DE4038921A1 - RENININHIBITIC PEPTIDES OF THE CYCLOHEXYLSTATIN TYPE, PROCESS FOR THEIR PREPARATION AND THEIR USE IN MEDICINAL PRODUCTS - Google Patents

Abstract

Renin-inhibiting peptides of the cyclohexylstatin type having general formula (I), in which A, B, D, E, Y, R<1>, R<2> and n have the meanings given in the description, are disclosed, as well as a process for producing the same and their use in medicaments, in particular medicaments that influence blood circulation.

Description

The present invention relates to renin inhibitory Cyclohexylstatin-type peptides, process for theirs Production and its use in medicines, 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 turn, in the lungs, kidneys or other tissues to the blood pressure-effective octapeptide angiotensin II dismantled. The different effects of angiotensin II as vasoconstriction, Na⁺ retention in the kidney, Aldosterone release in the adrenal gland and increase in tone of the sympathetic nervous system act synergistically 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 angiotensin  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, synthetic Peptides as substrate analogues and modified Peptides.

In EP-A 2 02 73 696, EP-A 2 02 78 158 and in the PCT WO 86/04901 describes renin inhibitory peptides, in which the scope of R² (see inventive Compounds) also heterocyclic radicals but without reference to the specific 1,3- Dithiolane or 1,3-dithiane group or a concrete one To give representatives of this class of substance.

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
- see for a tie or
represent a natural or unnatural amino acid which is optionally substituted by an amino-protecting group,
R¹ is hydrogen or
represents a typical amino protecting group,
represents straight-chain or branched alkyl or acyl having in each case up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms,
- for a remainder of the formula

stands,
wherein
a, a ', b, d, e, h and i are the same or different and are a number 0, 1, 2, 3, 4, 5, 6, 7 or 8, g is a number 1, 2, 3, 4 or 5 means that c and f are the same or different and denote a number 0, 1 or 2,
R³ and R³ 'are the same or different and
- aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, nitro, hydroxy or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms,
straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 10 carbon atoms, which are optionally substituted by aryl having 6 to 10 carbon atoms,
a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 carbon atoms from the series N, S or O and their N-oxides,
R⁴ and R¹⁰ are the same or different and
Hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, nitro or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms,
R⁵ denotes straight-chain or branched alkyl having up to 8 carbon atoms,
R⁶ is halogen or straight-chain or branched alkyl or alkoxy having in each case up to 8 carbon atoms,
m is the <NH group, an oxygen atom, a sulfur atom or the SO₂ group,
R⁷ and R⁸ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,
R⁹ is aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen or by straight-chain or branched alkyl or alkoxy having in each case up to 8 carbon atoms,
a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S and its N-oxides,
Hydroxy or straight-chain or branched alkyl or alkoxy having in each case up to 10 carbon atoms, which is optionally substituted up to twice by hydroxy or by acyl having up to 8 carbon atoms or by pyrrolidinyl which is optionally substituted on the nitrogen by an amino-protecting group,
a radical of the formula R¹⁶-S (O) ₁ or R¹⁷-CO,
wherein
l is a number 0, 1 or 2,
R¹⁶ 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 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S and the oxides thereof, which is optionally substituted by benzyl,
R¹⁷ represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms,
a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S, which is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms or benzyl,
or
a group of the formula -NR¹⁸R¹⁹ means
wherein
R¹⁸ and R¹⁹ are the same or different and are hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, optionally substituted by hydroxy, phenyl, a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, S or O, alkoxy having up to 6 carbon atoms, (C₁-C₆) dialkylamino, quaternary ammonium salts or by a radical of the formula

is substituted,
or
R¹⁸ or R¹⁹ cycloalkyl having 3 to 8 carbon atoms
or
R¹⁸ or R¹⁹ the rest of the formula

or
R¹⁸ and R¹⁹ 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,
R¹¹ and R¹² are the same or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or an amino-protecting group,
R¹³ straight or branched alkoxy having up to 8 carbon atoms or hydroxy or
- a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, S or O means or
- 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 nitro, or
a group of the formula -NR¹⁸'R¹⁹ ',
wherein
R¹⁸ 'and R¹⁹' have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R¹⁴ is hydrogen or the group -NR²⁰R²¹,
wherein
R²⁰ and R²¹ are identical or different and denote hydrogen, an amino-protecting group or acyl having up to 8 carbon atoms,
R¹⁵ is aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, nitro or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
or
is straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl or by quaternary ammonium salts,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R¹⁶'-SO₂-, R²²R²³-N-SO₂- or R²⁴-R²⁵-N-CO-,
wherein
R¹⁶ 'has the abovementioned meaning of R¹⁶ and is identical or different with this
and
R²², R²⁵, R²⁴ and R²⁵ have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R² is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or benzyl
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

(n = 1 or 2)

or  

or

or

or

where the definitions given there apply,
n is the number 1 or 2,
Y is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or
- represents an amino protecting group or
- represents a radical of the formula -NHR²⁶, NR²⁷R²⁸, S (O) _k (NH) _r -R²⁹ or -OR³⁰,
R²⁶, R²⁷ and R²⁸ 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 10 carbon atoms, which may be polysubstituted by hydroxy, protected hydroxy, alkoxy or alkoxycarbonyl each having up to 6 Carbon atoms, carboxy, sulfo, phenyl, or by a 5- to 7-membered, saturated or unsaturated 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 the formula

are substituted
or
R²⁷ and R²⁸ 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,
R²⁹ 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 a bonded via N 5- to 7-membered saturated heterocycle having up to 3 heteroatoms from the series N, O or S.
or
R³⁰ is 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
a remainder of the formula

means
wherein
R³¹ and R³² are the same or different and denote 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.

The compounds of the general Formula (I) has several 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 independent of each other in the optically pure, preferably in the L-form in front.

The compounds of the general formula according to the invention (I) may be in the form of their salts. This can Salts of the compounds of the invention with inorganic  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 acid as Acetic acid, propionic acid, oxalic acid, glycolic acid, succinic acid, Maleic acid, hydroxymaleic acid, methylmaleic acid, Fumaric acid, adipic acid, malic acid, tartaric acid, Citric acid, benzoic acid, cinnamic acid, lactic acid, Ascorbic acid, salicylic acid, 2-acetoxybenzoic acid, nicotinic acid, Isonicotinic acid, or sulfonic acids, such as methanesulfonic acid, Ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, Naphthalene-2-sulfonic acid or naphthalenedisulfonic acid.

