Diamino acid derivatives

BACKGROUND OF THE INVENTION 
This invention relates to new diamino acid compounds having valuable 
properties. 
Similar compounds are known from European Patent Application No. 77,028. 
SUMMARY OF THE INVENTION 
It is an object of the invention to provide new compounds with useful 
properties, in particular those which can be used for the preparation of 
medicaments. 
Upon further study of the specification and appended claims, further 
objects and advantages of this invention will become apparent to those 
skilled in the art. 
These objects have been achieved by providing new diamino acid derivatives 
of the formula I 
EQU X--Z--NH--CH(CH.sub.2 R.sup.1)--CH(NH.sub.2)--CH.sub.2 --CO--E--G--Y I 
wherein 
X is H, R.sup.2 --O--C.sub.n H.sub.2n --CO--, R.sup.2--C.sub.n H.sub.2n 
--O--CO--, R.sup.2 --C.sub.n H.sub.2n --CO--, R.sup.2 --SO.sub.2, (R.sup.2 
--C.sub.n H.sub.2n)--L(R.sup.2 --C.sub.r H.sub.2r)--C.sub.t H.sub.2t 
--CO--, H--(NHCH.sub.2 CH.sub.2).sub.n --NH--CH.sub.2 CO-- or 
9--fluorenyl--C.sub.n H.sub.2n --O--CO--, 
Z is 0 to 4 amino acid radicals, bonded to one another in a peptide-like 
manner, selected from the group consisting of Abu, Ada, Ala, Arg, Dab, 
Gly, His, Ile, Leu, tert.-Leu, Lys, Met, Nbg, Nle, N-Me-His, N-Me-Phe, 
Orn, Phe, Pro, Ser, Thr, Tic, Trp, Tyr and Val, 
R.sup.1 is H, A, cycloalkyl with 3-7 C atoms, Ar or C.sub.p H.sub.2p -W, 
E is absent or is Ala, Gly, Ile, Leu, tert.-Leu, Met, Ser, Thr or Val, 
G is absent or is His, Phe, Trp, Tyr or --NH--CH(CH.sub.2 
R.sup.1)--CH(NH.sub.2)--CH.sub.2 CO--, 
Y is --O--C.sub.m H.sub.2m --R.sup.3, --NH--C.sub.m H.sub.2m --R.sup.3, 
--NH--C.sub.m H.sub.2m-1 (R.sup.3).sub.2 or NA.sub.2, 
R.sup.2 is A, cycloalkyl with 3-7 C atoms, benzyl or Ar, 
L is CH or N. 
R.sup.3 is H, A, cycloalkyl with 3-7 C atoms, Ar, pyridyl, imidazolyl, 
piperidyl, N-benzyl-piperidyl or piperazinyl, 
W is OH, NH.sub.2, OA, NHA or NA.sub.2, 
A is alkyl with 1-6 C atoms, 
Ar is unsubstituted phenyl, phenyl which is mono- or polysubstituted by A, 
AO, F, Cl, Br, I, CF.sub.3 and/or NH.sub.2, or unsubstituted naphthyl and 
m, n, p, r and t are each 0, 1, 2,3,4 or 5, and salts thereof. 
DETAILED DESCRIPTION OF THE INVENTION 
It has been found that the compounds of the formula I and their salts have 
very useful properties. In particular, they inhibit the activity of human 
plasma renins. This action can be detected, for example, by the method of 
F. Fyhrquist et al., clin.Chem. 22, 250-256 (1976). It is remarkable that 
these compounds are very specific inhibitors of renin; substantially 
higher concentrations of these compounds are necessary for inhibition of 
other aspartylproteinases (for example pepsin and cathepsin D). 
The compounds can be used as medicament active compounds in human and 
veterinary medicine, in particular for the prophylaxis and treatment of 
cardiac, circulatory and vascular diseases, above all hypertension, 
cardiac insufficiency and hyperaldosteronism. The compounds can also be 
used for diagnostic purposes in order to determine the possible 
contribution of the renin activity towards maintenance of the pathological 
condition in patients with hypertension or hyperaldosteronism. 
The abbreviations of amino acid radicals given above and below represent 
the radicals --NH--CHR--CO-- (wherein R has the specific meaning known for 
each amino acid) of the following amino acids: 
______________________________________ 
Abu 2-Aminobutyric acid 
Ada Adamantylalanine 
Ala Alanine 
Arg Arginine 
Dab 2,4-Diaminobutyric acid 
Gly Glycine 
His Histidine 
Ile Isoleucine 
Leu Leucine 
tert.-Leu tert.-Leucine 
Lys Lysine 
Met Methionine 
Nbg (2-Norbornyl)-glycine 
Nle Norleucine 
N--Me--His N--Methyl-histidine 
N--Me--Phe N--Methyl-phenylalanine 
Orn Ornithine 
Phe Phenylalanine 
Pro Proline 
Ser Serine 
Thr Threonine 
Tic 1,2,3,4-Tetrahydroquinoline-1-carboxylic 
acid 
Trp Tryptophan 
Tyr Tyrosine 
Val Valine 
______________________________________ 
The other abbreviations have the following meanings in the text below: 
______________________________________ 
BOC tert.-Butoxycarbonyl 
CBZ Benzyloxycarbonyl 
DNP 2,4-Dinitrophenyl 
FMOC 9-Fluorenylmethoxycarbonyl 
imi-DNP 2,4-Dinitrophenyl in the 1-position 
of the imidazole ring 
OMe Methyl ester 
POA Phenoxyacetyl 
DCCI Dicyclohexylcarbodiimide 
HOBt 1-Hydroxybenzotriazole 
______________________________________ 
If the abovementioned amino acids can occur in several enantiomeric forms, 
all these forms and also their mixtures (for example the DL-forms) are 
included above and below, for example as a constituent of the compounds of 
the formula I. The L-forms are preferred. Where individual compounds are 
listed below, the abbreviations of these amino acids in each case relate 
to the L-form, unless expressly indicated otherwise. 
The compounds of the formula I include the 3,4-diamino acids of the formula 
I' (I; X=H; Z, E and G are absent; Y=OH): 
EQU H.sub.2 N--CH(CH.sub.2 R.sup.1)--CH(NH.sub.2)--CH.sub.2 --COOH I', 
functional derivatives thereof of the formula I" (I; Z, E and G are absent; 
X is only H if Y is other than OH): 
EQU X--NH--CH(CH.sub.2 R.sup.1)--CH(NH.sub.2)--CH.sub.2 --CO--Y I" 
and peptides derived therefrom and functional derivatives thereof of the 
formula I'" (=I, but wherein at least one of the radicals Z, E and/or G is 
at least one amino acid radical). 
If G is the group --NH--CH(CH.sub.2 R.sup.1)--CH.sub.2 --CO--, the two 
radicals R.sup.1 present in I can be identical or different. 
Particularly preferred compounds of the formula I' are those which are 
derived from naturally occurring amino acids of the formula H.sub.2 
N--CH(CH.sub.2 R.sup.1)--COOH, in particular 3,4-diamino-6-methylheptanoic 
acid (I', R.sup.1 =isopropyl; "DAMH") and 3,4-diamino-5-phenylpentanoic 
acid (I', R.sup.1 =phenyl; "DAPP"), furthermore 
3,4-diamino-5-cyclohexyl-pentanoic acid (I', R.sup.1 =cyclohexyl; "DACP"). 
Particularly preferred compounds of the formula I" are 
3-amino-4-BOC-amino-6-methyl-heptanoic acid (I", X=BOC, R.sup.1 
-isopropyl, Y=OH; ("BOC-DAMH") and 3-amino-4-BOC-amino-5-phenylpentanoic 
acid (I", X=BOC, R.sup.1 =phenyl, Y=OH; "BOC-DAPP"), furthermore 
3-amino-4-BOC-amino-5-cyclohexylpentanoic acid (I", X=BOC, R.sup.1 
=cyclohexyl, Y=OH; "BOC-DACP"). 
The compounds of the formulae I, I', I" and I'", in particular DAMH and 
DAPP, and derivatives thereof have at least two chiral centers in the 
group --NH--CH(CH.sub.2 R.sup.1)--CH(NH.sub.2)--CH.sub.2 --CO--. They can 
therefore occur in various--optically inactive or optically active--forms. 
The formulae I, I', I" and I'" include all these enantiomeric forms. The 
3S,4S-diamino enantiomers are preferred. Unless expressly indicated 
otherwise, the abbreviations DAMH, DAPP and DACP always relate to these 
3S,4S-forms. 
In the above formulae, A has 1-6, preferably 1, 2, 3 or 4, C atoms. A is 
preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl 
or tert.-butyl and furthermore also pentyl, 1-, 2- or 3-methylbutyl,, 
1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 
4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 
2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 
1,2,2-trimethylpropyl. 
