DE4038947A1 - DITHIOLANO- AND DITHIANOGLYCIN-CONTAINING RENININHIBITORIC PEPTIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS - Google Patents

Abstract

Dithiolano- and dithianoglycin-containing renin-inhibiting peptides having general formula (I), are disclosed, in which A, B, D, E, R<1>, R<2>, R<3>, n, X and Y have the meaning given in the description, as well as a process for producing the same and their use in medicaments, in particular in medicaments that influence blood circulation.

Description

The present invention relates dithiolano- and dithianoglycine-containing renin inhibitory peptides, Ver drive to their manufacture and their use in Medicaments, in particular in circulation-influencing Drugs.

Renin is a proteolytic enzyme that is predominantly of produced by the kidneys and secreted into the plasma. It is known that renin is in vivo derived from angiotensinogen the decapeptide angiotensin I cleaves off. Angiotensin I in turn, in the lungs, kidneys or other ge weave to the blood pressure-effective octapeptide angiotensin II grown. The different effects of angiotensin II as vasoconstriction, Na⁺ retention in the kidney, Aldosterone release in the adrenal gland and tonus hunger of the sympathetic nervous system act synergi Sting in the sense of a blood pressure increase.  

The activity of the renin-angiotensin system can by the inhibition of the activity of renin or the angiote sin conversion enzyme (ACE) and blockade of Angiotensin II receptors pharmacologically manipulated become. The development of oral ACE Inhibitors has thus led to new antihypertensive drugs (See DOS 36 28 650, Am. J. Med. 77, 690, 1984).

A recent approach is the renin-angiotensin cascade to intervene at an earlier stage, namely by Inhibition of the highly specific peptidase renin.

So far, various types of renin inhibitors have been used developed: renin-specific antibodies, phospholipids, Peptides with the N-terminal sequence of the prorenin, syn thetic peptides as substrate analogs and modified ones Peptides.

Surprisingly, peptides have now been found the usual amino acid residue -His (histidine) by a 1,3-dithiolane or dithiane residue has been replaced, and which have a renininhibitorische effect.

The invention relates to peptides of the general formula (I)

in which
A, B, D and E are the same or different and
- stand for a bond or
- stand for a natural or unnatural amino acid
R¹ - is hydrogen or
represents a typical amino protecting group,
- represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms, which in turn may be substituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
- for a remainder of the formula

stands in which
a, a ', b, d and e are the same or different and denote the number 0, 1 or 2,
h is the number 0, 1 or 2,
g is the number 1, 2, 3, 4, 5 or 6,
i is the number 0, 1, 2, 3 or 4,
c and f are the same or different and denote a number 0, 1, 2 or 3,
R⁴ and R⁴ 'are identical or different and denote phenyl, naphthyl, pyridyl or pyridyl N-oxide,
R⁵, R¹¹ and R¹⁸ are the same or different and are aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
R⁶ denotes straight-chain or branched alkyl having up to 8 carbon atoms,
R⁷ is halogen or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms
m is the -NH group, an oxygen atom, a sulfur atom or the SO₂ group,
R⁸ and R⁹ are the same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
R¹⁰ represents the radical of the formula (CH₃) ₃C-CO-CH₂- or (CH₃) ₃-C-CHOH-CH₂-,
R¹² via N-linked morpholine or piperidinyl,
R¹³ is aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or
- is a radical of the formula R¹⁹-S (O) ₁- or R²⁰-CO-, in which
R¹⁹ represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms,
1 is a number 0, 1 or 2,
R²⁰ morpholino, pyrrolidinyl or the rest

or a group of the formula -NR²¹R²², in which
R.sup.21 and R.sup.22 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally polysubstituted by hydroxyl, phenoxy, a 5- or 6-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S, alkoxy having up to 6 carbon atoms, (C₁-C₆) dialkylamino, quaternary ammonium salts or by a radical of the formula

is substituted, or
R²¹ or R²² mean cycloalkyl having 3 to 8 carbon atoms or
R²¹ and R²² together with the nitrogen atom form a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 hetero atoms from the series N, O or S,
R¹⁴ and R¹⁵ are the same or different and denote hydrogen or an amino protecting group,
R¹⁶ represents straight-chain or branched alkoxy having up to 8 carbon atoms or the group -NR²¹ 'R²²', in which
R²¹ 'and R²²' have the abovementioned meaning of R²¹ and R²² and are identical or different therefrom,
R¹⁷ is hydrogen or the group -NR²³R²⁴ in which
R²³ and R²⁴ are the same or different and are hydrogen, an amino protecting group or acyl having up to 6 carbon atoms be,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R²⁵-SO₂, R²²R²¹N-SO₂ or R²²R²¹N-CO, in which
R²⁵ represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms, or a radical of the formula

with r = 0.1 or 2, and in which
R²¹ and R²² have the abovementioned meaning,
R² - represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or
in the case that A and B simultaneously signify a bond,
R¹ and R² together with the nitrogen atom form the following rings:

or

or

or

or

or

or

n - stands for the number 1 or 2,
R³ - represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or
- represents cycloalkyl or phenyl which is optionally substituted by nitro,
X - together with the group

represents a mimic of the Leu-Val cleavage site in angiotensinogen common in renin inhibitor chemistry,
Y - depending on the meaning of the substituent X is either absent or
- is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, benzyl or cycloalkyl having 3 to 8 carbon atoms,
- represents an amino protecting group or
- for a radical of the formula -COR²⁶, -NHR²⁷,
-NR²⁸R²⁹, S (O) _k (NH) _r R³⁰ or -OR³¹, in which
R²⁶ represents hydrogen, straight-chain or branched alkyl, alkoxy or alkoxy- (C₁-C₆) -alkenyl having in each case up to 20 carbon atoms, which are optionally substituted by pyridyl or aryl having 6 to 10 carbon atoms, which in turn is supported by straight-chain or branched alkyl or alkoxy having up to 10 carbon atoms may be substituted, or
R²⁶ is the group -NR³²R³³ in which
R³² and R³³ are the same or different and are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, optionally substituted by 5- to 7-membered saturated or unsaturated heterocycle having up to 3 hetero atoms from the series N, S or O substitui is, or
R³² or R³³ are cycloalkyl having 3 to 8 carbon atoms or
R³² and R³³ together with the nitrogen form a 5- to 7-membered heterocycle having up to 3 heteroatoms from the series N, S or O or
R²⁶ is adamantyl or aryl having 6 to 10 carbon atoms, the latter being optionally substituted by alkyl or alkoxy each having up to 10 carbon atoms,
R²⁷, R²⁸ and R²⁹ are the same or different and are hydrogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 8 carbon atoms, which if given multiple by hydroxy, protected hydroxy, alkoxy or alkoxycarbonyl with each because up to 8 carbon atoms, carboxy, sulfo, phenyl, by a 5- to 7-membered, optionally substituted heterocycle having up to 3 heteroatoms from the series N, O or S or by C₁-C₈-dialkyl amino, C₁-C₆ dihydroxydialkylamino or by a remainder of the formula

substituted or
R²⁸ and R²⁹ together with the nitrogen atom form a saturated or unsaturated 5- to 7-membered heterocycle having up to 3 hetero atoms from the series O, S or N, which is optionally substituted by benzyl,
k is the number 0, 1 or 2,
r is the number 0 or 1,
R³⁰ is hydrogen, straight-chain or branched alkyl having up to 10 carbon atoms, benzyl or aryl having 6 to 10 carbon atoms, which is optionally substituted by methyl, or in the case where r is the number 0,
R³⁰ is an N-bonded 5- to 7-membered saturated heterocycle having up to 3 heteroatoms from the series N, O or S,
R³¹ hydrogen or straight-chain or branched alkyl having up to 20 carbon atoms be indicated, which is optionally substituted by phenyl, which in turn by alkoxy carbonyl having up to 8 carbon atoms, halides or by straight-chain or branched alkyl or alkoxy each having up to 8 Carbon atoms may be substituted, or a radical of the formula

means, in which
R³² and R³³ are the same or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl,
and their physiologically harmless salts
with the proviso that in case X is the radical

R³ may not be cyclohexyl.

The compounds of the general Formula (I), have multiple asymmetric carbon atoms. You can work independently in the D or  the L-form is present. The invention includes the optical Antipodes as well as the isomer mixtures or racemates. Preferably, the amino acid residues are independently Other in the optically pure, preferably in the L-form in front.

The compounds of general For Mel (I) may be present in the form of their salts. This can NEN salts of the compounds of the invention with anor ganic or organic acids or bases. To the acid addition products preferably include salts Hydrochloric acid, hydrobromic acid, hydroiodic acid, Sulfuric acid, phosphoric acid or with carboxylic acids such as Acetic acid, propionic acid, oxalic acid, glycolic acid, Bern tartaric acid, maleic acid, hydroxymaleic acid, methylma linoleic acid, fumaric acid, adipic acid, malic acid, tartaric acid citric acid, benzoic acid, cinnamic acid, lactic acid, Ascorbic acid, salicylic acid, 2-acetoxybenzoic acid, Nico tinsäure, isonicotinic acid, or sulfonic acids such as methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene olsulfonic acid, naphthalene-2-sulfonic acid or naphthalene disulfonic.

Salts of the compounds of the invention with salt bilbil groups can be prepared in a manner known per se be made, for example, by implementing the inventions Compounds of the invention containing acidic groups with appropriate bases or by implementation of he compounds according to the invention, the basic groups ent Keep with appropriate acids, preferably with each the abovementioned bases or acids.  

As the amino protecting group are those in the peptide chemistry commonly used amino protecting groups.