Salts of the compounds according to the invention with salt-forming Groups can be prepared in a conventional manner be, for example, by implementation of the invention Compounds containing acidic groups with appropriate bases or by reaction of the invention Compounds containing basic groups with appropriate acids, preferably with the abovementioned bases or acids.

Suitable amino protecting groups are those in peptide chemistry common amino protecting groups.

These include: Benzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, Dichlorobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,  4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5- Trimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, Isobutoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, Isopentoxycarbonyl, hexoxycarbonyl, cyclohexoxycarbonyl, Octoxycarbonyl, 2-ethylhexoxycarbonyl, 2-iodohexoxycarbonyl, 2-bromoethoxycarbonyl, 2-chloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl, Benzhydryloxycarbonyl, bis- (4-methoxyphenyl) methoxycarbonyl, phenacyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2- (di-n-butyl-methyl) silyl) ethoxycarbonyl, 2-triphenylsilylethoxycarbonyl, 2- (Dimethyl-tert-butylsilyl) ethoxycarbonyl, menthyloxycarbonyl, Vinyloxycarbonyl, allyloxycarbonyl, phenoxycarbonyl, Tolyloxycarbonyl, 2,4-dinitrophenoxycarbonyl, 4- Nitrophenoxycarbonyl, 2,4,5-trichlorophenoxycarbonyl, Naphthyloxycarbonyl, fluorenyl-9-methoxycarbonyl, Ethylthiocarbonyl, methylthiocarbonyl, butylthiocarbonyl, Tert-butylthiocarbonyl, phenylthiocarbonyl, Benzylthiocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, Methylthiocarbonyl, butylthiocarbonyl, tertiary Butylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, Methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, 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-nitrobenzyl, 4-nitrobenzoyl-naphthylcarbonyl, phenoxyacetyl, Adamantylcarbonyl, dicyclohexylphosphoryl, diphenylphosphoryl, Dibenzylphosphoryl, di (4-nitrobenzyl) phosphoryl,  Phenoxyphenylphosphoryl, diethylphosphinyl, diphenylphosphinyl, Phthaloyl, phthalimido, 3,3-dimethylpropanoyl, 3,3-dimethylpropoxycarbonyl, phenylacetyl, Phenylpropionyl, cinnamoyl, toluenesulfonyl, phenylsulfonyl or tert-butyl sulfonyl.

Particularly preferred amino-protecting groups are benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, Methoxycarbonyl, ethoxycarbonyl, Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, Isobutoxycarbonyl, tert-butoxycarbonyl, cyclohexoxycarbonyl, Hexoxycarbonyl, octoxycarbonyl, 2- Bromethoxycarbonyl, 2-chloroethoxycarbonyl, phenoxyacetyl, Naphthylcarbonyl, adamatylcarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butyl butoxycarbonyl, menthyloxycarbonyl, vinyloxycarbonyl, Allyloxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, Fluorenyl-9-methoxycarbonyl, formyl, acetyl, propionyl, Pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2,2,2- Trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido or Isovaleroyl, 3,3-dimethylpropanoyl, 3,3-dimethylpropoxycarbonyl, Phenylacetyl, phenylpropionyl, cinnamoyl, Toluylsulfonyl, phenylsulfonyl or tert-butylsulfonyl (see Th. W. Greene, Protective Groups in Organic Synthesi, John Wiley & Sons, New York, 1981).

For example, the term natural amino acids 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 valine (Val).

The term unnatural amino acids becomes p-F-, p-Cl, p-nitro and p-J-substituted phenylalanine, 4-C₁-C₆-alkoxyphenylalanine, in particular 4-methoxyphenylalanine, Homophenylalanine, (3-thionaphthenyl) glycine, O-benzyl-serine and 1- or 2-naphthylalanine detected.

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,
for Prolein (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-naphthylalanine (1-Nal, 2-Nal), 4-methoxyphenylalanine, (3-thionaphthenyl) glycine, homophenylalanine or O-benzyl-serine,
R¹ is hydrogen or tert-butoxycarbonyl (Boc), ethoxycarbonyl (Etoc), methoxycarbonyl (Metoc), benzyloxycarbonyl (Z), allyloxycarbonyl (Alloc), isopropoxycarbonyl, isopentoxycarbonyl (= 3,3-dimethylpropoxycarbonyl), N-fluorenyloxy-carbonyl ( F-Moc), phenoxyacetyl, acetyl, formyl, pivalolyl, isovaleroyl, phenylacetyl, phenylpropionyl, cinnamoyl, 3,3-dimethylpropionyl, toluenesulfonyl, phenylsulfonyl or tert-butyl-sulfonyl,
represents straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, which is optionally substituted by phenyl or naphthyl,
- for a remainder of the formula

stands,
wherein
a, a ', b, d, e, h and i are the same or different and are a number 0, 1, 2, 3, 4, 5, 6 or 7, g is a number 1, 2, 3, 4 or 5 c and f are the same or different and denote a number 0, 1 or 2,
R³ and R³ 'are the same or different and
Phenyl or naphthyl, which are optionally substituted by fluorine, chlorine, bromine, nitro, hydroxy or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 8 carbon atoms, which are optionally substituted by phenyl or naphthyl,
Morpholino, morpholino-N-oxide, pyridyl, pyridyl-N-oxide, pyrrolidinyl or piperidinyl,
R⁴ and R¹⁰ are identical or different and are hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or naphthyl, the latter being optionally substituted by fluorine, chlorine, bromine, nitro or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms are substituted
R⁵ denotes straight-chain or branched alkyl having up to 6 carbon atoms,
R⁶ is fluorine, chlorine 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,
R⁷ and R⁸ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
R⁹ is phenyl or naphthyl, which is optionally substituted by fluorine, chlorine, bromine or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
Morpholino, morpholino-N-oxide, piperidinyl, pyrrolidinyl, pyridyl or pyridyl-N-oxide,
Hydroxy or straight-chain or branched alkyl or alkoxy having in each case up to 8 carbon atoms, which is optionally substituted up to twice by hydroxy or by acyl having up to 6 carbon atoms or by pyrrolidinyl- (N-BOC),
a radical of the formula R¹⁶-S (O) ₁ or R¹⁷-CO,
wherein
l is a number 0, 1 or 2,
R¹⁶ represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or naphthyl, or
Morpholino, morpholino-N-oxide, pyridyl, pyridyl-N-oxide, pyrrolidinyl or piperidinyl, which are optionally substituted by benzyl,
R¹⁷ represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or naphthyl,
- Morpholino, morpholino-N-oxide, pyridyl, pyridyl-N-oxide, pyrrolidinyl or piperidinyl, which are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms or benzyl, or
a group of the formula NR¹⁸R¹⁹, in which
R¹⁸ and R¹⁹ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, optionally substituted by hydroxy, phenyl, pyridyl, morpholino, piperidinyl, alkoxy having up to 4 carbon atoms, (C₁-C₄) dialkylamino,
- or a remainder of the formula