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl 
or cycloheptyl, but also, for example, 1-, 2- or 3-methylcyclopentyl or 
1-, 2-, 3- or 4-methylcyclohexyl. 
Ar is preferably phenyl, or furthermore o-, m- or p-tolyl, o-, m- or 
p-ethylphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluorophenyl, o-, m- 
or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-iodophenyl, o-, m- 
or p-trifluoromethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 
3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, o-, m- or p-aminophenyl, 1- 
or 2-naphthyl. 
R.sup.1 is preferably H;, A, in particular methyl, ethyl, propyl, 
isopropyl, isobutyl or sec.-butyl; cyclohexyl; phenyl; p-chlorophenyl; OH; 
hydroxyalkyl, such as hydroxymethyl; NH.sub.2 ; aminoalkyl, such as 
aminomethyl, 1- or 2-aminoethyl or 1-, 2- or 3-aminopropyl; alkoxy, such 
as methoxy, ethoxy, propoxy, isopropoxy or butoxy; alkoxyalkyl, such as 
methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, 1- or 
2-methoxyethyl, 1- or 2-ethoxyethyl, 1- or 2-propoxyethyl, 1- or 
2-isopropoxyethyl or 1-, 2- or 3-methoxypropyl; alkylamino, such as 
methylamino, ethylamino, propylamino or isopropylamino; alkylaminoalkyl, 
such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, 
isopropylaminomethyl, 1- or 2-methylaminoethyl, 1- or 2-ethylaminoethyl, 
1- or 2-propylaminoethyl, 1- or 2-isopropylaminoethyl or 1-, 2- or 
3-methylaminopropyl; dialkylamino, such as dimethylamino, methylethylamino 
or diethylamino; or dialkylaminoalkyl, such as dimethylaminomethyl, 
methylethylaminomethyl, diethylaminomethyl, 1- or 2-dimethylaminoethyl, 1- 
or 2-methylethylaminoethyl, 1- or 2-diethylaminoethyl or 1-, 2- or 3 
-dimethylaminopropyl. Particularly preferred radicals R.sup.1 are 
isopropyl and phenyl, and secondly H, ethyl, OH, 2-aminoethyl and 
3-aminopropyl. 
R.sup.2 is preferably A, in particular, methyl, ethyl, propyl, isopropyl, 
butyl, isobutyl or tert.-butyl; or cyclopropyl, cyclopentyl, cyclohexyl, 
benzyl or phenyl. 
R.sup.3 is preferably H, A, in particular methyl, cyclohexyl, phenyl, o-, 
m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, 
o-, m- or p-aminophenyl, 2-, 3- or (in particular) 4-pyridyl, 1-, 2-, (in 
particular) 4- or 5-imidazolyl, 1-, 2-, 3- or (in particular) 4-piperidyl, 
N-benzyl-2-, -3- or (in particular) -4-piperidyl, or 1-, 2- or 
3-piperazinyl. 
X is preferably H, POA, alkoxycarbonyl, such as BOC, CBZ, alkanoyl, such as 
acetyl, propionyl, butyryl or isobutyryl, cycloalkylcarbonyl, such as 
cyclopentylcarbonyl or cyclohexylcarbonyl, aroyl, such as benzoyl, 
arylalkanoyl, such as phenylacetyl, 2-oder 3-phenylpropionyl, 2- or 3-o-, 
-m- or -p-fluorophenylpropionyl or 2- or 3-o-, -m- or 
-p-chlorophenylpropionyl, or cycloalkyl-alkanoyl, such as cyclohexylacetyl 
or 2- or 3-cyclohexylpropionyl. Particularly preferred radicals X are H, 
BOC and CBZ. 
Z is 0 (=valency bond) or 1, preferably, however, 2 or 3 or 4 amino acid 
radicals bonded to one another in a peptide-like manner, in particular the 
groups His, Phe-His, Pro-Phe-His or His-Pro-Phe-His, or furthermore 
preferably the groups Abu-His, Ada-His, Ala-His, Ala-Phe, Arg-His, 
Dab-His, Gly-His, His-His, Ile-His, Leu-His, tert.-Leu-his, Lys-His, 
Met-His, Nbg-His, Nle-His, (N-Me-His)-His, (N-Me-Phe)-His, Orn-His, 
Phe-Abu, Phe-Ada, Phe-Ala, Phe-Arg, Phe-Dab, Phe-Gly, Phe-Ile, Phe-Leu, 
Phe-tert.-Leu, Phe-Lys, Phe-Met, Phe-Nbg, Phe-Nle, Phe-(N-Me-His), 
Phe-(N-Me-Phe), Phe-Orn, Phe-Phe, Phe-Pro, Phe-Ser, Phe-Thr, Phe-Tic, 
Phe-Trp, Phe-Tyr, Phe-Val, Pro-His, Ser-His, Thr-His, Tic-His, Trp-His, 
Tyr-His, Val-His, Pro-Ala-His, Pro-Ala-Phe, Pro-Phe-Ala, Pro-Phe-Phe, 
His-Pro-Ala-His, His-Pro-Ala-Phe, His-Pro-Phe-Ala or His-Pro-Phe-Phe, 
furthermore Pro-Abu-His, Pro-Ada-His, Pro-Arg-His, Pro-Dab-His, 
Pro-Gly-His, Pro-His-His, Pro-Ile-His, Pro-Leu-His, Pro-tert.-Leu-His, 
Pro-Lys-His, Pro-Met-His, Pro-Nbg-His, Pro-Nle-His, Pro-(N-Me-His)-His, 
Pro-(N-Me-Phe)-His, Pro-Orn-His, Pro-Phe-Abu, Pro-Phe-Ada, Pro-Phe-Arg, 
Pro-Phe-Dab, Pro-Phe-Gly, Pro-Phe-Ile, Pro-Phe-Leu, Pro-Phe-tert.-Leu, 
Pro-Phe-Lys, Pro-Phe-Met, Pro-Phe-Nbg, Pro-Phe-Nle, Pro-Phe-(N-Me-His), 
Pro-Phe-(N-Me-Phe), Pro-Phe-Orn, Pro-Phe-Pro, Pro-Phe-Ser, Pro-Phe-Thr, 
Pro-Phe-Tic, Pro-Phe-Trp, Pro-Phe-Tyr, Pro-Phe-Val, Pro-Pro-His, 
Pro-Ser-His, Pro-Thr-His, Pro-Tic-His, Pro-Trp-His, Pro-Tyr-His, 
Pro-Va-His, His-Pro-Abu-His, His-Pro-Ada-His, His-Pro-Arg-His, 
His-Pro-Dab-His, His-Pro-Gly-His, His-Pro-His-His, His-Pro-Ile-His, 
His-Pro-Leu-His, His-Pro-tert.-Leu-His, His-Pro-Lys-His, His-Pro-Met-His, 
His-Pro-Nbg-His, His-Pro-Nle-His, His-Pro-(N-Me-His)-His, 
His-Pro-(N-Me-Phe)-His, His-Pro-Orn-His, His-Pro-Phe-Abu, His-Pro-Phe-Ada, 
His-Pro-Phe-Arg, His-Pro-Phe-Dab, His-Pro-Phe-Gly, His-Pro-Phe-Ile, 
His-Pro-Phe-Leu, His-Pro-Phe-tert.-Leu, His-Pro-Phe-Lys, His-Pro-Phe-Met, 
His-Pro-Phe-Nbg, His-Pro-Phe-Nle, His-Pro-Phe-(N-Me-His), 
His-Pro-Phe-(N-Me-Phe), His-Pro-Phe-Orn, His-Pro-Phe-Pro, His-Pro-Phe-Ser, 
His-Pro-Phe-Thr, His-Pro-Phe-Tic, His-Pro-Phe-Trp, His-Pro-Phe-Tyr, 
His-Pro-Phe-Val, His-Pro-Pro-His, His-Pro-Ser-His, His-Pro-Thr-His, 
His-Pro-Tic-His, His-Pro-Trp-His, His-Pro-Tyr-His, His-Pro-Val-His. 
E is preferably absent, or is preferably Ile, or furthermore preferably 
Leu, and additionally Ala, Gly, Met, Ser, Thr or Val. 
G is preferably absent or is preferably Phe, His or --NH--CH(CH.sub.2 
R.sup.1)--CH(NH.sub.2)--CH.sub.2 --CO--, in particular DAMH, DAPP or DACP, 
and additionally Trp or Tyr. 