To this end, preference is given to: Benzyloxycarbonyl, 4-bromine benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2-chloro benzyloxycarbonyl, dichlorobenzyloxycarbonyl, 3,4-di methoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbo nyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxy carbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycar bonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5- Trimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy carbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pent oxycarbonyl, isopentoxycarbonyl, hexoxycarbonyl, Cyc lohexoxycarbonyl, octoxycarbonyl, 2-ethylhexoxycarbonyl, 2-iodohexoxycarbonyl, 2-bromoethoxycarbonyl, 2-chloro ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tri chloro-tert-butoxycarbonyl, benzhydryloxycarbonyl, bis- (4-methoxyphenyl) methoxycarbonyl, phenacyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2- (di-n-butyl-methyl silyl) ethoxycarbonyl, 2-triphenylsilylethoxycarbonyl, 2- (dimethyl-tert-butylsilyl) ethoxycarbonyl, menthyloxy carbonyl, vinyloxycarbonyl, allyloxycarbonyl, phenoxy carbonyl, tolyloxycarbonyl, 2,4-dinitrophenoxycarbonyl, 4-nitrophenoxycarbonyl, 2,4,5-trichlorophenoxycarbonyl, Naphthyloxycarbonyl, fluorenyl-9-methoxycarbonyl, ethyl thiocarbonyl, methylthiocarbonyl, butylthiocarbonyl, Tert-butylthiocarbonyl, phenylthiocarbonyl, benzylthio carbonyl, methylaminocarbonyl, ethylaminocarbonyl, Methylthiocarbonyl, butylthiocarbonyl, tert-butylthio carbonyl, phenylthiocarbonyl, benzylthiocarbonyl, Methylaminocarbonyl, ethylaminocarbonyl, propylamino  carbonyl, iso-propylaminocarbonyl, formyl, acetyl, Propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2- Iodoacetyl, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, Benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 4-nitro benzyl, 4-nitrobenzoyl, naphthylcarbonyl, phenoxyacetyl, Adamantylcarbonyl, dicyclohexylphosphoryl, diphenyl phosphoryl, dibenzylphosphoryl, di (4-nitrobenzyl) phos phoryl, phenoxyphenylphosphoryl, diethylphosphinyl, di phenylphosphinyl, phthaloyl, phthalimido, 3,3-dimethyl propanoyl, 3,3-dimethylpropoxycarbonyl, isovaleroyl, Phenylacetyl, phenylpropionyl, cinnamoyl, 3,3-dimethyl propionyl, toluylsulfonyl, phenylsulfonyl or tert. Butylsulfonyl stands.

Particularly preferred amino-protecting groups are benzyloxy carbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxy benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitro benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5-tri methoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycar bonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycar bonyl, isobutoxycarbonyl, tert-butoxycarbonyl, cyclo hexoxycarbonyl, hexoxycarbonyl, octoxycarbonyl, 2- Bromethoxycarbonyl, 2-chloroethoxycarbonyl, phenoxyacet tyl, naphthylcarbonyl, adamatylcarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butyl butoxycarbonyl, methyloxycarbonyl, vinyloxycarbonyl, Allyloxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarb onyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, Pro pionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2,2,2- Trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, 4-chloro benzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido or Isovaleroyl, 3,3-dimethylpropanoyl, 3,3-dimethylpropoxy  carbonyl, isovaleroyl, phenylacetyl, phenylpropionyl, Cinnamoyl, 3,3-dimethylpropionyl, toluylsulfonyl, Phe nylsulfonyl or tert-butylsulfonyl [cf. Th. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York 1981].

Under the term natural amino acids are added For example, alanine (Ala), aspartic acid (Asp), asparagine (Asn), glutamic acid (Glu), glutamine (Gln), histidine (His), leucine (Leu), methionine (Met), proline (Pro), Threonine (Thr), tyrosine (Tyr), arginine (Arg), cysteine (Cys), Glycine (Gly), Isoleucine (Ile), Lysine (Lys), Phenylalanine (Phe), serine (Ser), tryptophan (Trp) and Valin (Val) recorded.

The term unnatural amino acids becomes p-F-, p-Cl, p-nitro and p-J substituted phenylalanine, 4- C₁-C₆-alkoxyphenylalanine, in particular 4-methoxyphenyl alanine, homophenylalanine, O-benzyl-serine and 1- or 2- Naphthylalanine detected.

As substituent X, which together with the rest

for a common in renin inhibitor chemistry Mimic of the Leu-Val cleavage site in angiotensinogen The usual residues are suitable, for example Patent literature such as EP 03 65 992 or from science publications are known.  

Preference is given to compounds of the general formula (I) in which
A, B, D and E are the same or different and
- stand for a bond or
for proline (Pro), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), glycine (Gly), valine (Val), histidine (His), alanine (Ala), lysine (Lys), tryptophan (Trp ), Tyrosine (Tyr), pF-phenylalanine, P-Cl-phenylalanine, p-nitrophenylalanine, 1- or 2-naphthalalanine (1-Nal, 2-Nal), 4-methoxyphenylalanine or homophenylalanine
R¹ - is hydrogen or
for tert-butoxycarbonyl (Boc), ethoxycarbonyl (EtOC), methoxycarbonyl (Metoc), benzyloxycarbonyl (Z), allyloxycarbonyl (Alloc), isopropoxycarbonyl, isopentoxycarbonyl (= 3,3-dimethylpropoxycarbonyl), N-fluorenyloxy-carbonyl (F-Moc) Phenoxyacetyl, acetyl, formyl, pivaloyl, isovaleroyl, phenylacetyl, phenylpropionyl, cinnamoyl, 3,3-dimethylpropionyl, toluenesulfonyl, phenylsulfonyl or tert-butylsulfonyl,
represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or naphthyl, which in turn may be substituted by fluorine, chlorine, methyl or methoxy,
- for a remainder of the formula

stands in which
a and a 'are the same or different and denote the number 0, 1 or 2,
g is the number 1, 2, 3, 4 or 5,
h is the number 0, 1 or 2,
i is the number 0, 1 or 2,
R⁴ and R⁴ 'are the same or different and are phenyl, naphthyl, pyridyl or pyridyl N-oxide,
R¹¹ and R¹⁸ are identical or different and are phenyl, 1-naphthyl or 2-naphthyl, which are optionally substituted by fluorine, chlorine or by straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
R⁷ is fluorine, chlorine or straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
m is the -NH group, an oxygen atom, a sulfur atom or the SO₂ group,
R⁸ and R⁹ are the same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R¹² via N-linked morpholine or piperidinyl,
R¹³ is phenyl, 1-naphthyl or 2-naphthyl, which is optionally substituted by fluorine, chlorine or by straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms, or
a radical of the formula R¹⁹-S (O) ₁- or R²⁰-CO-, in which
R¹⁹ represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, 1-naphthyl or 2-naphthyl,
l is a number 0, 1 or 2,
R²⁰ morpholino, pyrrolidinyl or a radical of the formula

means
R¹⁴ and R¹⁵ are identical or different and denote hydrogen or one of the amino-protecting groups listed above,
R¹⁶ represents straight-chain or branched alkoxy having up to 6 carbon atoms or denotes a group -NR²¹ 'R²²', in which
R²¹ 'and R²²' are the same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, or
R²¹ 'and R²² together with the nitrogen atom form a morpholine ring
R¹⁷ is the -NH₂- or -NH-CO-CH₃ group,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R²⁵-SO₂, R²²R²¹N-SO₂ or R²²R²¹N-CO, in which
R²⁵ denotes straight-chain or branched alkyl having up to 6 carbon atoms or benzyl,
R²¹ and R²² are the same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which optionally more than fold by hydroxy, pyridyl, morpholino, piperidinyl, alkoxy with up to 4 carbon atoms, (C₁-C₄) - Dialkylamino, quaternary ammonium salts or by a radical of the formula

is substituted or cyclopropyl, or
R²¹ and R²² together with the nitrogen atom form a morpholino, thiomorpholino, thiomorpholinosulfone or thiomorpholine sulfoxide ring,
R² is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or
in the case that A and B are simultaneously a bond R¹ and R² together form one of the rings listed above
n - stands for the number 1 or 2,
R³ represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or
- is cyclohexyl or phenyl, which is optionally substituted by nitro,
X - together with the group

represents a mimic of the Leu-Val cleavage site in angiotensitrogen common in renin inhibitor chemistry,
Y - depending on the meaning of the substituent X is either absent or
- represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or cyclopropyl or
- represents one of the above-listed amino protecting groups or
- is a radical of the formula -COR²⁶, -NHR²⁷, -NR²⁸R²⁹, S (O) _k (NH) _r R³⁰ or -OR³¹, in which
R²⁶ represents hydrogen, straight-chain or branched alkyl, alkoxy or alkoxy- (C₁-C₆) -alkenyl having in each case up to 16 carbon atoms, which are optionally substituted by pyridyl or phenyl, which in turn is represented by straight-chain or branched alkyl or alkoxy having up to 8 carbon atoms Substituted can be, or
R²⁶ is the group -NR³²R³³ in which
R³² and R³³ are the same or different and are hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by morpholino, pyridyl, thiomorpholine, thio morpholinsulfon or thiomorpholine sulfoxide, or R³² or R³³ cyclopropyl or phenyl or R³² and R³³ together with the nitrogen atom form a morpholine ring, or
R²⁶ is adamantyl or phenyl, the latter being optionally substituted by alkyl or alkoxy each having up to 8 carbon atoms,
R²⁷, R²⁸ and R²⁹ are the same or different and are hydrogen, cyclopropyl or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms, which may be polysubstituted by hydroxy, protected hydroxy, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, carboxy, sulfo , Phenyl, pyridyl, pyridyl-N-oxide, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino, thiomorpholinesulfone or -sulfoxide or C₁-C₆-dialkylamino, C₁-C₈-Dihydroxydialkylamino or by a radical of the formula

substituted or
R²⁸ and R²⁹ together with the nitrogen atom form a morpholine or piperidinyl ring, which are optionally substituted by benzyl,
k is the number 0, 1 or 2,
r is the number 0 or 1,
R³⁰ is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, tolyl, benzyl or phenyl, or in the case where r is the number 0, R³⁰ represents an N-bonded morpholine or pyrrolidinyl ring,
R³¹ represents hydrogen or straight or branched alkyl of up to 16 carbon atoms, optionally substituted by phenyl, which in turn is substituted by alkoxycarbonyl having up to 6 carbon atoms, fluorine, chlorine or by straight or branched alkyl or alkoxy each having up to 6 carbon atoms or a radical of the formula -CO-NR³²R³³, in which
R³² and R³³ are the same or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms or benzyl
and their physiologically acceptable salts
with the proviso that in case X is the radical

R³ may not be cyclohexyl.