is substituted,
or
R¹⁸ or R¹⁹ cyclopropyl mean
or
R¹⁸ and R¹⁹ together with the nitrogen atom form a morpholino or piperidinyl ring,
R¹¹ and R¹² are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or one of the amino-protecting groups listed above,
R¹³ represents straight-chain or branched alkoxy having up to 6 carbon atoms or hydroxyl,
Morpholino, pyridyl, piperidinyl or pyrrolidinyl,
- 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 or nitro, or
a group of the formula -NR¹⁸'R¹⁹ ',
wherein
R¹⁸ 'and R¹⁹' have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R¹⁴ is hydrogen or the group -NR²⁰R²¹,
wherein
R²⁰ and R²¹ are identical or different and denote hydrogen, one of the abovementioned amino-protecting groups or acyl having up to 6 carbon atoms,
R¹⁵ is phenyl or naphthyl, which is optionally substituted by fluorine, chlorine, nitro or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, or
represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl or by a radical of the formula (CH₃) ₃N⊕Cl⊖,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R¹⁶'-SO₂, R²²R²³N-SO₂ or R²⁴R²⁵N-CO,
wherein
R¹⁶ 'has the abovementioned meaning of R¹⁶ and is identical or different thereto and
R²², R²³, R²⁴ and R²⁵ have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R² is hydrogen, straight or branched alkyl having up to 6 carbon atoms or benzyl
or
in the case that A and B simultaneously signify a bond,
R¹ and R² together with the nitrogen atom form one of the abovementioned rings known from the literature,
n is the number 1 or 2,
Y is hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cyclopropyl,
- represents one of the above-listed amino protecting groups or
- represents a radical of the formula -NHR²⁶, -NR²⁷R²⁸ or -OR³⁰,
wherein
R²⁶, R²⁷ and R²⁸ are the same or different and denote hydrogen, cyclopropyl or straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, which are optionally substituted by hydroxyl, pyridyl or morpholino,
R³⁰ is hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,
and their physiologically acceptable salts.

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-fluorophenylalanine , p-Cl-phenylalanine, p-nitrophenylalanine, 2-naphthylalanine (2-Nal), 4-methoxyphenylalanine, (3-thionaphthenyl) glycine, homophenylalanine or O-benzyl-serine,
R¹ is hydrogen or
for tert-butoxycarbonyl (Boc), ethoxycarbonyl (Etoc), methoxycarbonyl (Metoc), benzyloxycarbonyl (Z), isopropoxycarbonyl, allyloxycarbonyl (Alloc), phenoxyacetyl, acetyl, pivaloyl, isovaleroyl, phenylpropionyl, tosyl, tert-butylsulfonyl or 3, 3-dimethylpropionyl,
represents straight-chain or branched alkyl or acyl each having up to 4 carbon atoms, which is optionally substituted by phenyl or naphthyl,
- for a remainder of the formula

stands,
wherein
a, a ', b, d, e, h and i are the same or different and are a number 0, 1, 2, 3, 4, 5 or 6, g is a number 1, 2, 3 or 4, c and f are the same or different and denote a number 0, 1 or 2,
R³ and R³ 'are the same or different and
Phenyl or naphthyl, which are optionally substituted by fluorine, chlorine, methyl, nitro or methoxy,
straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, which are optionally substituted by phenyl or naphthyl,
- morpholino, pyridyl or piperidinyl,
R⁴ and R¹⁰ are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or naphthyl, the latter optionally being substituted by fluorine, chlorine, nitro, methyl or methoxy,
R⁵ represents straight-chain or branched alkyl having up to 4 carbon atoms,
R⁶ is fluorine, chlorine or straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms,
m is the <NH group or an oxygen atom,
R⁷ and R⁸ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R⁹ is phenyl or naphthyl, which is optionally substituted by fluorine, chlorine, methyl or methoxy,
Morpholino, pyridyl or piperidinyl,
- hydroxy or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, which may be up to 2 times by hydroxy or by a radical of formula

a radical of the formula R¹⁶-SO₂- or R¹⁷-CO,
wherein
R¹⁶ represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or naphthyl,
Is morpholino, piperidinyl or pyridyl, which is optionally substituted by benzyl,
R¹⁷ represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or naphthyl,
Morpholino, pyridyl or piperidinyl, which is optionally substituted by methyl or benzyl,
a group of the formula -NR¹⁸R¹⁹,
wherein
R¹⁸ and R¹⁹ are the same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, optionally substituted by phenyl, hydroxy, pyridyl, morpholino, piperidinyl, methoxy, ethoxy, dimethylamino or a radical of the formula