The group --E--G-- is preferably absent or is preferably Ile, 
Ile--NH--CH(CH.sub.2 R.sup.1)--CH(NH.sub.2)--CH.sub.2 --CO-- or Ile-Phe, 
or furthermore preferably Leu-Phe, Ile-His or Leu-His. 
Y is preferably OR.sup.3, in particular OA, or --NH--C.sub.m H.sub.2m 
--R.sup.3, wherein the group C.sub.m H.sub.2m is preferably straight-chain 
alkylene with 1-5 C atoms, in particular --CH.sub.2 --, --CH.sub.2 
CH.sub.2 -- or --(CH.sub.2).sub.3 --, or furthermore also 
--CH.sub.2).sub.4 -- or --(CH.sub.2).sub.5)--, and also, for example, 
--CH(CH.sub.3)--, --CH(CH.sub.3)--CH.sub.2 -- or --CH.sub.2 
--CH(CH.sub.3)--. NH.sub.2 is also a preferred meaning of the group 
--NH--C.sub.m H.sub.2m --R.sup.3. 
If the group G is absent, Y is preferably --NH--C.sub.m H.sub.2m --R.sup.3. 
The invention accordingly particularly relates to those compounds of the 
formula I in which at least one of the radicals mentioned has one of the 
abovementioned preferred meanings. Some preferred groups of compounds can 
be expressed by the following part formulae Ia to Ij, which corresponds to 
the formula I, but wherein, in Ia, X is H, POA, BOC or CBA, Z is absent or 
is His, Phe-His, Pro-Phe-His or His-Pro-Phe-His, R.sup.1 is H, ethyl, 
isopropyl, OH, 2-aminoethyl or 3-aminopropyl, E is absent or is Ile or 
Leu, G is absent or is DAMH, His or Phe, Y is OH, OMe or 
--NH--(CH.sub.2).sub.2 --R.sup.3, R.sup.3 is H, phenyl, pyridyl, 
imidazolyl or N-benzylpiperidyl and m is 0, 1 or 2; in Ib X is H, POA or 
BOC, Z is absent or is His, Phe-His, Pro-Phe-His or His-Pro-Phe-His, 
R.sup.1 is H, isopropyl or phenyl, E is absent or is Ile, G is absent or 
is DAMH, His or Phe and Y is OH, OMe, NH.sub.2, N-benzyl-4-piperidylamino 
or 2-phenylethylamino; in Ic X is H or BOC, Z, E and G are absent, R.sup.1 
is isopropyl or phenyl and Y is OH or OMe. 
in Id 
(a) Z is 3 or 4 amino acid radicals bonded to one another in a peptide-like 
manner selected from the group consisting of Abu, Ada, Ala, Arg, Dab, Gly, 
His, Ile, Leu, Tert.-Leu, Lys, Met, Nbg, Nle, N-Me-His, N-Me-Phe, Orn, 
Phe, Pro-Ser, Thr, Tic, Trp, Tyr and Val, and/or 
(b) is --NH--CH(CH.sub.2 R.sup.1)--CH(NH.sub.2)--CH.sub.2 --CO--, and/or 
(c) R.sup.1 is --C.sub.p H.sub.2p --W and W is OA, NHA or NA.sub.2, and/or 
(d) Y is --O--C.sub.m H.sub.2m --R.sup.3 or --NH--C.sub.m H.sub.2m 
--R.sup.3, m is 2,3,4 or 5 and R.sup.3 is pyridyl, imidazolyl, piperidyl, 
N-benzyl-piperidyl or piperazinyl; 
in Ie 
Z is 3 or 4 amino acid radicals bonded to one another in a peptide-like 
manner selected from the group consisting of Abu, Ada, Ala, Arg, Dab, Gly, 
His, Ile, Leu, Tert.-Leu, Lys, Met, Nbg, Nle, N-Me-His, N-Me-Phe, Orn, 
Phe, Pro-Ser, Thr, Tic, Trp, Tyr and Val; 
in If 
G is --NH--CH(CH.sub.2 R.sup.1)--CH(NH.sub.2)--CH.sub.2 --CO--; 
in Ig 
Z is 3 to 4 amino acid radicals bonded to one another in a peptide-like 
manner selected from the group consisting of His, Phe and Pro; 
in Ih 
Z is Pro-Phe-His or His-Pro-Phe-His; 
in Ii 
G is DAMH, DAPP or DACP; 
in Ij 
G is DAMH. 
The invention furthermore relates to a process for the preparation of a 
diamino acid derivative of the formula I and of its salts, characterised 
in that it is liberated from one of its functional derivatives by 
treatment with a solvolyzing or hydrogenolyzing agent, or in that an 
amino-keto acid derivative of the formula II 
EQU X--Z--NH--CH(CH.sub.2 R.sup.1)--CO--CH.sub.2 --CO--E--G--Y II 
wherein R.sup.1, E, G, X, Y and Z have the meaning given in the case of 
formula I, is subjected to reductive amination, and in that, if 
appropriate, a functionally modified amino and/or hydroxyl group in a 
compound of the formula I is liberated by treatment with solvolyzing or 
hydrogenolyzing agents, and/or a compound of the formula I is converted 
into one of its salts by treatment with an acid or base. 
The compounds of the formula I and also the starting substances for their 
preparation are otherwise prepared by methods which are known per se, such 
as are described in the literature (for example in standard works such as 
Houben-Weyl, Methoden der Organischen Chemie (Methods of organic 
chemistry), Georg-Thieme-VerLag, Stuttgart; and furthermore European 
Patent Application Nos. 45,665, 77,028, 77,029 and 81,783), and in 
particular under reaction conditions which are known and suitable for the 
reactions mentioned. It is also possible to utilize variants which are 
known per se and are not mentioned here in more detail. 
If desired, the starting substances can also be formed in situ, so that 
they are not isolated from the reaction mixture but are immediately 
reacted further to give the compounds of the formula I. 
The compounds of the formula I are preferably obtained by a process in 
which they are liberated from their functional derivatives by solvolysis, 
in particular hydrolysis, or by hydrogenolysis. 
Preferred starting substances for the solvolysis or hydrogenolysis are 
those which contain corresponding protected amino and/or hydroxyl groups 
instead of one or more free amino and/or hydroxyl groups, preferably those 
which carry an amino-protective group instead of an H atom which is bonded 
to an N atom, in particular those of the formula III 
EQU X--Z--CH(CH.sub.2 R.sup.1)--CH(NHQ)--CH.sub.2 --CO--E--G--Y III 
wherein Q is an amino-protective group. 
Starting substances which carry a hydroxyl-protective group instead of the 
H atom of a hydroxyl group are furthermore preferred. 
It is also possible for several--identical or different--protected amino 
and/or hydroxyl groups to be present in the molecule of the starting 
substance. If the protective groups present differ, they can in many cases 
be split off selectively. 
The expression "amino-protective group" is generally known and relates to 
groups which are suitable for protecting (blocking) an amino group from 
chemical reactions but which can easily be removed after the desired 
chemical reaction has been carried out at other sites of the molecule. 
Typical groups of this type are, in particular, unsubstituted or 
substituted acyl groups, and furthermore unsubstituted or substituted aryl 
(for example 2,4-dinitrophenyl) or aralkyl (for example benzyl, 
4-nitrobenzyl or triphenylmethyl) groups. Since the aminoprotective groups 
are removed after the desired reaction (or reaction sequence), their 
nature and size is otherwise not critical; however, those with 1-20, in 
particular 1-8, C atoms are preferred. The expression "acyl group" needs 
to be interpreted in the broadest sense in connection with the present 
process. It includes acyl groups derived from aliphatic, araliphatic, 
aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in 
particular, alkoxycarbonyl, aryloxycarbonyl and, above all, 
aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such 
as acetyl, propinoyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, 
such as benzoyl or toluyl; aryloxyalkanoyl, such as phenoxyacetyl; 
alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 
2,2,2-trichloroethoxycarbonyl, BOC and 2-iodoethoxycarbonyl; and 
aralkyloxycarbonyl, such as CBZ ("carbobenzoxy"), 
4-methoxybenzyloxycarbonyl and FMOC. Preferred acyl groups are CBZ, FMOC, 
benzyl and acetyl. 
The expression "hydroxy-protective group" is also generally known and 
relates to groups which are suitable for protecting a hydroxyl group from 
chemical reactions but which can easily be removed after the desired 
chemical reaction has been carried out at other sites of the molecule. 
Typical groups of this type are the abovementioned unsubstituted or 
substituted aryl, aralkyl or acyl groups, and furthermore also alkyl 
groups. The nature and size of the hydroxy-protective groups is not 
critical, since they are removed again after the desired chemical reaction 
of reaction sequence; groups with 1-20, in particular 1-10, C atoms are 
preferred. Examples of hydroxy-protective groups, are, inter alia, benzyl, 
p-nitrobenzoyl, p-toluenesulfonyl and acetyl, benzyl and acetyl being 
particularly preferred. 