Particular preference is given to compounds of the general formula (I) in which
A, B, D and E are the same or different and
- stand for a bond or
for proline (Pro), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), valine (Val), histidine (His), alanine (Ala), lysine (Lys), tyrosine (Tyr), p-fluorine phenylalanine, 1-naphthylalanine (1-Nal), (4-methoxy) phenylalanine or homophenylalanine,
R¹ - is hydrogen or
for tert-butoxycarbonyl (BOC), ethoxycarbonyl (EtOC), methoxycarbonyl (Metoc), benzyloxycarbonyl (Z), isopropoxycarbonyl, isopentoxycarbonyl, allyloxycarbonyl (Alloc), phenoxyacetyl, acetyl, pivaloyl, isovaleroyl, phenylpropionyl, tosyl, tert. Butylsulfonyl or 3,3-dimethylpropionyl,
represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or naphthyl, which in turn may be substituted by fluorine, chlorine, methyl or methoxy,
- for a remainder of the formula

stands in which
a, a 'are the number 0, 1 or 2,
g is the number 1, 2, 3, 4 or 5,
h is the number 0, 1 or 2,
i is the number 0, 1 or 2,
R⁴ and R⁴ 'are the same or different and are pyridyl, phenyl, naphthyl or pyridyl N-oxide,
R¹¹ and R¹⁸ are identical or different and are phenyl, 1-naphthyl or 2-naphthyl, which are optionally substituted by fluorine, chlorine, methyl or methoxy,
R⁷ is fluorine or chlorine
m is the NH group or an oxygen atom,
R⁸ and R⁹ are the same or different and are hydrogen or methyl,
R¹² via N-linked morpholino or piperidinyl,
R¹³ is phenyl, 1-naphthyl or 2-naphthyl, which are optionally substituted by fluorine, chlorine, methyl or methoxy or a radical of the formula R¹⁹-S (O) _l or R²⁰-CO, wherein
R¹⁹ represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or 1-naphthyl,
l is a number 0, 1 or 2,
R²⁰ morpholino, pyrrolidinyl or a radical of the formula

means
R¹⁴ and R¹⁵ are the same or different and denote hydrogen or one of the amino-protecting groups listed above,
R¹⁶ denotes straight-chain or branched alkoxy having up to 4 carbon atoms or an N-linked morpholine ring,
R¹⁷ represents the NH₂- or the -NH-CO-CH₃ group,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R²⁵-SO₂, R²²R²¹N-SO₂, R²²R²¹N-CO, wherein
R²⁵ denotes straight-chain or branched alkyl having up to 4 carbon atoms or benzyl,
R²¹ and R²² are the same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which optionally more than fold by hydroxy, pyridyl, morpholino, piperidinyl, alkoxy with up to 4 carbon atoms, (C₁-C₄) - Dialkylamino, quaternary ammonium salts or by a radical of the formula

substituted or cyclopropyl be interpreted, or
R²¹ and R²² together with the nitrogen atom form a morpholino, thiomorpholino, thio morpholinsulfone or thiomorpholine sulfoxide ring,
R² represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or
in the case that A and B simultaneously signify a bond
R¹ and R² together form one of the rings listed above,
n - stands for the number 1 or 2,
R³ - represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or
- is cyclohexyl or phenyl, which is optionally substituted by nitro,
X - for the rest of the formula

wherein
G is methyl, isopropyl, butyl, isobutyl, benzyl,

means
M is a group of the formula

means
M 'is ethyl, vinyl, iso -propyl, 1,3-dithian-2-yl, 2-alkylthioethyl or 2-dialkylaminoethyl,
Q is methyl, isopropyl, benzyl or - (CH₂) ₂-C₆H₅,
R is hydrogen, methyl, isopropyl, isobutyl or benzyl,
T is methyl, isopropyl or isobutyl,
U is methyl, isopropyl, isobutyl or benzyl,
V the rest of the formula

means
T 'and T''are identical or different and denote hydrogen, methyl, isopropyl, isobutyl or benzyl,
Y - depending on the meaning of the substituent X is either absent or
is hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, benzyl or cyclopropyl, or
- represents one of the above-listed amino protecting groups or
- is a radical of the formula -CO-R²⁶, -NHR²⁷, -NR²⁸R²⁹, S (O) _k (NH) _r R³⁰ or -OR³¹, in which
R²⁶ is hydrogen, straight-chain or branched alkyl, alkoxy or alkoxy- (C₁-C₄) -alkenyl, each having up to 10 carbon atoms, which are optionally substituted by pyridyl or phenyl, or
R²⁶ is the group -NR³²R³³ in which
R³² and R³³ are the same or different and are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, optionally substituted by morpholino, pyridyl, thiomorpholino, thiomorpholinesulfone or thiomorpholine sulfoxide, or
R³² or R³³ is cyclopropyl or phenyl, or
R³² and R³³ together with the nitrogen atom form a morpholine ring, or
R²⁶ is adamantyl or phenyl,
R²⁷, R²⁸ and R²⁹ are the same or different and are hydrogen, cyclopropyl or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, where appropriate by hydroxy, phenyl, morpholino, piperidinyl, pyrrolidinyl, thiomorpholino, thiomorpholinesulfone or sulfoxide, pyridine -N- oxide, carboxy, sulfo, alkoxy or alkoxy carbonyl each having up to 4 carbon atoms, amino or by a radical of the formula

substituted or
R²⁸ and R²⁹ together with the nitrogen atom form a morpholine or piperidinyl ring, which are optionally substituted by benzyl,
k is the number 0, 1 or 2,
r is the number 0 or 1,
R³⁰ is hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl, tolyl or phenyl, or in the case where r is the number 0,
R³⁰ represents an N-linked morpholine or pyrrolidinyl ring,
R³¹ is hydrogen or straight or branched alkyl having up to 16 carbon atoms or benzyl or is a radical of the formula -CONR³²R³³ in which
R³² and R³³ are the same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or benzyl,
and their physiologically acceptable salts
with the proviso that in case X is the radical

R³ may not be cyclohexyl.  

The compounds of the general Formula (I)

in which
R¹, A, B, D, R², n, R³, X, E and Y are as defined above can be prepared by reacting

• (A) Compounds of the general formula (II) in which
  R³, X, D, E and Y are as defined above, and
  Z represents one of the amino-protecting groups listed above
  first by cleavage the group Z converted by conventional methods in amines and these subsequently with compounds of the general formula (III) in which
  n and R² are as defined above, and
  Z 'has the abovementioned meaning of Z and is identical or different with this
  with activation of the carboxylic acid by conventional methods in inert read agents to give compounds of the general formula (IV) in which
  R², n, R³, X, D, E, Y and Z 'have the abovementioned meaning
  converts, the protective group Z 'cleaved by the usual method and in a further step with connec tions of the general formula (V) R¹-AB-OH (V) in which
  R¹, A and B have the abovementioned meaning,
  optionally condensed under the above-mentioned carboxylic acid activation, or
• (B) Compounds of general formula (Ia) in which
  R¹, A, B, R², n, R³, X, D and E have the abovementioned meaning and
  Y 'in this case together with X, D and / or E forms a C₁-C₆ alkoxycarbonyl
  saponified by the usual method to the corresponding acids and in a further step, if appropriate in the presence of excipients, by conventional methods, for example by substitution or addition tution, the radical Y introduced and derivatized, or
• (C) Compounds of general formula (VI) in which
  Z ', R², n, R³, X, D and E have the abovementioned meaning and
  R²⁶ 'has the abovementioned meaning of R²⁶ but has not been hydrogen
  hydrolyzed to the corresponding acids and then with amines of general formula (VII) or (VIIa) H₂NR³⁴ (VII)
  or
  HNR³⁵R³⁶ (VIIa) in which
  R³⁴, R³⁵, R³⁶ are the same or different and encompass the scope of meaning of the respective amino groups listed above
  optionally condensed in the presence of auxiliaries.

The methods can be obtained by the following equation be explained playfully:  

The preparation of the compounds according to the invention is also after further usual variants of the described Method has been carried out (see, for example, Houben-Weyls "Methods of Organic Chemistry" XV / 1 and 2; M. Bodans zky, A. Bodanszky in "The Practical Cl of Peptide Synthe sis ", Springer Verlag, Berlin, 1984; George R. Pettit in "Synthetic Peptides", Volume 4, Elsevier Scientific Publishing Company, Amsterdam-Oxford-New York, 1976; E. Gross and J. Meienhofer (editors) in "The Peptides", Vol. 1-3, Academic Press, New York-London-Toronto Sydney-San Francisco, 1981; M. Bodanszky in "Principles of Peptide Synthesis ", Springer Verlag, Berlin-Heidel Berg-New York-Tokyo, 1984; R. Uhmann and K. Radscheit, Offenlegungsschrift, DE 34 11 244 A1) or after the "Solid-phase method", as used for example by M. Bodanszky, A. Bodanszky in "The Practice of Peptides Synthesis ", Springer-Verlag, Berlin, 1984, or G. Barany, R.B. Merrifield in "Solid-Phase Peptides Synthesis "from" The Peptides ", Vol. 2, pp. 3-254, edited E. Gross, J. Meienhofer, Academic Press, New York London-Toronto-Sydney-San Francisco (1980) becomes.