is substituted,
or
R¹⁸ and R¹⁹ together with the nitrogen atom form a morpholino or piperidinyl ring,
R¹³ represents straight-chain or branched alkoxy having up to 4 carbon atoms or hydroxy,
Morpholino, pyridyl or piperidinyl,
- 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 or nitro,
a group of the formula -NR¹⁸'R¹⁹ ',
wherein
R¹⁸ 'and R¹⁹' have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R¹⁴ is hydrogen or the group -NR²⁰R²¹,
wherein
R²⁰ and R²¹ are identical or different and denote hydrogen, one of the abovementioned amino-protecting groups or acyl having up to 4 carbon atoms,
R¹⁵ is phenyl or naphthyl, which is optionally substituted by fluorine, chlorine, nitro, methyl or methoxy,
is straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl or by a radical of the formula (CH₃) ₃N⊕Cl⊖,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R¹⁶'-SO₂-, R²²R²³N-SO₂- or R²⁴R²⁵N-CO,
wherein
R¹⁶ 'has the abovementioned meaning of R¹⁶ and is identical or different thereto and
R²², R²³ and R²⁵ have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R 2 is hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or benzyl,
n is the number 1 or 2,
Y is hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms,
- represents one of the above-listed amino protecting groups or
- represents a radical of the formula -NHR²⁶, -NR²⁷R²⁸ or -OR³⁰,
wherein
R²⁶, R²⁷ and R²⁸ are the same or different and are hydrogen, cyclopropyl or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, which are optionally substituted by hydroxyl, pyridyl or morpholino,
R³⁰ is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
and their physiologically acceptable salts.

The group of the formula

has three asymmetric carbon atoms, which are independent each other in the R or S configuration can. Preferably, this group is in the 5R, 3S, 4S configuration, 5R, 3R, 4S configuration, 5S, 3S, 4S configuration or 5S, 3R, 4S configuration, especially preferred in the 5R, 3S, 4S or 5S, 3S, 4S Configuration before. Likewise, the grouping is a mixture of isomers used.

Stereoisomer mixtures, in particular mixtures of diastereomers, can 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 Conversion of the optical antipodes into diastereomers, be split.

The compounds of the general Formula (I)

in which
R¹, A, B, R², n, D, E and Y have the abovementioned meaning,
one obtains by one

• [A] Compounds of the general formula (II) in which
  D, E, R² and Y have the meaning given above
  and
  Z is an amino protecting group,
  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 have the meaning given above
  and
  Z 'has the abovementioned meaning of Z and is identical or different with it,
  with activation of the carboxylic acid by conventional methods in inert solvents to give compounds of the general formula (Ia) in which
  Z ', R², n, D, E and X have the abovementioned meaning,
  converts the protective group Z 'according to the usual method and in a further step with compounds of general formula (IV) R¹-AB · OH (IV) in which
  R¹, A and B have the abovementioned meaning,
  optionally condensed under the above-mentioned carboxylic acid activation,
  and, if appropriate, saponifying the corresponding esters by the customary method or first reacting the compounds of the general formula (III) and (IV) by the method indicated above and then adding a further peptide bond with the compounds of the general formula (II),
  or by
• [B] Compounds of the general formula (Ib) in which
  A, B, R¹, R², n, D and E have the abovementioned meaning and
  Y 'is alkoxy having up to 8 carbon atoms or benzyloxy,
  hydrolyzed by the usual method first to the corresponding acids and in a further step in the presence of excipients with amines of the general formula (V) or (VI) H₂NR '(V) orHNR'R''(VI) in which
  R, R 'and R "are identical or different and correspond to the scope of meaning of the respective amino groups listed under Y,
  condenses, or by
• [C] either compounds of the general formula (Ic) in which
  A, B, R¹, R² and n are as defined above
  and
  R³³ is alkyl having up to 6 carbon atoms or benzyl,
  or compounds of the general formula (Id) in which
  Z ', n, R² and R³³ have the abovementioned meaning,
  first saponified to the corresponding acids by the usual method and then with the fragment of the general formula (VII) DEY (VII) in which
  D, E and Y are as defined above,
  in inert solvents, if appropriate in the presence of auxiliaries,
  and in the case of the compounds of the general formula (Id) in a next step according to the method described under process [A] with gradual cleavage of the respective protective group Z 'with compounds of the general formula (IV) or (IVa) R¹-A-OH ( IVa) or R¹-AB-OH (IV) in which
  R¹, A and B have the abovementioned meaning,
  implements,
  and the substituent Y optionally derivatized by customary methods, for example by substitution.

The synthesis scheme can be exemplified by the following reaction scheme:

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. Bodanszky, A. Bodanszky in "The Practical Cl of Peptide Synthesis", 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-Heidelberg 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 hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons, such as methylene chloride, Chloroform, carbon tetrachloride or  Acetone, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric 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, dimethylformamide and ethyl acetate.

Usually, the process variants [A], [B] and [C] in the presence of suitable solvents or diluents, optionally 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.

Carboxylic acid azides (obtainable, for example, by reaction of protected or unprotected carboxylic acid hydrazides with nitrous acid, their salts or alkyl nitrites (for example isoamyl nitrite) are suitable as activated carboxyl groups in process variants [A], [B] and [C],
or unsaturated esters, in particular vinyl esters (obtainable, for example, by reacting a corresponding ester with vinyl acetate), carbamoylvinyl esters (obtainable, for example, by reacting a corresponding acid with an isoxazolium reagent), alkoxyvinyl esters (obtainable, for example, by reacting the corresponding acids with alkoxyacetylenes, preferably ethoxyacetylene),
or amidinoester, e.g. N, N'- or N, N-disubstituted amidinoesters (obtainable, for example, by reaction of the corresponding acid with an N, N'-disubstituted carbodiimide (preferably dicyclohexylcarbodiimide, diisopropylcarbodiimide or N- (3-dimethylaminopropyl) -N '-Ethylcarbodiimide hydrochloride) or with an N, N-disubstituted cyanamide,
or aryl esters, in particular by electron-withdrawing substituents substituted phenyl esters, for. 4-nitrophenyl, 4-methylsulfonylphenyl, 2,4,5-trichlorophenyl, 2,3,4,5,6-pentachlorophenyl, 4-phenyldiazophenyl ester (obtainable, for example, by reaction of the corresponding acid with a optionally substituted phenol, optionally in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, isobutylchloroformate, propanephosphonic anhydride), benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate,
or cyanomethyl esters (obtainable, for example, by reaction of 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, isobutylchloroformate , 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-hydroxy-phthalimide, 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)
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 acid with thionyl chloride, phosphorus pentoxide or oxalyl chloride),
or anhydrides with carbonic acid derivatives, e.g. B. Kohlensiederiederalkylhalbester (obtainable eg by reaction of the appropriate acid with Halogenameisensäureniedrigalkylestern, eg., Methyl chloroformate, ethyl ester, propylester, -isopropylester, butyl ester or -isobutylester or with 1-Niedrigalkoxycarbonyl-2-lower alkoxy-1,2 dihydroquinoline, 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 phosphorus acetic 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 reacting 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 metal salt of a corresponding acid with a sulfonic acid halide, especially methane, ethane, benzene or toluenesulfonic acid chloride),
or symmetrical anhydrides (obtainable, for example, by condensation of appropriate acids, if appropriate 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'-dicyclohexylcarbodiimide, N, N'-diisopropylcarbodiimide, N- (3-dimethylaminopropyl) - N'-ethylcarbodiimide hydrochloride, isobutyl chloroformate, Propanephosphonic anhydride, benzotriazolyloxy tris (dimethylamino) phosphonium hexafluorophosphate 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.  