The functional derivatives of the compounds of the formula I to be used as 
starting substances can be prepared by the customary methods of amino acid 
and peptide synthesis, such as are described, for example, in the standard 
works and patent applications mentioned. 
The liberation of the compounds of the formula I from their functional 
derivatives is effected--depending on the protective group used --with, 
for example, strong acids, advantageously with trifluoroacetic acid or 
perchloric acid, and also with other strong inorganic acids, such as 
hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such 
as trichloroacetic acid, or sulfonic acids, such as benzene- or 
p-toluene-sulfonic acid. The presence of an additional inert solvent is 
possible but not always necessary. Preferred suitable inert solvents are 
organic solvents, for example carboxylic acids, such as acetic acid, 
ethers, such as tetrahydrofuran or dioxane, amides, such as 
dimethylformamide (DMF), halogenated hydrocarbons, such as methylene 
chloride, and furthermore also alcohols, such as methanol, ethanol or 
isopropanol, and water. Mixtures of the abovementioned solvents can 
furthermore be used. Trifluoroacetic acid is preferably used in excess, 
without the addition of a further solvent, and perchloric acid is used in 
the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 
9:1. The reaction temperatures for the splitting reaction are 
advantageously between about 0.degree. and about 50.degree., and the 
reaction is preferably carried out between 15.degree. and 30.degree. (room 
temperature). 
The BOC group can preferably be split off, for example, with 40% 
trifluoroacetic acid in methylene chloride or with about 3 to 5N HCL in 
dioxane at 15.degree.-30.degree., and the FMOC group can be split off with 
an approximately 5 to 20% solution of dimethylamine, diethylamine or 
piperidine in DMF at 15.degree.-30.degree.. The DNP group can also be 
split off, for example, with an approximately 3 to 10% solution of 
2-mercaptoethanol in DMF/water at 15.degree.-30.degree.. 
Protective groups which can be removed hydrogenolytically (for example CBZ 
or benzyl) can be split off, for example, by treatment with hydrogen in 
the presence of a catalyst, (for example a noble metal catalyst, such as 
palladium, advantageously on a support, such as charcoal). Suitable 
solvents here are those mentioned above, in particular, for example, 
alcohols, such as methanol or ethanol, or amides, such as DMF. The 
hydrogenolysis is as a rule carried out at temperatures between about 
0.degree. and 100.degree. under pressures between about 1 and 200 bar, 
preferably at 20.degree.-30.degree. under 1-10 bar. Hydrogenolysis of the 
CBZ group is readily effected, for example, on 5-10% Pd-C in methanol at 
20.degree.-30.degree.. 
The compounds of the formula I can also be prepared by reductive amination 
of amino-keto acid derivatives of the formula II. 
These are obtainable, for example, from amino acids of the formula 
X--Z--NH--CH(CH.sub.2 R.sup.1)--COOH by conversion into the corresponding 
imidazolides with carbonyldiimidazole and subsequent reaction with malonic 
acid derivatives of the formula HOOC--CH.sub.2 --CO--E--G--Y or salts 
thereof. 
The reductive amination can be carried out in one or several stages. First, 
the compound II can be treated with ammonium salts, for example ammonium 
acetate, and NaCNBH.sub.3, preferably in an inert solvent, for example an 
alcohol, such as methanol, at temperatures between about 0.degree. to 
50.degree., in particular between 15.degree. and 30.degree.. 
It is furthermore possible first to convert the ketone II into the oxime 
with hydroxylamine in the customary manner and to reduce this oxime to the 
amine, for example by catalytic hydrogenation on Raney nickel. 
If desired, a functionally modified amino and/or hydroxyl group in a 
compound of the formula I can be liberated by solvolysis or hydrogenolysis 
by one of the methods described above. 
Thus, in particular, a compound of the formula I wherein X is other than H 
can be converted into a compound of the formula I (X=H) advantageously by 
hydrogenolysis, if X is CBZ, and otherwise by selective solvolysis. If X 
is BOC, and BOC group can be split off, for example, with HCL in dioxane 
at room temperature. 
It is furthermore possible, for example, to hydrolyse an ester of the 
formula I (Y=--O--C.sub.m H.sub.2m R.sup.3) to the corresponding acid of 
the formula I (Y=OH), for example with aqueous-dioxanic sodium hydroxide 
solution at room temperature. 
A base of the formula I can be converted into the associated acid addition 
salt with an acid. Acids which give physiologically acceptable salts are 
particularly suitable for this reaction. Thus, it is possible to use 
inorganic acids, for example sulfuric acid, nitric acid, hydrogen halide 
acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, 
such as orthophosphoric acid and sulfamic acid, and furthermore organic 
acids, in particular aliphatic, alicyclic, araliphatic, aromatic or 
heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric 
acids, for example formic acid, acetic acid, propionic acid, pivalic acid, 
diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric 
acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, 
salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconic acid, 
ascorbic acid, nicotinic acid, isonicotinic acid, methane- or 
ehtane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 
benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and 
-di-sulfonic acids and laurylsulfuric acid. Salts with physiologically 
unacceptable acids, for example picrates, can be used to isolate and/or 
purify compounds of the formula I. 
An acid of the formula I can be converted into one of its physiologically 
acceptable metal or ammonium salts by reaction with a base. Possible salts 
are, in particular, sodium, potassium, magnesium, calcium and ammonium 
salts, and furthermore substituted ammonium salts, for example the 
dimethyl-, diethyl- or diisopropyl-ammonium, monoethanol-, diethanol- and 
triethanol-ammonium, cyclohexylammonium, dicyclohexylammonium and 
dibenzylethylenediammonium salts, and moreover, for example, salts with 
N-methyl-D-glucamine or with basic amino acids, such as arginine or 
lysine. 
The new compounds of the formula I and their physiologically acceptable 
salts can be used to prepare pharmaceutical products by a process in which 
they are brought into a suitable dosage form together with at least one 
excipient or auxiliary and, if desired, together with one or more other 
active compound(s). The formulations thus obtained can be employed as 
medicaments in human or veterinary medicine. Possible excipients are 
organic or inorganic substances which are suitable for enteral (for 
example rectal) or parenteral administration or for administration in the 
form of an inhalation spray and do not react with the new compounds, for 
example water, vegetable oils, benzyl alcohols, polyethylene glycols, 
glycerol triacetate and other fatty acid glycerides, gelatin and soya 
lecithin. Suppositories are used for rectal administration and solutions, 
preferably oily or aqueous solutions, and furthermore suspensions, 
emulsions or implants are used for parenteral administration. Sprays which 
contain the active compound either dissolved or suspended in a propellant 
gas mixture (for example fluoro-chlorohydrocarbons) can be used for 
administration as an inhalation spray. The active compound is 
advantageously used here in micronized form, it being possible for one or 
more additional physiologically acceptable solvents, for example ethanol, 
to be present. Inhalation solutions can be administered with the aid of 
customary inhalers. The new compounds can also be lyophilized and the 
resulting lyophilizates can be used, for example, for the preparation of 
injection products. The formulations mentioned can be sterilized and/or 
can contain auxiliaries, such as preservatives, stabilizers and/or wetting 
agents, emulsifiers, salts for influencing the osmotic pressure, buffer 
substances, colorants and/or aroma substances. If desired, they can also 
contain one or more other active compounds, for example one or more 
vitamins. 
The substances according to the invention are as a rule administered 
analogously to other known commercially available peptides, for each of 
the uses mentioned above, and in particular analogously to the compounds 
described in European Patent Application No. 77,028, preferably in dosages 
of about 100 mg to 30 g, in particular about 500 mg to 5 g, per dosage 
unit. The daily dosage is preferably about 2 to 600 mg/kg of body weight. 
For example, renin-associated hypertension and hyperaldosteronism are 
effectively treated by administration of from 10 mg to 300 mg/kg of body 
weight. For diagnostic purposes, the noval peptides may be administered in 
a single dose of from 0.1 to 10 mg/kg of body weight. 
The specific dose for each particular patient depends, however, on the most 
diverse factors, for example on the efficacy of the particular compound 
employed, the age, body weight, general state of health, sex, diet, time 
and mode of administration, rate of excretion, medicament combination and 
severity of the particular disease to which the therapy applies. 
Parenteral administration is preferred. 
Without further elaboration, it is believed that one skilled in the art 
can, using the preceding description, utilize the present invention to its 
fullest extent. The following preferred specific embodiments are, 
therefore, to be construed as merely illustrative, and not limitative of 
the remainder of the disclosure in any way whatsoever. In the following 
examples, all temperatures are set forth uncorrected in degrees Celsius; 
unless otherwise indicated, all parts and percentages are by weight.