Suitable solvents are in the process variants [A], [B] and [C] the usual inert solvents, the under the reaction conditions chosen Don `t change. These include water or organic Solvents such as diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbon substances such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride or  Acetone, dimethyl sulfoxide, dimethylformamide, hexamethyl phosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline.

It is likewise possible to use mixtures of the solvents mentioned to use.

Preference is given to tetrahydrofuran, methylene chloride, dime ethylformamide and ethyl acetate.

Usually, the process variants [A], [B] and [C] in the presence of appropriate dissolution or dilution if appropriate, in the presence of an adjuvant or catalyst in a temperature range of -80 ° C up to 300 ° C, preferably from -30 ° C to + 30 ° C at normal Pressure performed. Likewise, it is possible at elevated or reduced pressure to work.

Suitable activated carboxyl groups in process variants [A], [B] and [C] are, for example, carboxylic acid azide (obtainable, for example, by reaction of protected or unprotected carboxylic acid hydrazides with nitrous acid, their salts or alkyl nitrites (eg. isoamyl)
or unsaturated esters, in particular vinyl esters (obtainable, for example, by reacting a corresponding ester with vinyl acetate), carbamoylvinyl esters (obtainable, for example, by reaction of a corresponding acid with an isoxazolium reagent), alkoxyvinyl esters (obtainable, for example, by reaction of the corresponding acids with alkoxyacetylenes, preferably ethoxyacetylene),
or amidinoester z. N, N'- or N, N-disubstituted amidinoesters (obtainable, for example, by reacting the ent speaking acid with an N, N'-disubstituted carbodiimide (preferably dicyclohexylcarbodiimide, diisopropyl carbodiimide or N- (3-dimethylaminopropyl ) -N'-ethyl carbodiimide hydrochloride) or with an N, N-disubstituted cyanamide,
or aryl esters, in particular by electron-withdrawing substituents substituted phenyl esters, for. For example, 4-nitro phenyl, 4-methylsulfonylphenyl, 2,4,5-trichlorophenyl, 2,3,4,5,6-pentachlorophenyl, 4-Phenyldiazophenylester (available, for example, by reaction of the corresponding acid with an appropriately substituted phenol, optionally in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, isobutylchloroformate, propanephosphonic acid anhydride), benzotriazolyloxytris (dimethylamino) phosphonium,
or cyanomethyl esters (obtainable, for example, by reacting the corresponding acid with chloroacetonitrile in the presence of a base),
or thioesters, in particular nitrophenyl thioesters (obtainable, for example, by reacting the corresponding acid with nitrothiophenols, if appropriate in the presence of condensing agents such as N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, Isobutyl chloroformate, propanephosphonic anhydride, benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate),
or amino or amido esters (obtainable, for example, by reacting the corresponding acid with an N-hydroxyamino or N-hydroxyamido compound, in particular N-hydroxy-succinimide, N-hydroxypiperidine, N-hydroxyphthalamide, N-hydroxy-5-norbornene-2,3-dicarboximide or 1-hydroxybenzotriazole, optionally in the presence of condensing agents such as N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, isobutylchloroformate or n-propanephosphonic anhydride),
or anhydrides of acids, preferably symmetrical or unsymmetrical anhydrides of the corresponding acids, in particular anhydrides with inorganic acids (obtainable, for example, by reaction of the corresponding acids with thioyl chloride, phosphorus pentoxide or oxalyl chloride),
or anhydrides with carbonic acid derivatives z. Carbonic acid lower alkyl esters (obtainable, for example, by reaction of the corresponding acid with haloformic acid, eg methyl, ethyl, propyl, isopropyl, butyl or isobutyl ester, or with 1-lower alkoxycarbonyl-2-lower alkoxy 1,2-dihydro-quinoline, eg 1-methoxycarbonyl-2-ethoxy-1,2-dihydroquinoline),
or anhydrides with dihalophosphoric acids (obtainable, for example, by reaction of the corresponding acid with phosphorus oxychloride),
or anhydrides with phosphoric acid derivatives or phosphoric acid derivatives, (for example propanephosphonic anhydride, H. Wissmann and HJ Kleiner, Angew. Chem. Int Ed 19, 133 (1980)
or anhydrides with organic carboxylic acids (obtainable, for example, by reaction of the corresponding acids with an optionally substituted lower alkane or phenylalkanecarboxylic acid halide, in particular phenylacetic acid, pivalic acid or trifluoroacetic acid chloride),
or anhydrides with organic sulfonic acids (obtainable, for example, by reacting an alkali salt of a corresponding acid with a sulfonic acid halide, especially methane, ethane, benzene or toluene sulfonic acid chloride),
or symmetrical anhydrides (obtained, for example, by condensation of appropriate acids, optionally in the presence of condensing agents such as N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, isobutylchloroformate, propanephosphonic anhydride or benzotriazolyloxy tris (dimethylamino) phosphonium hexafluorophosphate.

Reactive cyclic amides are in particular amides with five-membered heterocycles with 2 nitrogen atoms and optionally aromatic character, preferred Amides with imidazoles or pyrazoles (available eg. by reacting the corresponding acids with N, N'- Carbonyldiimidazole or - optionally in the presence of condensing agents such. N, N'-dicyclohexyl carbodiimide, N, N'-diisopropylcarbodiimide, N- (3-dimethyl aminopropyl) -N'-ethylcarbodiimide hydrochloride, isobutyl chloroformate, propanephosphonic anhydride, benzotria zolyloxy-tris (dimethylamino) phosphonium hexafluorphos phat- with z. B. 3,5-dimethyl-pyrazole, 1,2,4-triazole or Tetrazole.

As auxiliaries are preferably condensing agents  used, which may also be bases, in particular when the carboxyl group is activated as anhydride is present.

The usual condensing agents are preferred here such as carbodiimides z. N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3 Dimethylaminoisopropyl) -N'-ethylcarbodiimide chloride, or carbonyl compounds such as carbonyldiimi dazole, or 1,2-oxazolium compounds such as 2-ethyl-5- phenyl-1,2-oxazolium-3-sulphate or 2-tert-butyl-5- methyl isoxazolium perchlorate, or acylamino compound such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro quinoline, or propanephosphonic anhydride, or iso butylchloroformate, or benzotriazolyloxy-tris (dimethyl amino) phosphonium hexafluorophosphate, and as bases Alkaline carbonates z. For example, sodium or potassium carbonate or bicarbonate, or organic bases such as trialkyl amine z. Triethylamine, N-ethylmorpholine, N-methyl piperidine or diisopropylethylamine used.

The cleavage of the amino protecting group takes place in itself known manner under acidic or basic conditions, or reductive by catalytic hydrogenation example with Pd / C in organic solvents such as ethers, z. As tetrahydrofuran or dioxane, or alcohols z. B. Methanol, ethanol or isopropanol.

The saponification of the carboxylic acid ester takes place according to methods in one of the above-mentioned solutions by treating the esters with customary bases delt, where the initially resulting salts by Be  act with acid into the free carboxylic acids can be.

Suitable bases for saponification are the usual ones inorganic bases. These include preferably alkali hydroxides or alkaline earth hydroxides such as Sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali carbonates such as sodium or potassium carbonate or sodium bicarbonate, or alkali metal alcoholates such as Sodium ethoxide, sodium methoxide, potassium ethanolate, Potassium methoxide or potassium tert-butoxide. Especially preferred are sodium hydroxide or potassium hydroxide used.

The saponification generally becomes at a temperature range from 0 ° C to + 100 ° C, preferably + 20 ° C is + 80 ° C carried out.

In general, the saponification is at atmospheric pressure carried out. But it is also possible with negative pressure or to work at overpressure (eg from 0.5 to 5 bar).

When carrying out the saponification, the base is in general in an amount of 1 to 3 mol, preferably from 1 to 1.5 mol based on 1 mol of the ester puts. Particular preference is given to using molar amounts the reactants.

The cleavage of the esters can also be customary Method with acids, such as hydrogen chloride acid or trifluoroacetic acid in the case of tert-butyl  ester or by hydrogenolysis in the case of benzyl esters respectively.

The compounds of the general formulas (II) and (V) are known per se or can be determined by conventional methods of peptide chemistry can be constructed by a corresponding fragment consisting of one or more amino acid groups, with one free, possibly present in activated form Carboxyl group with a complementing fragment, consisting of one or more amino acid group ments, with an amino group, optionally in activated form, and this process given so often with corresponding fragments again picks up the desired peptides of the general Subsequently formulas (II) and (V) if necessary, splits off protective groups or against others Exchanges protective groups.

In this case, additional reactive groups, such as. B. Amino or hydroxy groups, in the side chains of Fragments optionally by conventional protecting groups to be protected [cf. Houben-Weyl, Eugen Müller, Methods of Organic Chemistry, Volume XV / 1 and Volume XV / 2, Georg Thieme Verlag, Stuttgart, 1974].

The reaction with amines of the formulas (VII) and (VIIa) generally takes place in one of the above inert solvents, in the presence of one of the above listed bases, preferably in triethylamine and Methylene chloride at a temperature of -40 ° C to 0 ° C. at, preferably at -20 ° C and atmospheric pressure.  