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 hydrochloride, or carbonyl compounds such as carbonyldiimidazole, 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 compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate, and as bases Alkaline carbonates z. For example, sodium or potassium carbonate or bicarbonate, or organic bases such as trialkylamines z. Triethylamine, N-ethylmorpholine, N-methylpiperidine or diisopropylethylamine used.

The cleavage of the amino protecting group takes place in itself known manner under acidic or basic conditions, or reductively by catalytic hydrogenation, for 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 is carried out according to customary Methods in one of the solvents listed above, by treating the esters with common bases, wherein the initially formed salts by treatment converted into the free carboxylic acids with acid can be.  

Suitable bases for saponification are the usual ones inorganic bases. These include preferably alkali metal 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 in a temperature range from 0 ° C to + 100 ° C, preferably from + 20 ° C to + 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 used. Particular preference is given to using molar amounts the reactants.

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

The compounds of the general formulas (II), (IV), (IVa) and (VII) are known or can after customary methods of peptide chemistry are built up, by implementing a corresponding fragment, consisting of one or more amino acid groups, with a free, if necessary in activated form present carboxyl group with a complementing fragment, consisting of one or several amino acid groups, with an amino group, optionally in activated form, produces, and if necessary, this process as often as necessary Repeat fragments until you get the desired peptides of the general formulas (II), (IV), (IVa) and (VII) then, optionally, protecting groups splits off or exchanges with other protecting 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 (V) and (VI) takes place generally 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 compounds of the general formula (III)

in which
n and Z 'are as defined above,
are mostly new and can then be made by
Compounds of the general formula (VIII)

in which
n has the meaning given above,
with an introducing reagent, such as (Z'-O-CO) ₂O, Z'-O-CO-Cl or (Z'-O-CO) -ON-succinimide, the amino protecting group Z 'according to the method described above [A ] in inert solvents in the presence of a base, preferably in a mixture dioxane / water with sodium hydroxide or in dioxane with triethylamine in a temperature range of 0 ° to + 50 ° C, preferably at room temperature and atmospheric pressure, and in the case where R² = H, alkylated by the usual method.

The compounds of the general formula (Ia) and (Ib) are new and are named after the under procedures [A] and [B] described method.

The compounds of general formula (Id) are also new and can be prepared
by
Compounds of the general formula (III)

in which
Z ', R² and n have the abovementioned meaning,
with compounds of the general formula (IX)

in which
Z, R² and R³³ have the abovementioned meaning,
with elimination of the protective group Z, converts.

The compounds of general formula (IX) are known [see. Boger et al., J. Med. Chem. 28, 1779-1790 (1985)].

The compounds of general formula (VIII) are known or can be prepared by known methods become [M. P. Mertes, A.A. Ramsey, J. Med. Chem. 12, 342 (1969)].

The compounds of general formula (Ic) are also new and will be through implementation of the compounds of the formula (III), (IV) and (IX) according to the method [A] described customary peptide coupling method.

The amines of general formula (V) and (VI) are known [see. G.C. Barrett, Chemistry and Hell Chemistry of the Amino Acids, Chapman and Hell, New York, London, 1988 and EP-A2 02 78 158].

The compounds of the invention have a circulation-influencing Effect and therefore can be used in medicines for the treatment of blood pressure and heart failure be used.

In vitro test

The inhibitory potency of the peptides according to the invention against endogenous renin from human plasma is determined in vitro. Pooled human plasma is obtained with the addition of ethylenediaminetetraacetic acid (EDTA) as anticoagulant and stored at -20 ° C. Plasma renin activity (PRA) is determined as the rate of formation of angiotensin I from endogenous angiotensinogen and renin after incubation at 37 ° C. The reaction solution contains 150 μl of plasma, 3 μl of 6.6% 8-hydroxyquinoline sulfate solution, 3 μl of 10% dimercaprolizing solution and 144 μl of sodium phosphate buffer (0.2 M, 0.1% EDTA, pH 5.6) with or without the present invention Substances in different concentrations. The angiotensin I formed per unit time is determined by radioimmunoassay (Sorin Biomedica, Italy). The percent inhibition of plasma renin activity is calculated by comparing the substances claimed herein. The concentration range in which the substances claimed here show a 50% inhibition of the plasma renin activity is between 10 ^-7 to 10 ^-10 M.

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 from about 0.5 to 90% by weight of the total mixture be, d. H. in amounts that are sufficient to that to achieve the indicated 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. In the case of using water as a diluent 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 alcohol, glycerol), carriers, e.g. Ground natural minerals (eg, kaolins, clays, talc, chalk), ground synthetic minerals (eg, fumed silica, silicates), sugars (eg, cane, milk, and grape sugar), emulsifying agents (e.g. Polyoxyethylene fatty alcohol ethers), polyoxyethylene fatty alcohol ethers (e.g., lignin, spent liquors, methyl cellulose, starch, and polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium sulfate).

The application is carried out in the usual way, preferably orally or parenterally, especially perlingually or 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 additives, such as starch, preferably potato starch, gelatin 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 flavor enhancers or dyes are added.

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 of body weight to achieve effective results, and for oral administration, the dosage is about 0.01 to 30 mg / kg, preferably 0.1 to 10 mg / 33063 00070 552 001000280000000200012000285913295200040 0002004038921 00004 32944kg 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 dosage margin intended. Analogously, this applies also the above statements.  