In the following examples, "customary working up" means: water is added, if 
necessary, the mixture is extracted with ether or methylene chloride, the 
organic phase is separated off, dried with sodium sulfate, filtered and 
evaporated and the residue is purified by chromatography on silica gel 
and/or crystallization. 
EXAMPLE 1 
4.6 g of NaCNBH.sub.3 are added to a solution of 28.7 g of methyl 
3-oxo-4S-BOC-amino-6-methylheptanoate and 77 g of ammonium acetate in 500 
ml of methanol and the mixture is stirred at 20.degree. for 12 hours. The 
excess NaCNBH.sub.3 is hydrolysed by addition of 1N HCl to pH 2. The pH is 
brought to 9 with sodium hydroxide solution and the mixture is worked up 
in the customary manner. Methyl 3S-amino-4S-BOC-amino-6-methylheptanoate 
(m.p. 88.degree.) and methyl 3R-amino-4S-BOC-amino-6-methylheptanoate 
(m.p. 97.degree.) are obtained by chromatography on silica gel (methylene 
chloride/ethyl acetate/methanol). 
The following compounds are obtained analogously by reductive amination of 
the corresponding 3-oxo-4S-BOC-amino esters: 
3S-Methylamino-4S-BOC-amino-5-cyclohexylpentanoate 
3R-Methylamino-4S-BOC-amino-5-cyclohexylpentanoate 
3S-Methylamino-4-S-BOC-amino-5-phenylpentanoate 
3R-Methylamino-4S-BOC-amino-5-phenylpentanoate 
Methyl 3S-amino-4S-BOC-amino-5-p-chlorophenylpentanoate 
Methyl 3R-amino-4S-BOC-amino-5-p-chlorophenylpentanoate 
Methyl 3S-amino-4S-BOC-amino-pentanoate 
Methyl 3R-amino-4S-BOC-amino-pentanoate 
Methyl 3S-amino-4S-BOC-amino-hexanoate 
Methyl 3R-amino-4S-BOC-amino-hexanoate 
Methyl 3S-amino-4S-BOC-amino-8-CBZ-amino-octanoate 
Methyl 3R-amino-4S-BOC-amino-8-CBA-amino-octanoate 
Methyl 3S-amino-4S-BOC-amino-5-hydroxypentanoate 
Methyl 3R-amino-4S-BOC-amino-5-hydroxypentanoate 
Methyl 3S-amino-4S-BOC-amino-5-methoxypentanoate 
Methyl 3R-amino-4S-BOC-amino-5-methoxypentanoate 
Methyl 3S-amino-4S-BOC-amino-5-ethylaminopentanoate 
Methyl 3R-amino-4S-BOC-amino-5-ethylaminopentanoate 
Methyl 3S-amino-4S-BOC-amino-5-dimethylaminopentanoate 
Methyl 3R-amino-4S-BOC-amino-5-dimethylaminopentanoate 
EXAMPLE 2 
A solution of 37.8 g of methyl 
3-benzylamino-4S-BOC-amino-6-methyl-heptanoate (obtainable by stirring 
methyl 4S-BOC-amino-6-methyl-2-heptanoate with excess benzylamine at 
0.degree. for 48 hours) in 250 ml of ethanol is hydrogenated over 10 g of 
5% palladium hydroxide-on-charcoal at 20.degree. under 1 bar for 8 hours. 
The mixture is filtered and the filtrate is evaporated to give methyl 
3S-amino- (m.p. 88.degree.) and 3R-amino-4S-BOC-amino-6-methyl-heptanoate 
(m.p. 97.degree.), which are separated on silica gel (methylene 
chloride/ethyl acetate/methanol). 
EXAMPLE 3 
140 ml of 2N sodium hydroxide solution are added to a solution of 28.8 g of 
methyl 3S-amino-4S-BOC-amino-6-methyl-heptanoate in 140 ml of dioxane and 
the mixture is stirred at 20.degree. for 2 hours. It is then brought to pH 
6 and the resulting 3S-amino-4S-BOC-amino-6-methyl-heptanoic acid 
("BOC-DAMH") is filtered off (m.p. 221.degree.-222.degree.). 
3R-Amino-4S-BOC-amino-6-methyl-heptnaoic acid, m.p. 
248.degree.-250.degree., is obtained analogously from the 3R,4S-epimer. 
The following compounds are obtained by hydrolysis: 
3S-Amino-4S-BOC-amino-5 -cyclohexylpentanoic acid 
3R-Amino-4S-BOC-amino-5-cyclohexylpentanoic acid 
3S-Amino-4S-BOC-amino-5-phenylpentanoic acid ("BOC-DAPP"), m.p. 
214.degree.-215.degree. 
3R-Amino-4S-BOC-amino-5-phenylpentanoic acid 
3S-Amino-4S-BOC-amino-5-p-chlorophenylpentanoic acid 
3R-Amino-4S-BOC-amino-5-p-chlorophenylpentanoic acid 
3S-Amino-4S-BOC-amino-pentanoic acid 
3R-Amino-4S-BOC-amino-pentanoic acid 3S-Amino-4S-BOC-amino-hexanoic acid 
3R-Amino-4S-BOC-amino-hexanoic acid 
3S-Amino-4S-BOC-amino-8-CBZ-amino-octanoic acid 
3R-Amino-4S-BOC-amino-8-CBZ-amino-octanoic acid 
3S-Amino-4S-BOC-amino-5-hydroxypentanoic acid 
3R-Amino-4S-BOC-amino-5-hydroxypentanoic acid 
3S-Amino-4S-BOC-amino-5-methoxypentanoic acid 
3R-Amino-4S-BOC-amino-5-methoxypentanoic acid 
3S-Amino-4S-BOC-amino-5-ethylaminopentanoic acid 
3R-Amino-4S-BOC-amino-5-ethylaminopentanoic acid 
3S-Amino-4S-BOC-amino-5-dimethylaminopentanoic acid 
3R-Amino-4S-BOC-amino-5-dimethylaminopentanoic acid. 
EXAMPLE 4 
A solution of 276 mg of BOC-DAMH in 5 ml of 4N HCl in dioxane is stirred at 
20.degree. for 30 minutes and then evaporated. 
3S,4S-Diamino-6-methylheptanoic acid ("DAMH"), dihydrochloride, m.p. 
136.degree.-138.degree., is obtained. 
3R,4S-diamino-6-methylheptanoic acid dihydrochloride is obtained 
analogously from the 3R,4S-epimer. 
The following compounds are obtained analogously by splitting of the 
corresponding 4-BOC-NH derivatives: 
3S,4S-Diamino-5-cyclohexylpentanoic acid ("DACP") 
3R,4S-Diamino-5-cyclohexylpentanoic acid 
3S,4S-Diamino-5-phenylpentanoic acid ("DAPP"), dihydrochloride, m.p. 
138.degree.-140.degree. 
3R,4S-Diamino-5-phenylpentanoic acid 
3S,4S-Diamino-5-chlorophenylpentanoic acid 
3R,4S-Diamino-5-chlorophenylpentanoic acid 
3S,4S-Diaminopentanoic acid 
3R,4S-Diaminopentanoic acid 
3S,4S-Diaminohexanoic acid 
3R,4S-Diaminohexanoic acid 
3S,4S-Diamino-8-CBZ-amino-octanoic acid 
3R,4S-Diamino-8-CBZ-amino-octanoic acid 
3S,4S-Diamino-5-hydroxypentanoic acid 
3R,4S-Diamino-5-hydroxypentanoic acid 
3S,4S-Diamino-5-methoxypentanoic acid 
3R,4S-Diamino-5-methoxypentanoic acid 
3S,4S-Diamino-5-ethylaminopentanoic acid 
3R,4S-Diamino-5-ethylaminopentanoic acid 
3S,4S-Diamino-5-dimethylaminopentanoic acid 
3R,4S-Diamino-5-dimethylaminopentanoic acid. 
EXAMPLE 5 
1.2 g of 
3S-FMOC-amino-4S-(BOC-L-phenylalanyl-L-histidyl-amino)-6-methyl-heptanoyl- 
L-isoleucyl-N-(1-benzyl-4-piperidyl)-amide [m.p. 187.degree.-180.degree.; 
obtainable by reaction of BOC-Ile-OH with 
1-benzyl-4-aminopiperidine/DCCI/HOBt to give 
Boc-Ile-N-(1-benzyl-4-piperidyl)-amide (m.p. 127.degree.-128.degree.), 
hydrolysis with 4N HCL/dioxane to give Ile-N-(1-benzyl-4-piperidyl)-amide 
(m.p. 219.degree.-221.degree.), reaction with 
3S-FMOC-amino-4S-BOC-amino-6-methyl-heptanoic acid (m.p. 