In general, 1 to 5, preferably 1.5 to 1 mol of amine, based on 1 mol of the reactant, on.

The compound of general formula (III) are mostly new and can be made from the corresponding free amine by introduction of a protective group according to the above method are produced.

The compounds of the general formulas (Ia), (IV) and (VI) are new and can be listed after the ones listed above Methods are made by peptide linkage.

The compounds of the general formulas (VII) and (VIIa) are known (see G. C. Burrett, Chemistry and Hell Chemistry of the Amino Acids, Chapman and Hell, New York, London 1988).

Stereoisomer mixtures, in particular Diastereomerenge mix, in a conventional manner, for. B. by fractionated crystallization or chromatography in the individual isomers are separated.

Racemates can in a conventional manner, for. B. by Transfer of the optical antipodes into diastereomers ge be split.

The new agents can in a known manner in the conventional formulations, such as tablets, Dragees, pills, granules, aerosols, syrups, emulsions Suspensions and solutions, using inert,  non, toxic, pharmaceutically suitable excipients or solvent. Here is the therapeutic effective compound, each in a concentration of about 0.5 to 90 wt .-% of the total mixture be, d. H. in amounts sufficient to the indicated to achieve dosing game.

The formulations are prepared, for example by stretching the active ingredients with solvents and / or carriers, optionally using of emulsifiers and / or dispersants, wherein z. B. in the case of using water as a dilution optionally organic solvents as Auxiliary solvents can be used.

Examples of adjuvants are:
Water, non-toxic organic solvents such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut / sesame oil), alcohols (e.g., ethyl alcohols, glycerin), carriers such as. Ground natural minerals (eg kaolin, clays, talc, chalk), ground synthetic minerals (eg highly disperse silicic acid, silicates), sugars (eg cane, milk and dextrose), emulsifying agents (eg eg polyoxyethylene fatty acid esters), polyoxyethylene fatty alcohol ethers (eg lignin, liquor liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium sulphate).

The application is carried out in the usual way, preferably oral or parenteral, especially perlingual or in intravenously. In case of oral administration, tablets of course except the mentioned carriers also additives, such as sodium citrate, calcium carbonate and Dicalcium phosphate together with various supplement such as starch, preferably potato starch, Ge contain latine and the like. Furthermore you can Lubricants, such as magnesium stearate, sodium lauryl sulfate and talcum for tableting. in the Case of aqueous suspensions, the active ingredients except the abovementioned excipients with different Ge flavor enhancers or colorants.

In the case of parenteral use, solutions the active ingredients using suitable liquid Carrier materials are used.

In general, it has proved to be advantageous in intravenous administration amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg Körperge to achieve effective results and oral dosage about 0.01 to 30 mg / kg, preferably 0.1 to 10 mg / kg Body weight.

Nevertheless, it may possibly be necessary from to deviate from the stated quantities, depending on from the body weight of the test animal or the species the application, but also due to the species and  their individual behavior towards the drug or their type of formulation and time or interval at which the administration takes place. So it may be sufficient in some cases with to manage less than the aforementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In case of application Larger quantities may be recommended in these to distribute several single doses throughout the day. For the Application in human medicine is the same Do provided for sierungsspielraum. Analogously, this applies also the above statements.  

Explanations to the Experimental Part DC systems Stationary phase

Merck DC Finished Plates Kieselgel 60 F-254, 5 × 10 cm, Layer thickness 0.25 mm, item no. 5719th

Mobile phases (in the test as "DC system")

HPLC Systems

HPLC system I: column Merck LiChrosorb® RP-8, 250-4, 10 μm, cat.-No. 50318
HPLC-System II: column Merck LiChrosorb® RP-18, 250-4, 10 μm, Cat.-No. 50334
Eluens at System I and II
A: pH 7.00 phosphate buffer, Merck, Art. 9439 / H₂O 1:50
B: acetonitrile
A / B as 1/1, flow: 2 ml / min, isocratic,
Detection: 254 nm

List of used abbreviations

1. general analytical methods DC TLC PDC preparative thick-layer chromatography GC Gas chromatography HPLC Hochdruckflüsigkeitschromatographie SC column NMR Nuclear magnetic resonance spectroscopy (protons) MS Mass spectrometry (electron impact ionization) (+) FAB-MS Fast atomic bombardment mass spectrometry, positive ions, matrix substance: m-nitrobenzyl alcohol MS DCI Mass spectrometry, chemical ionization

2. Amino acids

In general, the name of the configuration is made by d 08717 00070 552 001000280000000200012000285910860600040 0002004038947 00004 08598as Provision of an L or D before the amino Acid abbreviation, in the case of the racemate by a D, L- for convenience in L-amino acids the configura  can be omitted and then only in the case the D-form or the D, L mixture Explicit designation tion takes place.

a) natural amino acids Ala L-alanine bad L-arginine Asn L-asparagine Asp L-aspartic acid Cys L-cysteine Gln L-glow amine Glu L-amino acid glow Gly L-glycine His L-histidine Ile L-isoleucine Leu L-leucine Lys L-lysine mead L-methionine Orn L-ornithine Phe L-phenylalanine Ser L-serine Sar L-sarcosine (N-methylglycine) Thr L-threonine Trp L-tryptophan Tyr L-tyrosine Val L-valine

b) unnatural amino acids D- or L-Nal (1) β- (1-naphthyl) -D- or -L-alanine D- or L-Nal (2) β- (2-naphthyl) -D- or -L-alanine D- or L-Phe (2NO₂) b- (2-nitrophenyl) -D- or -L-alanine D or L-Phe (3NO₂) β- (3-nitrophenyl) -D- or -L-alanine D or L-Phe (4NO₂) β- (4-nitrophenyl) -D- or -L-alanine D- or L-Phe (2NH₂) β- (2-aminophenyl) -D- or -L-alanine D or L-Phe (3NH₂) β- (3-aminophenyl) -D- or -L-alanine D- or L-Phe (4NH₂) β- (4-aminophenyl) -D- or -L-alanine D- or L-Phe (3,4-Cl₂) β- (3,4-dichlorophenyl) -D- or -L-alanine D- or L-phg D- or L-phenylglycine D- or L-pyr (2) β- (2-pyridyl) -D- or -L-alanine D- or L-pyr (3) β- (3-pyridyl) -D- or -L-alanine D- or L-pyr (4) β- (4-pyridyl) -D- or -L-alanine D or L Trz (1) β- (1-triazolyl) -D- or -L-alanine D or L-Phe (4I) β- (4-iodophenyl) -D- or -L-alanine D- or L-Phe (4OCH₃) β- (4-methoxyphenyl) -D- or -L-alanine

3. Activation Groups HOBT 1-hydroxybenzotriazole HOSU N-hydroxysuccinimide

4. coupling reagents DCC dicyclohexylcarbodiimide DPPA diphenylphosphorylazide PPA n-propanephosphonic BOP Benzotriazolyloxy-tris (dimethylamino) phosphonium

5. Reagents NEM N-ethylmorpholine NMM N-methylmorpholine TEA triethylamine TFA trifluoroacetic

6. Solvents HOAc acetic acid DMF dimethylformamide EtOAc ethyl acetate MeOH methanol EtOH ethanol THF tetrahydrofuran DMSO dimethyl sulfoxide HMPT hexamethylphosphoramide

7. Protecting Groups Boc Tertbutoxycarbonyl Z benzyloxycarbonyl DNP dinitrophenyl Fmoc 9-fluorenylmethoxycarbonyl OEt ethyl ester OMe Methylester

8. Other DCU N, N'-dicyclohexylurea

Example I N-tert-butoxycarbonyl-2-R, S-amino-2- [2- (1,3-dithiolano)] acetic acid

19.9 g (0.11 mol) of 2-amino-2-R, S-2- [2- (1,3-dithiolano)] acetic acid [M. P. Mertes, A.A. Ramsey, J. Med. Chem. 12, 342 (1969)] are dissolved in 100 ml of dioxane and with 6.6 g (0.16 mol) of sodium hydroxide and 29 g (0.13 mol) of di-tert-butyl carbonate added. It is left overnight at room temperature stir and draw the dioxane on a rotary evaporator from. The mixture is made up with 200 ml of water and extracted several times with ether. The basic aqueous phase is adjusted to pH 3 with hydrochloric acid and extracted several times with methylene chloride. The United organic phases are washed with saturated saline washed, dried over sodium sulfate and concentrated.

Yield: 18.1 g (60.6% of theory)
MS-DCI: m / z 280 (M + H); m / z 297 (m + NH₄)
DC system IV: R _f = 0.55

Example II 4S-amino-5-phenyl-3 (R, S)-hydroxyl-1-pentene hydrochloride

1.5 g (5.4 mmol) of 4S-tert-butoxycarbonylamino-5-phenyl 3 (R, S) -hydroxyl-1-pentene (prepared according to the procedure by D.J. Kempf et. al., EP 03 42 541, there example 112; however, using Boc-L-phenylalanine methyl ester instead of Boc-Cyclohexylalaninmethylester) are with 10 ml of 4N hydrochloric acid (gas) in dioxane and 3 h im Ice bath stirred. After abreaction of the dioxane / Hcl evaporated, repeatedly coevaporated with diethyl ether and the residue was dried in a desiccator over potassium hydroxide.