Explanations to the experimental part DC systems Stationary phase

Merk 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: Merck column Lichrosorb® RP-8, 250-4, 10 μm, cat.-No. 50 318.
HPLC-System II: column Merck Lichrosorb® RP-18, 250-4, 10 μm, Cat.-No. 50 334.

List of used abbreviations

1. general analytical methods DC TLC GC Gas chromatography HPLC High Pressure Liquid Chromatography 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 prefixing an L or D before the amino acid abbreviation, in the case of the racemate by a D, L, where for convenience in L-amino acids the configuration name can be omitted and then only in the case the D-form or the D, L-mixture explicate designation he follows.

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) D- or L- (1-naphthyl) alanine D- or L-Nal (2) D- or L- (2-naphthyl) alanine D- or L-Phe (2NO₂) D- or L- (2-nitrophenyl) alanine D or L-Phe (3NO₂) D- or L- (3-nitrophenyl) alanine D or L-Phe (4NO₂) D- or L- (4-nitrophenyl) alanine D- or L-Phe (2NH₂) D- or L- (2-aminophenyl) alanine D or L-Phe (3NH₂) D- or L- (3-aminophenyl) alanine D- or L-Phe (4NH₂) D- or L- (4-aminophenyl) alanine D- or L-Phe (3,4-Cl₂) D- or L- (3,4-dichlorophenyl) alanine D or L-Phe (4i) 4iODO D- or L-phg D- or L-phenylglycine D- or L-pyr (2) D- or L- (2-pyridyl) alanine D- or L-pyr (3) D- or L- (3-pyridyl) alanine D- or L-pyr (4) D- or L- (4-pyridyl) alanine D or L Trz (1) D- or L- (1-triazolyl) alanine D- or L-Phe (OCH₃) D- or L- (4-methoxyphenyl) alanine Phe (OMe)

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. Solvent 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

starting compounds example I N-tert-butoxycarbonyl-L-isoleucine (2-picolyl) amide

To a solution of 100 g (0.432 mol) of N-tert-butoxycarbonyl L-isoleucine and 46.72 g (0.432 mol) of 2-picolylamine in 1 l of methylene chloride is added at 0 ° C 419.13 ml (3.024 mol) of triethylamine. It is allowed to stir for 10 minutes, Cool to -20 ° C (dry ice / acetone) and drip this temperature 365 ml (0.561 mol) of a 50% Solution of propanephosphonic anhydride in methylene chloride (Hoechst AG). The batch is added for 1 hour Stirred at -20 ° C and overnight at room temperature brought. The reaction mixture is successively 3 times with 300 ml of 5% sodium bicarbonate solution, 3 times with 300 ml buffer solution pH 4 each (Merck, Item No. 9435) and finally 2 times with 300 ml of saturated saline solution shaken. The organic phase becomes dried over sodium sulfate and concentrated in vacuo. The crude product is stirred by stirring with diethyl ether crystallized, filtered off with suction and then from diisopropyl ether / recrystallized n-hexane.

Yield: 85.9 g (61.8% of theory).
DC system II: R _f = 0.35.
DC system III: R _f = 0.49.
DC system IV: R _f = 0.57.

example II L-isoleucine (2-picolyl) amide dihydrochloride

40 g (0.124 mol) of the compound of Example I are with 250 ml of 4 N hydrochloric acid (gas) in dioxane and added stirred with ice cooling. The suspension is through Add 10 ml of methanol to solution. To Abreaktion (TLC control) is concentrated 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: 37.2 g (100% of theory),
DC system III: R _f = 0.30.

example III N-tert-butoxycarbonyl-4S-amino-3S-hydroxy-5-cyclohexyl- pentanoyl-L-isoleucine (2-picolyl) amide

13.2 g (41.8 mmol) of N-tert-butoxycarbonyl-4S-amino-3S- hydroxy-5-cyclohexyl-pentasic acid [J. Boger et al., J. Med. Chem. 28, 1779 (1985)] and 13.5 g (46 mmol) of the Compound from Example II are mixed with 420 ml of methylene chloride added. The suspension is made by adding 31 ml (230 mmol) of triethylamine brought into solution and on Cooled to -20 ° C (acetone / dry ice). Dripping while stirring at this temperature 39 ml of a 50% solution of Add propanephosphonic anhydride in methylene chloride and Let the batch come to room temperature overnight. The methylene chloride is stripped off on a rotary evaporator and the residue taken up in 400 ml of ethyl acetate. The organic phase is washed successively 1 time with 200 ml saturated sodium bicarbonate solution, 2 times with each 200 ml buffer solution pH 7 (Merck, Item No. 9439) and Washed 4 times with 200 ml of demineralized water. The Buffer solutions are back-extracted with 100 ml of ethyl acetate. The combined organic phases become Washed twice with 500 ml of saturated saline solution each time, dried over sodium sulfate and on a rotary evaporator concentrated to a volume of about 125 ml. The solution is mixed with 125 ml of n-hexane and transferred Night in the refrigerator (5 ° C). That crystallized Product is sucked off, with little cold Essigester / n-hexane 1: 1 washed and in vacuo dried.

Yield: 17.2 g (79% of theory).
MS DCI; m / z 519 (M + H).
DC system III: R _f = 0.48.
DC system IV: R _f = 0.63.
DC system V: R _f = 0.48.
HPLC system II: R _t = 6.02 min.

example IV 4S-amino-3S-hydroxy-5-cyclohexyl-pentanoyl-L-isoleucine (2-picolyl) amide dihydrochloride

16 g (30.8 mmol) of the compound from Example III under ice-cooling with 160 ml of 4N hydrochloric acid (gas) in dioxane added. The suspension is made by adding 5 ml of methanol brought into solution. After abreaction (DC control) Concentrate on a rotary evaporator. After several times Coevaporation with diethyl ether becomes the crude product Stirred with diethyl ether, filtered with suction and in a desiccator dried over potassium hydroxide.

Yield: 16.56 g (95% of theory).
MS-DCI: m / z 419 (M + H).
DC system III: R _f = 0.35.

example V 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 treated 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.