115.degree.-117.degree.; obtainable from 
3S-amino-4S-BOC-amino-6-methylheptanoic acid and FMOC chloride)/DCCI/HOBt 
to give 
3S-FMOC-amino-4S-BOC-amino-6-methylheptanoyl-Ile-N-(1-benzyl-4-piperidyl)- 
amide (m.p. 208.degree., decomposition), hydrolysis with 4N HCl/dioxane to 
give 
3S-FMOC-amino-4S-amino-6-methyl-heptanoyl-Ile-N-(1-benzyl-4-piperidyl)-ami 
de hydrochloride (m.p. 176.degree., decomposition), reaction with 
BOC-(imi-DNP)-His-OH/DCCI/HOBt to give 
3S-FMOC-4S-[BOC-(imi-DNP)-His-NH]-6-methyl-heptanoyl-Ile-N-(1-benzyl-4-pip 
eridyl)-amide (m.p. 198.degree., decomposition), hydrolysis with 4N 
HCl/dioxane to give 
3S-FMOC-amino-4S-[(imi-DNP)-His-NH]-6-methyl-heptanoyl-Ile-N-(1-benzyl-4-p 
iperidyl)-amide hydrochloride (m.p. 225.degree., decomposition), reaction 
with BOC-Phe-OH/DCCI/HOBt to give 
3S-FMOC-amino-4S-[BOC-Phe-(imi-DNP)-His-NH]-6-methyl-heptanoyl-Ile-N-(1-be 
nzyl-4-piperidy)-amide (m.p. 185.degree.) and stirring for 2 hours with 
mercaptoethanol in DMF/water 1:1 at pH 8] are dissolved in 50 ml of a 10% 
solution of dimethylamine in DMF, the solution is stirred at 20.degree. 
for 30 minutes and evaporated and the residue is chromatographed on silica 
gel with methylene chloride/methanol/acetone to give 
3S-amino-4S-(BOC-L-phenylalanyl-L-histidyl-amino)-6-methyl-heptanoyl-L-iso 
leucyl-N-(1-benzyl-4-piperidyl)-amide 
["BOC-Phe-His-DAMH-Ile-N-(1-benzyl-4-piperidyl)-amide"], m.p. 
175.degree.-176.degree.. 
The following compounds are obtained analogously by splitting the 
corresponding 3S-FMOC-amino derivatives: 
POA-His-DAMH-Ile-Phe-OMe, m.p. 160.degree.-162.degree. 
BOC-Pro-Phe-His-DAMH-Ile-Phe-OMe, m.p. 104.degree.-106.degree. 
BOC-Phe-His-DAMH-Ile-Phe-OMe, m.p. 181.degree.-183.degree. 
BOC-His-His-DAMH-Ile-Phe-OMe 
BOC-Tyr-His-DAMH-Ile-Phe-OMe 
BOC-Trp-His-DAMH-Ile-Phe-OMe 
BOC-Pro-His-DAMH-Ile-Phe-OMe 
CBZ-Phe-His-DAMH-Ile-Phe-OMe 
CBZ-Phe-His-DAMH-Ile-N-(2-phenylethyl-amide), m.p. 192.degree.-194.degree. 
CBZ-His-DAMH-Ile-Phe-OMe. 
EXAMPLE 6 
70 mg of hydroxylamine hydrochloride are added to a solution of 773 mg of 
3-oxo-4S-(BOC-L-phenylalanyl-L-histidyl-NH) 
-6-methylheptanoyl-L-isoleucyl-N-(2-phenylethyl)-amide and 1.43 g of 
Na.sub.2 CO.sub.3.10H.sub.2 O in 5 ml of methanol and 5 ml of water and 
the mixture is stirred at 20.degree. for 14 hours. The oxime precipitated 
is filtered off with suction, dried, dissolved in 10 ml of methanol and 
hydrogenated over 0.5 g of Raney Ni at 20.degree. under 5 bar. The mixture 
is filtered, the filtrate is evaporated and the residue is separated on 
silica gel (methylene chloride/methanol/acetic acid/water) to give 
3S-amino-4S-(BOC-L-phenylalanyl-L-histidyl-NH)-6-methyl-heptanoyl-L-isoleu 
cyl-N-(2-phenylethyl)-amide ("BOC-Phe-His-DAMH-Ile-2-phenylethylamide"; 
m.p. 180.degree.-182.degree.) and 
3R-amino-4S-(BOC-Phe-His-NH)-6-methylheptanoyl-Ile-N-(2-phenylethyl)-amide 
EXAMPLE 7 
A solution of 831 mg of 
3-oxo-4S-(BOC-Phe-His-NH)-6-methyl-heptanoyl-Ile-Phe-OMe and 250 mg of 
benzylamine in 10 ml of ethanol is stirred at 20.degree. for 16 hours. 
After addition of 0.5 g of Pd-charcoal (5%), the resulting Schiff's base 
is hydrogenated at 20.degree. under 1 bar for 8 hours. After one 
equivalent of H.sub.2 has been taken up, the mixture is filtered, the 
filtrate is evaporated, the resulting diastereoisomer mixture of the two 
3-benzylamino compounds is dissolved in 5 ml of 50% ethanol, 0.5 g of 
palladium hydroxide-on-charcoal is added and hydrogenation is again 
carried out at 20.degree. under 1 bar for 16 hours. After filtration, 
evaporation and fractional recrystallization from ethanol, 
3S-amino-4S-(BOC-Phe-His-NH)-6-methylheptanoyl-Ile-Phe-OMe 
("BOC-Phe-His-DAMH-Ile-Phe-Ome"; m.p. 181.degree.-183.degree.) and 
3R-amino-4S-(BOC-Phe-His-NH)-6-methyl-heptanoyl-Ile-Phe-OMe are obtained. 
The following compounds are obtained analogously from the corresponding 3 
-oxo-compounds: 
BOC-Phe-His-DAMH-Val-Phe-OMe 
BOC-Phe-His-DAMH-Gly-Phe-OMe 
BOC-Phe-His-DAMH-Thr-Phe-OMe 
BOC-Phe-His-DAMH-Leu-Phe-OMe 
BOC-Phe-His-DAMH-Ala-Phe-OMe 
BOC-Phe-His-DAMH-Met-Phe-OMe 
BOC-Phe-His-DAMH-Ser-Phe-OMe 
BOC-Phe-His-DAMH-Ile-Tyr-OMe 
BOC-Phe-His-DAMH-Ile-His-OMe 
BOC-Phe-His-DAMH-Ile-Trp-OMe. 
EXAMPLE 8 
A solution of 863 mg of oily 
3S-benzylamino-4S-(BOC-Phe-His-NH)-6-methyl-heptanoyl-Ile-(2-phenylethylam 
ide) [obtainable by reaction of 
4S-(BOC-Phe-His-NH)-6-methyl-2-heptenoyl-Ile-N-(2-phenylethylamide) with 
benzylamine at 0.degree.] in 10 ml of methanol is hydrogenated over 0.5 g 
of palladium hydroxide-on-charcoal at 20.degree. under 1 bar until the 
uptake of H.sub.2 has ended. The mixture is filtered and the filtrate is 
evaporated to give BOC-Phe-His-DAMH-Ile-(2-phenylethylamide), m.p. 
180.degree.-182.degree.. 
EXAMPLE 9 
1 g of 3S-CBZ-amino-4S-(POA-His-amino)-5-phenylpentanoyl-Ile-Phe-OMe 
[obtainable by reaction of BOC-DAPP-OMe with benzyloxycarbonyl chloride to 
give methyl 3S-CBZ-amino-4S-BOC-amino-5-phenylpentanoate (m.p 
111.degree.-112.degree.), hydrolysis to give 
3S-CBZ-amino-4S-BOC-amino-5-phenyl-pentanoic acid (m.p. 
126.degree.-127.degree.), reaction with H-Ile-Phe-OMe to give 
3S-CBZ-amino-4S-BOC-amino-5-phenylpentanoyl-Ile-Phe-OMe and reaction with 
POA-His-OH] is dissolved in 10 ml of methanol and hydrogenated over 0.5 g 
of 10% Pd-C at 20.degree. under 1 bar for 3 hours, the mixture is filtered 
and the filtrate is evaporated to give POA-His-DAPP-Ile-Phe-OMe, m.p. 
113.degree.-115.degree.. 
