents a radical of the formula IV in which q is fl

0, p denotes 1 or 2, X is -CFj-, -CO- or -CHR - and o

R denotes OH, F, Cl, Br, ( C •)-C^ ) - a I k o xy or (C-j-C^)-a I k y I , and

□

R represents OH,

as well as the physiologically tolerated salts thereof.

11. A process for the preparation of a compound of the formula I as claimed in any one of claims 1 to

10* which comprises coupling a fragment having a terminal carboxyl group, or a reactive derivative thereof, to a cor-responding fragment having 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 a physiologically tolerated ^

salt thereof.

/<*

12. A compound as claimed in any one of claims l//v j' 38 ~ '

to 10 suitable for use as a medicine. ^ 300C7 1991™

\A.

N'v.C g \ \1

13- A compound as claimed in any one of claims 1

to 10,suitable for use as a medicine for the treatment of"™"™""" ""

high blood pressure.

14. A pharmaceutical composition containing a compound as claimed in any one of claims 1 to 10, or a physiologically tolerated salt thereof.

15. A process for the preparation of a composition as claimed in claim 14, which comprises converting a compound of the formula I, or a physiologically tolerated salt thereof, into a suitable dosage form together with a physiologically acceptable vehicle and, where appropriate,

further additives, auxiliaries and/or preservatives.

22t;:u;i

- 41 -

16. A compound according to claim 1 substantially as herein described or exemplified.

17.~ a process according to claim 11 substantially as herein described or exemplified.

18. A process according to claim 15 substantially as herein described or exemplified.

19. A composition according to claim 14 substantially as herein described or exemplified.

20- A compound as claimed in claim 10, wherein R8 is F,

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