Preparation Examples General Formula (I) example 1 N-tert-butoxycarbonyl-2-R, S-amino-2- [2- (1,3-dithiolano)] - acetyl-4S-amino-3S-hydroxy-5-cyclohexyl-pentanoyl- L-isoleucine (2-picolyl) amide

4.4 g (15.7 mmol) of the compound from Example V and 7.3 g (15 mmol) of the compound from Example IV with 20 ml of methylene chloride and 18.3 ml (105 mmol) of diisopropylethylamine added. The solution is stirred and on Cooled to -20 ° C (dry ice / acetone). You drip at this Temperature 11.7 ml of a 50% solution of propane phosphoric anhydride in methylene chloride (Hoechst AG) and leaves the batch overnight at room temperature 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.

Yield: 9 g (79.8% of theory).
(+) FAB-MS: m / z 680 (M + H); m / z 686 (M + Li).
DC system III: R _f = 0.59.
DC system IV: R _f = 0.67.
HPLC system II: R _t = 6.16 min.

Example 2 2-R, S-amino-2- [2- (1,3-dithiolanol)] - acetyl-4S-amino-3S- hydroxy-5-cyclohexyl-pentanoyl-L-isoleucine (2-picolyl) - amide dihydrochloride

9 g (13.24 mmol) of the compound from Example 1 become with ice cooling with 150 ml of 4N hydrochloric acid in dioxane and stirred for 4 hours. The dioxane / hydrochloric acid mixture is distilled off on a rotary evaporator. The obtained after repeated coevaporation with diethyl ether Product is filtered off, washed with diethyl ether and dried in a desiccator over potassium hydroxide.

Yield: 8.6 g (100% of theory).
(+) FAB-MS: m / z 580 (M + H); m / z 602 (M + Na).
DC system III: R _f = 0.38 (isomer A), R _f = 0.33 (isomer B).
DC system IV: R _f = 0.21.

Example 3 N-tert-butoxycarbonyl-2-R, S-amino-2- [2- (1,3-dithiolano)] - acetyl-4S-amino-3S-hydroxy-5-cyclohexylpentansäuremethylester

The title compound is analogous to Example 1 by Propanphosphonsäureanhydridkopplung from 2.2 g (7.8 mmol) of Compound from Example V and 2.4 g (6.5 mmol) of 4-S- Amino-3S-hydroxy-5-cyclohexylpentansäuremethylester Hydrochloride [obtainable by esterification of the 4S amino 3S-hydroxy-5-cyclohexylpentanoic acid (J. Boger et al., J. Med. Chem. 28, 1779 (1985) and R.F. Schuda et al., J. Org. Chem. 1988, 53, 873-875) with diazomethane and Precipitation as hydrochloride] and subsequent silica gel chromatography receive.

Example 4 2-R, S-amino-2- [2- (1,3-dithiolano)] - acetyl-4S-amino-3S- hydroxy-5-cyclohexylpentansäuremethylester hydrochloride

The title compound is analogous to Example 2 by cleavage of the Boc protecting group from 3.5 g (7.1 mmol) of the compound obtained from Example 3.

Yield: 3.0 g (100% of theory).
DC system III:: R _f = 0.40 (isomer A), R _f = 0.34 (isomer B).
DC system IV: R _f = 0.21.
(+) FAB-MS: m / z 391 (M + H); m / z 397 (M + Li).

Example 5 2-R-amino-2- [2- (1,3-dithiolano)] - acetyl-4S-amino-3S- hydroxy-5-cyclohexylpentanoic acid-methylester

The title compound is purified by chromatographic separation the isomer mixture from Example 4 on silica gel 60 (Merck, Item No. 9385) 0.040-0.063 mm (230- 400 mesh) with a step gradient of methylene chloride / Methanol 25% aqueous ammonia solution (100/0 / 0.2, 99/1 / 0.2, 98/2 / 0.2, 97/3 / 0.2, 95/5 / 0.2; 9/1 / 0.2) separately.

The detection takes place at 214 nm, the fraction control thin-layer and high-pressure liquid chromatography.

First, the R isomer elutes (Example 5), then the S- Isomers.

Analytical data:
DC system III: R _f = 0.40.
(+) FAB-MS: m / z = 391 (M + H); m / z 397 (M + Li).

Example 6 Methyl-N-tert-butoxycarbonyl-2-R-amino-2- [2- (1,3- dithiolano)] - acetyl-4S-amino-3S-hydroxy-5- cyclohexylpentanoate

The title compound is analogous to Example V by reaction the compound from Example 5 with di-tert. butyl carbonate with triethylamine as auxiliary base and dioxane as a solvent. The reaction mixture is diluted with water and 1N hydrochloric acid and with methyl chloride extracted. The organic phase is separated off, dried over sodium sulfate and concentrated. The Crude product is purified by flash chromatography (silica gel). Dichloromethane).

Analytical data:
DC system IV: R _f = 0.88.
HPLC system II: R _f = 7.06 min.
(+) FAB-MS: m / z 497 (M + Li).

Example 7 N-tert-butoxycarbonyl-2-R-amino-2- [2- (1,3-dithiolano)] - acetyl-4S-amino-3S-hydroxy-5-cyclohexyl-pentanoic acid

The title compound is obtained by basic saponification analogously to Example 16 from 2.1 g (4.28 mmol) of the compound obtained from Example 6 and standard work-up.

Yield: 195 g (95.6% of theory).
DC system IV: R _f = 0.57.
(+) FAB-MS: m / z 477 (M + H), m / z 421, m / z 377.

Example 8 2-R-amino-2- [2- (1,3-dithiolano)] - acetyl-4S-amino-3S- hydroxy-5-cyclohexyl-pentanoyl-L-isoleucine (2- picolyl) amide

The title compound is prepared analogously to Example 5, starting from R, S mixture of the compound from Example 2 by Chromatography obtained. First, the R- elutes (example 8) then the S-isomer.

Analytical data:
DC system III: R _f = 0.38.
(+) FAB-MS: m / z 580 (M + H), m / z 602 (M + Na).