The following compounds are obtained analogously by hydrogenolysis of the 
corresponding CBZ derivatives: 
3R-Amino-4S-(POA-His-NH)-5-phenyl-pentanoyl-Ile-Phe-OMe [obtainable via 
methyl 3R-CBZ-amino-4S-BOC-amino-5-phenyl-pentanoate (m.p. 
159.degree.-160.degree.)] 
BOC-Phe-His-DAMH-Ile-Phe-NH.sub.2, m.p. 175.degree. [decomposition; 
obtainable via methyl 3S-CBZ-amino-4S-BOC-amino-6-methyl-heptanoate (m.p. 
67.degree.-68.degree.) and 3S-CBZ-amino-4S-BOC-amino-6-methyl-heptanoic 
acid (m.p. 118.degree.-120.degree.)] 
3R-Amino-4S-(BOC-Phe-His-NH)-6-methyl-heptanoyl-Ile-Phe-NH.sub.2 
[obtainable via methyl 3R-CBZ-amino-4S-BOC-amino-6-methyl-heptanate (m.p. 
146.degree.-148.degree.) and 3R-CBZ-amino-4S-BOC-amino-6-methyl-heptanoic 
acid] 
BOC-Phe-His-DAPP-Ile-Phe-OMe, m.p. 180.degree.-181.degree. 
BOC-Phe-His-DAMH-Ile-His-OMe 
BOC-His-Pro-Phe-His-DAMH-Ile-Phe-NH.sub.2, m.p. 150.degree. (decomposition) 
BOC-Phe-His-DAMH-Leu-Phe-OMe 
BOC-His-Pro-Phe-His-DAMH-Ile-His-OMe 
BOC-Phe-His-DAMH-Ile-His-NH.sub.2 
BOC-Phe-His-DAMH-Leu-Phe-NH.sub.2 
BOC-His-Pro-Phe-Phe-DAMH-Leu-Phe-NH.sub.2 
BOC-His-Pro-Phe-His-DAMH-Leu-Tyr-NH.sub.2 
BOC-Ala-His-DAMH-Ile-Phe-OMe 
BOC-Arg-His-DAMH-Ile-Phe-OMe 
BOC-Gly-His-DAMH-Ile-Phe-OMe 
BOC-His-His-DAMH-Ile-Phe-OMe 
BOC-Ile-His-DAMH-Ile-Phe-OMe 
BOC-Leu-His-DAMH-Ile-Phe-OMe 
BOC-Lys-His-DAMH-Ile-Phe-OMe 
BOC-Met-His-DAMH-Ile-Phe-OMe 
BOC-Orn-His-DAMH-Ile-Phe-OMe 
BOC-Pro-His-DAMH-Ile-Phe-OMe 
BOC-Ser-His-DAMH-Ile-Phe-OMe 
BOC-Thr-His-DAMH-Ile-Phe-OMe 
BOC-Val-His-DAMH-Ile-Phe-OMe 
BOC-Phe-His-DAMH-Ile-Phe-OMe, m.p. 181.degree.-183.degree. 
BOC-Phe-Phe-DAMH-Ile-Phe-OMe 
BOC-Phe-Tyr-DAMH-Ile-Phe-OMe 
BOC-Phe-Trp-DAMH-Ile-Phe-OMe 
BOC-Phe-Lys-DAMH-Ile-Phe-OMe 
BOC-Phe-Orn-DAMH-Ile-Phe OMe 
BOC-Phe-Arg-DAMH-Ile-Phe-OMe 
BOC-Phe-His-DAMH-Ile-N-(2-cyclohexylethyl)-amide 
BOC-Phe-His-DAMH-Ile-N-benzylamide p0 
BOC-Phe-His-DAMH-Ile-N-(2-phenylethyl)-amide 
BOC-Phe-His-DAMH-Ile-N-(3-phenylpropyl)-amide, m.p. 158.degree. (dec.) 
BOC-Phe-His-DAMH-Ile-N-(5-p-toly-pentyl)-amide 
BOC-Phe-His-DAMH-Ile-N-(2-p-methoxyphenyl-ethyl)-amide 
BOC-Phe-His-DAMH-Ile-N-[2-(3,4-dimethoxyphenyl)-ethyl]-amide 
BOC-Phe-His-DAMH-Ile-N-(2-p-fluorophenylethyl)-amide 
BOC-Phe-His-DAMH-Ile-N-(2-p-chlorophenylethyl)-amide 
BOC-Phe-His-DAMH-Ile-N-(2-p-bromophenylethyl)-amide 
BOC-Phe-His-DAMH-Ile-N-(2-p-iodophenylethyl)-amide 
BOC-Phe-His-DAMH-Ile-N-(2-m-trifluoromethylphenylethyl)-amide 
BOC-Phe-His-DAMH-Ile-N-(2-p-aminophenylethyl)-amide 
BOC-Phe-His-DAMH-Ile-N-(4-pyridylmethyl)-amide 
BOC-Phe-His-DAMH-Ile-N-[2-(4-imidazolyl)-ethyl]-amide 
BOC-Phe-His-DAMH-Ile-N-(4-piperidyl)-amide 
BOC-Phe-His-DAMH-Ile-N-(4-piperidylmethyl)-amide 
BOC-Phe-His-DAMH-Ile-N-[2-(1-piperazinyl)-ethyl]-amide 
Acetyl-Phe-His-DAMH-Ile-Phe-OMe 
Acetyl-Pro-Phe-His-DAMH-Leu-Phe-NH.sub.2 
Acetyl-Phe-His-DAMH-Leu-Phe-NH.sub.2 
Isobutyryl-His-Pro-Phe-His-DAMH-Ala-Phe-NH.sub.2 
Isobutyryl-Phe-His-DAMH-Ile-Phe-OMe 
Isobutyryl-His-Pro-Phe-His-DAMH-Ile-His-NH.sub.2 
Isovaleryl-His-Pro-Phe-His-DAMH-Ile-His-NH.sub.2 
Isovaleryl-His-Pro-Phe-His-DAMH-Leu-His-NH.sub.2 
Isovaleryl-His-Pro-Phe-His-DAMH-Leu-Phe-NH.sub.2 
Benzoyl-His-DAMH-Ile-Phe-OMe 
Phenylacetyl-His-DAMH-Ile-Phe-OMe 
.alpha.-Naphthylacetyl-His-DAMH-Ile-Phe-NH.sub.2, m.p. 
224.degree.-226.degree. 
3-Phenylpropionyl-His-DAMH-Ile-Phe-OMe 
3-p-Tolylpropionyl-His-DAMH-Ile-Phe-OMe 
3-o-Methoxyphenylpropionyl-His-DAMH-Ile-Phe-OMe 
3-p-Methoxyphenylpropionyl-His-DAMH-Ile-Phe-OMe 
3-p-Fluorophenylpropionyl-His-DAMH-Ile-Phe-OMe 
3-p-Chlorophenylpropionyl-His-DAMH-Ile-Phe-OMe 
3-p-Bromophenylpropionyl-His-DAMH-Ile-Phe-OMe 
3-p-Iodophenylpropionyl-His-DAMH-Ile-Phe-OMe 
3-m-Trifluoromethylphenylpropionyl-His-DAMH-Ile-Phe-OMe 
3-Cuclohexylpropionyl-His-DAMH-Ile-Phe-OMe 
6-Cycloheptylhexanoyl-His-DAMH-Ile-Phe-OMe 
POA-His-DAMH-Ile-Phe-OMe 
Cyclopropylcarbonyl-Phe-His-DAMH-Phe-OMe 
Cyclopentylcarbonyl-Phe-His-DAMH-Ile-Phe-OMe 
Cyclohexylcarbonyl-Phe-His-DAMH-Ile-Phe-OMe 
3S-Amino-4S-BOC-Phe-His-amino-pentanoyl-Ile-Phe-OMe [m.p. 
179.degree.-180.degree. (dec.); obtainable via methyl 
3S-CBZ-amino-4S-BOC-aminopentanoate (m.p. 140.degree.) and 
3S-CBZ-amino-4S-BOC-aminopentanoic acid (oil; rf 0.18 on silica gel with 
dichloromethane/methanol 9:1)] 
3R-Amino-4S-BOC-Phe-His-amino-pentanoyl-Ile-Phe-OMe [obtainable via methyl 
3R-CBZ-amino-4S-BOC-aminopentanoate (m.p. 138.degree.-139.degree.)] 
3S-Amino-4S-BOC-Phe-His-amino-5-hydroxypentanoyl-Ile-Phe-OMe 
3S,8-Diamino-4S-Phe-His-amino-octanoyl-Ile-Phe-OMe [obtainable via methyl 
3S,8-bis-(CBZ-amino)-4S-BOC-aminooctanoate (m.p. 101.degree.-102.degree.) 
and 3S,8-bis-(CBZ-amino)-4S-BOC-aminooctanoic acid (m.p. 