Yield: 1.2 g (100% of theory)
DC System III: R _f = 0.56 and 0.51
MS-DCI: m / z 178 (M + H)

example 1 N-tert-butoxycarbonyl-2-R-amino-2- [2-1,3-dithiolano)] - acetyl-4S-amino-3S-hydroxy-5- (4-nitrophenyl) pentanoyl-L- isoleucine methyl ester

261 mg (933 .mu.mol) of the compound of Example I and 300 mg (718 μmol) of 4S-amino-3S-hydroxy-5- (4-nitrophenyl) - pentanoyl-L-isoleucine methyl ester hydrochloride [W. Bender et. al .; EP 2 36 874 A] are dissolved in 10 ml of methylene chloride dissolved and treated with 875 .mu.l (5 mmol) of diisopropylethylamine. The solution is stirred and cooled to -20 ° C (Dry ice / acetone). It drips at this temperature 606 μl (933 μmol) of a 50% solution of propanephosphoric anhydride in methylene chloride (Hoechst AG) Add and leave the approach overnight on Raumtempertur come. The methylene chloride is on a rotary evaporator subtracted and the residue taken up in ethyl acetate. The organic phase is 3 times with saturated Sodium bicarbonate solution, pH 4 buffer solution (Merck, Article no. 9435) and saturated saline, dried over sodium sulfate, concentrated and dried in a high vacuum.  

The crude product (380 mg) is chromatographed on silica gel 60 (Merck, Item No. 9385) 0.040 to 0.063 mm (230 to 400 mesh) with a step gradient of methyl chloride / methanol (100/0, 99/1, 98/2, 97/3, 95/5, 9/1). The Detection takes place at 214 nm, the fraction control thin-layer and high-pressure liquid chromatography.

The product-containing fractions are combined and concentrated.

Yield: 160 mg (26.6% of theory)
DC system I: R _f = 0.64 (Example 1, R isomer) (S isomer: R _f = 0.69)
HPCL system II: R _f = 7.26 min

Example 2 2-R-amino-2- [2- (1,3-dithiolano)] acetyl-4S-amino-3S- hydroxy-5- (4-nitrophenyl) pentanoyl-L-isoleucine methyl ester hydrochloride

160 mg (249 μmol) of the compound from Example 1 are added in 5 ml of 4N hydrochloric acid (gas) in dioxane and Stirred for 30 minutes.

After Abreaktion (TLC control) narrows on a rotary evaporator on. After repeated coevaporation with diethyl ether if the crude product is stirred with diethyl ether, sucked off and in a desiccator over potassium hydroxide dried.

Yield: 130 mg (90% of theory)
DC system III: R _f = 0.51

Example 3 N-tert-butoxycarbonyl-L- (4-methoxy) phenylalanyl {2-R- amino-2- [2- (1,3-dithiolano)]} acetyl-4S-amino-3S-hydroxy- 5- (4-nitrophenyl) pentanoyl-L-isoleucine

The title compound is determined by chromatographic Separation (analogous to Example 1) of the analog Example 1 from the compound of Example 2 and N-tert-butoxycarbonyl L- (4-methoxy) phenylalanine (Bissendorf Biochemicals) obtained synthesized crude product.

DC system I: R _f = 0.62
HPLC system II: R _f = 11.30 min
(+) FAB-MS: m / z 820 (M + H)

The examples listed in the table are prepared analogously to the instructions of Examples 1 to 3.

Claims (8)