201.degree.-203.degree.)] 
3R,8-Diamino-4S-BOC-Phe-His-amino-octanoyl-Ile-Phe-OMe [obtainable via 
methyl 3R,8-bis-(CBZ-amino)-4S-BOC-aminooctanoate (m.p. 
137.degree.-138.degree.) and 3R,8-bis-(CBZ-amino)-4S-BOC-aminooctanoic 
acid (m.p. 201.degree.-203.degree.)] 
Benzoyl-His-DAMH-Ile-DAMH-OMe 
Phenylacetyl-His-DAMH-Ile-DAMH-OMe 
Phenoxyacetyl-His-DAMH-Ile-DAMH-OMe 
3-Phenylpropionyl-His-DAMH-Ile-DAMH-OMe 
2-Benzyl-3-phenylpropionyl-His-DAMH-Ile-DAMH-OMe 
BOC-Phe-His-(3R,4S)-DAMH-Ile-Phe-OMe, m.p. 140.degree.-143.degree. 
BOC-Phe-His-DAMH-tert.-Leu-Phe-OMe, m.p. 141.degree.-142.degree. 
BOC-Pro-Phe-His-DAMH-Ile-N-(2-phenylethylamide), formiate, m.p. 125.degree. 
(dec.) 
BOC-His-Pro-Phe-His-DAMH-Ile-N-(2-phenylethylamide), acetate, m.p. 
169.degree. (dec.) 
BOC-Phe-His-DAMH-Ile-N-(2-(4-pyridyl)-amide), acetate, m.p. 135.degree. 
BOC-Phe-His-DAMH-Ile-N-(2-(3,4-dimethoxyphenyl)-ethylamide), m.p. 
168.degree.-170.degree. 
BOC-Phe-His-DAMH-Leu-N-(2-phenylethylamide), m.p. 160.degree.-161.degree. 
BOC-Phe-Abu-DAMH-Ile-Phe-NH.sub.2, formiate, m.p. 209.degree.-210.degree. 
3S-Amino-4S-(BOC-Phe-His-amino)-5-cyclohexyl-pentanoyl-Ile-Phe-NH.sub.2 
("BOC-Phe-His-DACP-Ile-Phe-NH.sub.2 "), formiate, m.p. 188.degree. (dec.) 
BOC-Phe-His-DAMH-Ile-N-(2,2-diphenylethylamide), 
m.p.177.degree.-179.degree. 
BOC-Nbg-His-DAMH-Ile-N-(2-phenylethylamide), m.p. 138.degree.-139.degree. 
BOC-Tic-His-DAMH-Ile-N-(2-phenylethylamide), m.p. 124.degree.-128.degree. 
BOC-(N-Me-Phe)-His-DAMH-Ile-N-(2-phenylethylamide), m.p. 
112.degree.-116.degree. 
BOC-Ada-His-DAMH-Ile-N-(2-phenylethylamide), m.p. 145.degree. (dec.) 
BOC-(D-Phe)-His-DAMH-Ile-N-(2-phenylethylamide), m.p. 
163.degree.-165.degree. 
BOC-Phe-His-DACP-Ile-N-(2-cyclohexylethylamide), m.p. 
155.degree.-156.degree. 
BOC-Phe-His-DACP-Ile-DAMH-OMe, m.p. 150.degree.-151.degree. 
BOC-Phe-His-DAMH-Ile-(3R,4S)-DAMH-OMe, m.p. 159.degree.-162.degree. 
BOC-Phe-His-DACP-Ile-N-(2-phenylethylamide), m.p. 158.degree.-159.degree. 
Isovaleryl-Phe-His-DAMH-Ile-N-(2-phenylethylamide), m.p. 
174.degree.-175.degree. 
Cyclopentylcarbonyl-Phe-His-DAMH-Ile-N-(2-phenylethylamide), m.p. 
175.degree.-176.degree. 
Acetyl-Phe-His-DAMH-Ile-N-(2-phenylethylamide), m.p. 
198.degree.-200.degree. 
BOC-Phe-Nle-DACP-Ile-DAMH-OMe, m.p. 191.degree. (dec.) 
BOC-Phe-Abu-DAMH-Ile-DAMH-OMe 
BOC-Phe-Nle-DAMH-Ile-DAMH-OMe 
BOC-Tic-His-DAMH-Ile-DAMH-OMe 
BOC-(N-Me-Phe)-His-DAMH-Ile-DAMH-OMe 
BOC-Phe-Orn-DAMH-Ile-DAMH-OMe 
BOC-Phe-Lys-DAMH-Ile-DAMH-OMe 
BOC-Phe-Dab-DAMH-Ile-DAMH-OMe 
BOC-(N-Me-His)-His-DAMH-Ile-DAMH-OMe. 
EXAMPLE 10 
The following compounds are obtained analogously to Example 4 by splitting 
the corresponding (terminal, obtainable according to Examples 5 or 9) BOC 
derivatives: 
Pro-Phe-His-DAMH-Ile-Phe-OMe, hydrochloride, m.p. 205.degree.-208.degree. 
Phe-His-DAMH-Ile-Phe-NH.sub.2 
Phe-His-DAPP-Ile-Phe-OMe 
Phe-His-DAMH-Ile-His-OMe 
His-Pro-Phe-His-DAMH-Ile-Phe-NH.sub.2, hydrochloride, m.p. 210.degree. 
Phe-His-DAMH-Leu-Phe-OMe 
Phe-His-DAMH-Ile-N-[2-(4-imidazolyl)-ethyl]-amide 
Phe-His-DAMH-Ile-N-(4-piperidyl)-amide 
Phe-His-DAMH-Ile-N-(4-pyridylmethyl)-amide 
His-Pro-Phe-His-DAMH-Ile-His-OMe 
Phe-His-DAMH-Ile-His-NH.sub.2 
Phe-His-DAMH-Leu-Phe-NH.sub.2 
His-Pro-Phe-Phe-DAMH-Leu-Phe-NH.sub.2 
His-Pro-Phe-His-DAMH-Leu-Tyr-NH.sub.2 
EXAMPLE 11 
Analogously to Example 9, methyl 
3S-amino-4S-[3S-amino-4S-(BOC-Phe-His-amino)-6-methylheptanoyl)-Ile-amino] 
-6-methylheptanoate ("BOC-Phe-His-DAMH-Ile-DAMH-OMe"), m.p. 
158.degree.-159.degree. (decomposition), is obtained from methyl 
3S-CBZ-amino-4S-[(3S-CBZ-amino-4S-(BOC-Phe-His-amino)-6-methyl-heptanoyl)- 
Ile-amino]-6-methylheptanoate [m.p. 204.degree.-260.degree., obtainable 
from methyl 3S-CBZ-amino-4S-amino-6-methylheptanoate (hydrochloride, m.p. 
148.degree.-149.degree.) via methyl 
3S-CBZ-amino-4S-(BOC-Ile-amino)-6-methylheptanoate, methyl 
3S-CBZ-amino-4S-(Ile-amino)-6-methylheptanoate, methyl 
3S-CBZ-amino-4S-(3S-CBZ-amino-4S-BOC-amino-6-methyl-heptanoyl-Ile-amino)-6 
-methylheptanoate and methyl 
3S-CBZ-amino-4S-(3S-CBZ-amino-4S-amino-6-methylheptanoyl-Ile-amino)-6-meth 
ylheptanoate] by hydrogenolysis. 
The following examples relate to pharmaceutical formulations. 
EXAMPLE A 
Injection glasses 
A solution of 1 kg of His-Pro-Phe-His-DAMH-Ile-Phe-NH.sub.2 hydrochloride 
and 50 g of disodium hydrogen phosphate in 30 l of doubly distilled water 
is brought to pH 6.5 with 2N hydrochloride acid, sterile-filtered, filled 
into injection glasses and lyophilized under sterile conditions and the 
glasses are closed under sterile conditions. Each injection glass contains 
500 mg of active compound. 
EXAMPLE B 
Suppositories 
A mixture of 500 g of BOC-Phe-His-DAMH-Ile-Phe-OMe with 100 g of soya 
lecithin and 1400 g of cacao butter is melted, poured into molds and 
allowed to cool. Each suppository contains 500 mg of active compound. 
The preceding examples can be repeated with similar success by substituting 
the generically or specifically described reactants and/or operating 
conditions of this invention for those used in the preceding examples. 
From the foregoing description, one skilled in the art can easily ascertain 
the essential characteristics of this invention, and without departing 
from the spirit and scope thereof, can make various changes and 
modifications of the invention to adapt it to various usages and 
conditions.