1. Peptides of the general formula (I) in which
A, B, D and E are the same or different and
- stand for a bond or
- represent a natural or unnatural amino acid,
R¹ - is hydrogen or
represents a typical amino protecting group,
- represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms, which in turn may be substituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
- for a remainder of the formula stands in which
a, a ', b, d and e are the same or different and denote the number 0, 1 or 2,
h is the number 0, 1 or 2,
g is the number 1, 2, 3, 4, 5 or 6,
i is the number 0, 1, 2, 3 or 4,
c and f are the same or different and denote a number 0, 1, 2 or 3,
R⁴ and R ^{4 'are the} same or different and are phenyl, naphthyl, pyridyl or pyridyl N-oxide,
R⁵, R¹¹ and R¹⁸ are the same or different and are aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
R⁶ denotes straight-chain or branched alkyl having up to 8 carbon atoms,
R⁷ is halogen or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms
m is the -NH group, an oxygen atom, a sulfur atom or the SO₂ group,
R⁸ and R⁹ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
R¹⁰ represents the radical of the formula (CH₃) ₃C-CO-CH₂- or (CH₃) ₃-C-CHOH-CH₂-,
R¹² via N-linked morpholine or piperidinyl,
R¹³ is aryl having 6 to 10 carbon atoms which is optionally substituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or
- is a radical of the formula R¹⁹-S (O) ₁- or R²⁰-CO-, in which
R¹⁹ represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms,
1 is a number 0, 1 or 2,
R²⁰ morpholino, pyrrolidinyl or the rest or a group of the formula -NR²¹R²², in which
R²¹ and R²² are the same or different and are hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally polysubstituted by hydroxy, phenoxy, a 5- or 6-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S, alkoxy having up to 6 carbon atoms, (C₁-C₆) dialkylamino, quaternary ammonium salts or by a radical of the formula is substituted, or
R²¹ or R²² is cycloalkyl having 3 to 8 carbon atoms or R²¹ and R²² together with the nitrogen atom form a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S,
R¹⁴ and R¹⁵ are the same or different and denote hydrogen or an amino protecting group,
R¹⁶ represents straight-chain or branched alkoxy having up to 8 carbon atoms or the group -NR ^{21 '} R ^22' , in which
R ^{21 '} and R ^{22' have} the abovementioned meaning of R ²¹ and R ²² and are identical or different therefrom,
R¹⁷ is hydrogen or the group -NR²³R²⁴ in which
R²³ and R²⁴ are the same or different and denote hydrogen, an amino-protecting group or acyl having up to 6 carbon atoms,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R²⁵-SO₂, R²²R²¹N-SO₂ or R²²R²¹N-CO, in which
R²⁵ represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms or a radical of the formula with r = 0, 1 or 2, and wherein
R²¹ and R²² have the abovementioned meaning,
R² represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or
in the case that A and B simultaneously signify a bond,
R¹ and R² together with the nitrogen atom form the following rings: or or or or or or n - for the number 1 or 2, stands,
R³ - represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or
- represents cycloalkyl or phenyl which is optionally substituted by nitro,
X - together with the group represents a mimic of the Leu-Val cleavage site in angiotensinogen common in renin inhibitor chemistry,
Y - depending on the meaning of the substituent X is either absent or
- is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, benzyl or cycloalkyl having 3 to 8 carbon atoms,
- represents an amino protecting group or
- is a radical of the formula -COR²⁶, -NHR²⁷, -NR²⁸R²⁹, S (O) _k (NH) _r R³⁰ or -OR³¹, in which
R²⁶ represents hydrogen, straight-chain or branched alkyl, alkoxy or alkoxy- (C₁-C₆) -alkenyl each having up to 20 carbon atoms, which are optionally substituted by pyridyl or aryl having 6 to 10 carbon atoms, which in turn is represented by straight-chain or branched alkyl or Alkoxy can be substituted with up to 10 carbon atoms or
R²⁶ is the group -NR³²R³³ in which
R³² and R³³ are the same or different and are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, S or O, or
R³² or R³³ is cycloalkyl having 3 to 8 carbon atoms or
R³² and R³³ together with the nitrogen form a 5- to 7-membered heterocycle having up to 3 heteroatoms from the series N, S or O or
R²⁶ adamantyl or aryl having 6 to 10 carbon atoms, the latter being optionally substituted by alkyl or alkoxy each having up to 10 carbon atoms,
R²⁷, R²⁸ and R²⁹ are the same or different and are hydrogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 8 carbon atoms, which may be polysubstituted by hydroxy, protected hydroxy, alkoxy or alkoxycarbonyl each having up to 8 Carbon atoms, carboxy, sulfo, phenyl, by a 5- to 7-membered, optionally substituted heterocycle having up to 3 heteroatoms from the series N, O or S or by C₁-C₈-dialkylamino, C₁-C₆ dihydroxydialkylamino or by a radical of the formula are substituted or
R²⁸ and R²⁹ together with the nitrogen atom form a saturated or unsaturated 5- to 7-membered heterocycle having up to 3 heteroatoms from the series O, S or N, which is optionally substituted by benzyl,
k is the number 0, 1 or 2,
r is the number 0 or 1,
R³⁰ is hydrogen, straight-chain or branched alkyl having up to 10 carbon atoms, benzyl or aryl having 6 to 10 carbon atoms, which is optionally substituted by methyl, or in the case where r is the number 0,
R³⁰ is an N-bonded 5- to 7-membered saturated heterocycle having up to 3 heteroatoms from the series N, O or S,
R³¹ represents hydrogen or straight-chain or branched alkyl having up to 20 carbon atoms, which is optionally substituted by phenyl, which in turn may be substituted by alkoxycarbonyl having up to 8 carbon atoms, halogen or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, or one
Remainder of the formula means, in which
R³² and R³³ are the same or different and are hydrogen, phenyl or straight or branched chain alkyl of up to 8 carbon atoms, optionally substituted by phenyl, and their physiologically acceptable salts provided that in the event X is the radical R³ may not be cyclohexyl. 2. Compounds of general formula (I) according to claim 1, in which
A, B, D and E are the same or different and
- stand for a bond or
for proline (Pro), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), glycine (Gly), valine (Val), histidine (His), alanine (Ala), lysine (Lys), tryptophan (Trp ), Tyrosine (Tyr), pF-phenylalanine, P-Cl-phenylalanine, p-nitrophenylalanine, 1- or 2-naphthalalanine (1-Nal, 2-Nal), 4-methoxyphenylalanine or homophenylalanine
R¹ - is hydrogen or
for tert-butoxycarbonyl (Boc), ethoxycarbonyl (EtOC), methoxycarbonyl (Metoc), benzyloxycarbonyl (Z), allyloxycarbonyl (Alloc), isopropoxycarbonyl, isopentoxycarbonyl (= 3,3-dimethylpropoxycarbonyl), N-fluorenyloxy-carbonyl (F-Moc) Phenoxyacetyl, acetyl, formyl, pivaloyl, isovaleroyl, phenylacetyl, phenylpropionyl, cinnamoyl, 3,3-dimethylpropionyl, toluenesulfonyl, phenylsulfonyl or tert-butylsulfonyl,
represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or naphthyl, which in turn may be substituted by fluorine, chlorine, methyl or methoxy,
- for a remainder of the formula stands in which
a and a 'are the same or different and denote the number 0, 1 or 2,
g is the number 1, 2, 3, 4 or 5,
h is the number 0, 1 or 2,
i is the number 0, 1 or 2,
R⁴ and R ^{4 'are the} same or different and are phenyl, naphthyl, pyridyl or pyridyl N-oxide,
R¹¹ and R¹⁸ are the same or different and are phenyl, 1-naphthyl or 2-naphthyl, which are optionally substituted by fluorine, chlorine or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms
R⁷ is fluorine, chlorine or straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
m is the -NH group, an oxygen atom, such as sulfur atom or the SO₂ group,
R⁸ and R⁹ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R¹² via N-linked morpholine or piperidinyl,
R¹³ is phenyl, 1-naphthyl or 2-naphthyl, which is optionally substituted by fluorine, chlorine or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, or
- is a radical of the formula R¹⁹-S (O) ₁- or R²⁰-CO-, in which
R¹⁹ represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, 1-naphthyl or 2-naphthyl,
l is a number 0, 1 or 2,
R²⁰ morpholino, pyrrolidinyl or a radical of the formula means
R¹⁴ and R¹⁵ are identical or different and denote hydrogen or one of the amino-protecting groups listed above,
R¹⁶ represents straight-chain or branched alkoxy having up to 6 carbon atoms or denotes a group -NR²¹'R²² ', in which
R²¹ 'and R²²' are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, or
R²¹ 'and R²² together with the nitrogen atom form a morpholine ring
R¹⁷ is the -NH₂- or -NH-CO-CH₃ group,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R²⁵-SO₂, R²²R²¹N-SO₂ or R²²R²¹N-CO, in which
R²⁵ denotes straight-chain or branched alkyl having up to 6 carbon atoms or benzyl,
R²¹ and R²² are the same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, optionally substituted by hydroxy, pyridyl, morpholino, piperidinyl, alkoxy having up to 4 carbon atoms, (C₁-C₄) dialkylamino, quaternary ammonium salts or by a remainder of the formula is substituted or cyclopropyl, or
R²¹ and R²² together with the nitrogen atom form a morpholino, thiomorpholino, thiomorpholinosulfone or thiomorpholine sulfoxide ring,
R² is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or
in the case that A and B simultaneously signify a bond
R¹ and R² together form one of the rings listed in claim 1,
n - stands for the number 1 or 2,
R³ - represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or
is cyclohexyl or phenyl which is optionally substituted by nitro,
X - together with the group represents a mimic of the Leu-Val cleavage site in angiotensitrogen common in renin inhibitor chemistry,
Y - depending on the meaning of the substituent X is either absent or
- represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or cyclopropyl or
- represents one of the above-listed amino protecting groups or
- is a radical of the formula -COR²⁶, -NHR²⁷, -NR²⁸R²⁹, S (O) _k (NH) _r R³⁰ or -OR³¹, in which
R²⁶ represents hydrogen, straight-chain or branched alkyl, alkoxy or alkoxy- (C₁-C₆) -alkenyl having in each case up to 16 carbon atoms, which are optionally substituted by pyridyl or phenyl, which in turn is represented by straight-chain or branched alkyl or alkoxy having up to 8 carbon atoms may be substituted or
R²⁶ is the group -NR³²R³³ in which
R³² and R³³ are the same or different and are hydrogen, straight chain or branched alkyl of up to 6 carbon atoms optionally substituted by morpholino, pyridyl, thiomorpholine, thiomorpholinesulfone or thiomorpholinesulfoxide, or R³² or R³³ is cyclopropyl or phenyl; or R³² and R³³ are in common with the nitrogen atom form a morpholine ring, or
R²⁶ is adamantyl or phenyl, the latter being optionally substituted by alkyl or alkoxy each having up to 8 carbon atoms,
R²⁷, R²⁸ and R²⁹ are the same or different and are hydrogen, cyclopropyl or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms, which may be polysubstituted by hydroxy, protected hydroxy, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, carboxy, sulfo , Phenyl, pyridyl, pyridyl-N-oxide, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino, thiomorpholinesulfone or -sulfoxide or C₁-C₆-dialkylamino, C₁-C₈-Dihydroxydialkylamino or by a radical of the formula substituted or
R²⁸ and R²⁹ together with the nitrogen atom form a morpholine or piperidinyl ring, which are optionally substituted by benzyl,
k is the number 0, 1 or 2,
r is the number 0 or 1,
R³⁰ is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, tolyl, benzyl or phenyl, or in the case where r is the number 0, R³⁰ represents an N-bonded morpholine or pyrrolidinyl ring,
R³¹ represents hydrogen or straight or branched alkyl of up to 16 carbon atoms, optionally substituted by phenyl, which in turn is substituted by alkoxycarbonyl of up to 6 carbon atoms, fluorine, chlorine or straight chain or branched alkyl or alkoxy of up to 6 carbon atoms each or a radical of the formula -CO-NR³²R³³, in which
R³² and R³³ are the same or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms or benzyl
and their physiologically acceptable salts
with the proviso that in case X is the radical R³ may not be cyclohexyl. 3. Compounds of general formula (I) according to claim 1, in which
A, B, D and E are the same or different and
- stand for a bond or
- for proline (Pro), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), valine (Val), histidine (His), alanine (Ala), lysine (Lys), tyrosine (Tyr), p-fluorophenylalanine , 1-naphthylalanine (1-Nal), (4-methoxy) -phenylalanine or homophenylalanine,
R¹ - is hydrogen or
for tert-butoxycarbonyl (BOC), ethoxycarbonyl (EtOC), methoxycarbonyl (Metoc), benzyloxycarbonyl (Z), isopropoxycarbonyl, isopentoxycarbonyl, allyloxycarbonyl (Alloc), phenoxyacetyl, acetyl, pivaloyl, isovaleroyl, phenylpropionyl, tosyl, tert -butylsulfonyl or 3,3-dimethylpropionyl,
- represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or naphthyl, which in turn may be substituted by fluorine, chlorine, methyl or methoxy
- for a remainder of the formula stands in which
a, a 'are the number 0, 1 or 2,
g is the number 1, 2, 3, 4 or 5,
h is the number 0, 1 or 2,
i is the number 0, 1 or 2,
R⁴ and R⁴ 'are the same or different and are pyridyl, phenyl, naphthyl or pyridyl N-oxide,
R¹¹ and R¹⁸ are identical or different and are phenyl, 1-naphthyl or 2-naphthyl, which are optionally substituted by fluorine, chlorine, methyl or methoxy,
R⁷ is fluorine or chlorine,
m is the NH group or an oxygen atom,
R⁸ and R⁹ are the same or different and denote hydrogen or methyl,
R¹² via N-linked morpholino or piperidinyl,
R¹³ is phenyl, 1-naphthyl or 2-naphthyl, which are optionally substituted by fluorine, chlorine, methyl or methoxy or a radical of the formula R¹⁹-S (O) ₁ or R²⁰-CO, wherein
R¹⁹ represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or 1-naphthyl
1 is a number 0, 1 or 2,
R²⁰ morpholino, pyrrolidinyl or a radical of the formula means
R¹⁴ and R¹⁵ are the same or different and denote hydrogen or one of the amino-protecting groups listed above,
R¹⁶ represents straight-chain or branched alkoxy having up to 4 carbon atoms or an N-bonded morpholine ring,
R¹⁷ represents the NH₂- or the -NH-CO-CH₃ group,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R²⁵-SO₂, R²²R²¹N-SO₂, R²²R²¹N-CO, wherein
R²⁵ denotes straight-chain or branched alkyl having up to 4 carbon atoms or benzyl,
R²¹ and R²² are the same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, optionally substituted by hydroxy, pyridyl, morpholino, piperidinyl, alkoxy having up to 4 carbon atoms, (C₁-C₄) dialkylamino, quaternary ammonium salts or by a remainder of the formula is substituted or cyclopropyl, or
R 21 and R 22 together with the nitrogen atom form a morpholino, thiomorpholino, thiomorpholinesulfone or thiomorpholine sulfoxide ring,
R² represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or
in the case that A and B simultaneously signify a bond
R¹ and R² together form one of the rings listed in claim 1,
n - stands for the number 1 or 2,
R³ - represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or
is cyclohexyl or phenyl which is optionally substituted by nitro,
X - for the rest of the formula wherein
G is methyl, isopropyl, butyl, isobutyl, benzyl, means
M is a group of the formula means
M 'is ethyl, vinyl, iso -propyl, 1,3-dithian-2-yl, 2-alkylthioethyl or 2-dialkylaminoethyl,
Q is methyl, isopropyl, benzyl or - (CH₂) ₂-C₆H₅,
R is hydrogen, methyl, isopropyl, isobutyl or benzyl,
T is methyl, isopropyl or isobutyl,
U is methyl, isopropyl, isobutyl or benzyl,
V the rest of the formula means
T 'and T''are identical or different and denote hydrogen, methyl, isopropyl, isobutyl or benzyl,
Y - depending on the meaning of the substituent X is either absent or
is hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, benzyl or cyclopropyl, or
- represents one of the above-listed amino protecting groups or
- is a radical of the formula -CO-R²⁶, -NHR²⁷, -NR²⁸R²⁹, S (O) _k (NH) _r R³⁰ or -OR³¹, in which
R²⁶ is hydrogen, straight-chain or branched alkyl, alkoxy or alkoxy- (C₁-C₄) -alkenyl, each having up to 10 carbon atoms, which are optionally substituted by pyridyl or phenyl, or
R²⁶ is the group -NR³²R³³ in which
R³² and R³³ are the same or different and are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by morpholino, pyridyl, thiomorpholino, thiomorpholinsulfone or thiomorpholinesulfoxide, or
R³² or R³³ cyclopropyl or phenyl or
R³² and R³³ together with the nitrogen atom form a morpholine ring or
R²⁶ is adamantyl or phenyl,
R²⁷, R²⁸ and R²⁹ are identical or different and denote hydrogen, cyclopropyl or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms which are optionally substituted by hydroxyl, phenyl, morpholino, piperidinyl, pyrrolidinyl, thiomorpholino, thiomorpholinesulfone or sulfoxide, pyridine N-oxide, carboxy, sulfo, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, amino or by a radical of the formula substituted or
R²⁸ and R²⁹ together with the nitrogen atom form a morpholine or piperidinyl ring, which are optionally substituted by benzyl,
k is the number 0, 1 or 2,
r is the number 0 or 1,
R³⁰ is hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl, tolyl or phenyl, or
in the case where r is the number 0,
R³⁰ represents an N-linked morpholine or pyrrolidinyl ring,
R³¹ is hydrogen or straight or branched chain alkyl having up to 6 carbon atoms or benzyl or is a radical of the formula -CONR³²R³³ in which
R³² and R³³ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or benzyl,
and their physiologically acceptable salts
with the proviso that in case X is the radical R³ may not be cyclohexyl. 4. Process for the preparation and compounds of the general formula (I) in which
A, B, D and E are the same or different and
- stand for a bond or
- stand for a natural or unnatural amino acid
R¹ - is hydrogen or
- represents a typical amino protecting group
- represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms, which in turn may be substituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
- for a remainder of the formula stands in which
a, a ', b, d and e are the same or different and denote the number 0, 1 or 2,
h is the number 0, 1 or 2,
g is the number 1, 2, 3, 4, 5 or 6,
i is the number 0, 1, 2, 3 or 4,
c and f are the same or different and denote a number 0, 1, 2 or 3,
R⁴ and R⁴ 'are identical or different and denote phenyl, naphthyl, pyridyl or pyridyl N-oxide,
R⁵, R¹¹ and R¹⁸ are the same or different and are aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
R⁶ denotes straight-chain or branched alkyl having up to 8 carbon atoms,
R⁷ is halogen or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms
m is the -NH group, an oxygen atom, a sulfur atom or the SO₂ group,
R⁸ and R⁹ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
R¹⁰ represents the radical of the formula (CH₃) ₃C-CO-CH₂- or (CH₃) ₃-C-CHOH-CH₂-,
R¹² via N-linked morpholine or piperidinyl,
R¹³ is aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or
- is a radical of the formula R¹⁹-S (O) ₁- or R²⁰-CO-, in which
R¹⁹ represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms,
l is a number 0, 1 or 2
R²⁰ morpholino, pyrrolidinyl or the rest or a group of the formula -NR²¹R²², in which
R²¹ and R²² are the same or different and are hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally polysubstituted by hydroxy, phenoxy, a 5- or 6-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S, alkoxy having up to 6 carbon atoms, (C₁-C₆) dialkylamino, quaternary ammonium salts or by a radical of the formula is substituted, or
R²¹ or R²² mean cycloalkyl having 3 to 8 carbon atoms or
R²¹ and R²² together with the nitrogen atom form a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S.
R¹⁴ and R¹⁵ are the same or different and denote hydrogen or an amino protecting group,
R¹⁶ represents straight-chain or branched alkoxy having up to 8 carbon atoms or the group -NR²¹'R²² ', in which
R²¹ 'and R²²' have the abovementioned meaning of R²¹ and R²² and are identical or different therefrom,
R¹⁷ is hydrogen or the group -NR²³R²⁴ in which
R²³ and R²⁴ are the same or different and denote hydrogen, an amino-protecting group or acyl having up to 6 carbon atoms,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R²⁵-SO₂, R²²R²¹N-SO₂ or R²²R²¹N-CO, in which
R²⁵ represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms or a radical of the formula with r = 0, 1 or 2, and wherein
R²¹ and R²² have the abovementioned meaning,
R² represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or
in the case that A and B simultaneously signify a bond
R¹ and R² together with the nitrogen atom form the following rings: or or or or or or n - stands for the number 1 or 2,
R³ - represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or
- represents cycloalkyl or phenyl which is optionally substituted by nitro,
X - together with the group represents a mimic of the Leu-Val cleavage site in angiotensinogen common in renin inhibitor chemistry,
Y - depending on the meaning of the substituent X is either absent or
- is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, benzyl or cycloalkyl having 3 to 8 carbon atoms,
- represents an amino protecting group or
- is a radical of the formula -COR²⁶, -NHR²⁷, - NR²⁸R²⁹, S (O) _k (NH) _r R³⁰ or -OR³¹, in which
R²⁶ represents hydrogen, straight-chain or branched alkyl, alkoxy or alkoxy- (C₁-C₆) -alkenyl each having up to 20 carbon atoms, which are optionally substituted by pyridyl or aryl having 6 to 10 carbon atoms, which in turn is represented by straight-chain or branched alkyl or Alkoxy can be substituted with up to 10 carbon atoms, or
R²⁶ is the group -NR³²R³³ in which
R³² and R³³ are the same or different and are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, S or O, or
R³² or R³³ is cycloalkyl having 3 to 8 carbon atoms or
R³² and R³³ together with the nitrogen form a 5- to 7-membered heterocycle having up to 3 heteroatoms from the series N, S or O or
R²⁶ is adamantyl or aryl having 6 to 10 carbon atoms, the latter being optionally substituted by alkyl or alkoxy each having up to 10 carbon atoms,
R²⁷, R²⁸ and R²⁹ are the same or different and are hydrogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 8 carbon atoms, which may be polysubstituted by hydroxy, protected hydroxy, alkoxy or alkoxycarbonyl each having up to 8 Carbon atoms, carboxy, sulfo, phenyl, by a 5- to 7-membered, optionally substituted heterocycle having up to 3 heteroatoms from the series N, O or S or by C₁-C₈-dialkylamino, C₁-C₆ dihydroxydialkylamino or by a radical of the formula substituted or
R²⁸ and R²⁹ together with the nitrogen atom form a saturated or unsaturated 5- to 7-membered heterocycle having up to 3 heteroatoms from the series O, S or N, which is optionally substituted by benzyl,
k is the number 0, 1 or 2,
r is the number 0 or 1,
R³⁰ is hydrogen, straight-chain or branched alkyl having up to 10 carbon atoms, benzyl or aryl having 6 to 10 carbon atoms, which is optionally substituted by methyl, or in the case where r is the number 0,
R³⁰ is an N-bonded 5- to 7-membered saturated heterocycle having up to 3 heteroatoms from the series N, O or S,
R³¹ represents hydrogen or straight or branched alkyl of up to 20 carbon atoms, optionally substituted by phenyl, which in turn may be substituted by alkoxycarbonyl having up to 8 carbon atoms, halogen or by straight or branched alkyl or alkoxy each having up to 8 carbon atoms; a remainder of the formula means, in which
R³² and R³³ are the same or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl,
and their physiologically acceptable salts with the proviso that in the event that X is the radical R³ may not be cyclohexyl, characterized in that

• (A) Compounds of the general formula (II) in which
  R³, X, D, E and Y are as defined above, and
  Z represents one of the amino-protecting groups listed above
  first by cleavage the group Z converted by conventional methods in amines and these subsequently with compounds of the general formula (III) in which
  n and R² are as defined above, and
  Z 'has the abovementioned meaning of Z and is identical or different with this
  with activation of the carboxylic acid by conventional methods in inert read agents to give compounds of the general formula (IV) in which
  R², n, R³, X, D, E, Y and Z 'have the abovementioned meaning
  converts the protective group Z 'according to the usual method and in a further step with compounds of general formula (V) R¹ - A - B - OH (V) in which
  R¹, A and B have the abovementioned meaning,
  optionally condensed under the above-mentioned carboxylic acid activation, or
• (B) Compounds of general formula (Ia) in which
  R¹, A, B, R², n, R³, X, D and E have the abovementioned meaning and
  Y 'in this case together with X, D and / or E forms a C₁-C₆ alkoxycarbonyl
  hydrolyzed by the usual method to the corresponding acids and introduced and derivatized in a further step, optionally in the presence of excipients, by conventional methods, for example by substitution or addition, the radical Y, or
• (C) Compounds of general formula (VI) in which
  Z ', R², n, R³, X, D and E have the abovementioned meaning and
  R²⁶ 'has the abovementioned meaning of R²⁶ but has not been hydrogen
  saponified to the corresponding acids and then with amines of general formula (VII) or (VIIa) H₂NR³⁴ (VII) orHNR³⁵R³⁶ (VIIa) in which
  R³⁴, R³⁵, R³⁶ are the same or different and encompass the scope of meaning of the respective amino groups listed above
  optionally condensed in the presence of auxiliaries.

5. Compounds of general formula (I) according to claim 1 for use in combating Diseases. 6. Medicaments containing at least one compound of the general formula (I) according to claim 1. 7. Process for the preparation of medicaments, characterized in that at least one Compound of general formula (I) according to Claim 1 optionally using customary excipients and carriers in a suitable Transferred application form. 8. Use of compounds of the general formula (I) according to claim 1 in the manufacture of circulatory agents.