Example 9 N-tert-butoxycarbonyl-L- (4-methoxy) -phenylalanyl- {2- R, S-amino-2- [2- (1,3-dithiolano)]} - acetyl-4S-amino-3S- hydroxy-5-cyclohexyl-pentanoyl-L-isoleucine (2- picolyl) amide

0.6 g (0.95 mmol) of the compound from Example 2 and 364 mg (1.2 mmol) of N-tert-butoxycarbonyl-L- (4-methoxy) - phenylalanine (Bissendorf Biochemicals) are mixed with 20 ml Methylene chloride and 1.2 ml (6.6 mmol) of diisopropylethylamine added. The solution is stirred and cooled to -20 ° C cooled (dry ice / acetone). You drip at this Temperature 860 ml (1.3 mmol) of a 50% solution of Phosphonic anhydride in methylene chloride (Hoechst AG) Add and leave the approach overnight to room temperature come. Add 20 ml of methylene chloride and shake 3 times with saturated sodium bicarbonate solution, 3 times with buffer solution pH 7 (Merck, article no. 9439) and once with half-saturated saline. The organic phase is dried over sodium sulfate, concentrated and dried in a high vacuum.

Crude yield: 60 mg.
DC system I: R _f = 0.59 (isomer A), R _f = 0.56 (isomer B).
HPLC system II: R _t = 11.77 min (isomer A), R _t = 10.49 min (isomer B).
(+) FAB-MS: m / z 857 (M + H); m / z = 879 (M + Na).

Example 10 and Example 11 N-tert-butoxycarbonyl-L- (4-methoxy) phenylalanyl {2- S-amino-2- [2- (1,3-dithiolano)]} - acetyl-4S-amino-3S- hydroxy-5-cyclohexylpentanoyl-L-isoleucine (2-picolyl) - amide (Example 10) N-tert-butoxycarbonyl-L- (4-methoxy) phenylalanyl {2- R-amino-2- [2- (1,3-dithiolano)]} - acetyl-4S-amino-3S- hydroxy-5-cyclohexylpentanoyl-L-isoleucine (2-picolyl) - amide (Example 11)

* S = Example 10 (isomer A).
* R = Example 11 (isomer B).

The title compound is purified by chromatographic separation of the mixture from Example 9 (600 mg) Silica gel 60 (Merck, Item No. 9385) 0.040-0.063 mm (230-400 mesh) with a graded gradient of methylene chloride / Methanol (100/0, 99/1, 98/2, 97/3, 95/5, 9/1) separated. The detection takes place at 214 nm, the fraction control thin-layer and high-pressure liquid chromatography. First, Example 10 elutes (Isomer A, S-isomer), then example 11 (isomer B, R-isomer).  

After combination and evaporation of the solvent receives you:

150 mg of the compound from Example 10 (isomer ≡ S),
10 mg of the compound from Example 10 and Example 11 (mixed fraction from A and B),
160 mg of the compound from Example 11 (isomer B ≡ R).

Analytical Data for Example 10 (Isomer A):
DC system I: R _f = 0.59.
HPLC system II: R _f = 11.77 min.
(+) FAB-MS: m / z 857 (M + H); m / z + 879 (M + Na).

Analytical data for example 11 (isomer B):
DC system I: R _f = 0.56.
HPLC system II: R _f = 10.49 min.
(+) FAB-MS: m / z 857 (M + H); m / z 879 (M + Na).

Example 12 L- (4-methoxy) phenylalanyl {2-R, S-amino-2- [2- (1,3- dithiolano)]} acetyl-4S-amino-3S-hydroxy-5-cyclohexylpentanoyl- L-isoleucine (2-picolyl) amide

The title compound is analogous to Example 2 by cleavage the Boc protecting group from a mixture of Compounds of Examples 10 and 11 were obtained.

Analytical data:
DC system III: R _f = 0.42; R _f = 0.38.

Example 13 L- (4-methoxy) phenylalanyl {2-R-amino-2- [2- (1,3- dithiolano)]} acetyl-4S-amino-3S-hydroxy-5-cyclohexylpentanoyl- L-isoleucine (2-picolyl) amide

The title compound is analogous to Example 2 by cleavage the Boc protecting group from the compound of Example 11 obtained.

Analytical data:
(+) FAB-MS: m / z 757 (M + H).

Example 14 and Example 15 N-tert-butoxycarbonyl-L- (4-methoxy) phenylalanyl {2- S-amino-2- [2- (1,3-dithiolano)]} - acetyl-4S-amino-3S- hydroxy-5-cyclohexylpentansäuremethylester (Example 14) N-tert-butoxycarbonyl-L- (4-methoxy) phenylalanyl {2- R-amino-2- [2- (1,3-dithiolano)]} - acetyl-4S-amino-3S- hydroxy-5-cyclohexylpentansäuremethylester (Example 15)

* S = Example 14 (Isomer A).
* R = Example 15 (isomer B).

The title compounds are analogous to Example 10 and Example 11 starting from 1.9 g (6.3 mmol) of N-tert-butoxycarbonyl L- (4-methoxy) phenylalanine (Bissendorf, Biochemicals) and 2.4 g (5.7 mmol) of the compound from Example 4 received.

Analytical Data Isomer A (Example 14):
DC system II: R _f = 0.58.
HPLC system II: R _f = 12.33 min.
(+) FAB-MS: m / z 668 (M + H).

Analytical Data Isomer B (Example 15):
DC system II: R _f = 0.56.
HPLC system II: R _f = 11.25 min.
(+) FAB-MS: m / z 668 (M + H).

Example 16 N-tert-butoxycarbonyl-L- (4-methoxy) phenylalanyl {2- R, S-amino-2- [2- (1,3-dithiolano)]} - acetyl-4S-amino-3S- hydroxy-5-cyclohexylpentanoic acid (Example 16)

790 mg (1.18 mmol) of a mixture of the compounds Example 14 and Example 15 are in 5 ml dioxane / water 1/1 suspended, mixed with 283 .mu.l (1.5 eq) of 6N NaOH and stirred overnight at room temperature. The approach becomes  adjusted to pH 3 with 1N HCl and evaporated off from the dioxane. The precipitate is filtered off, washed with water and dried over KOH in desiccator.

Yield: 560 mg (84% of theory).
DC system I: R _f = 0.18.
DC system II: R _f = 0.05.
DC system III: R _f = 0.82.
(+) FAB-MS: m / z = 660 (M + Li).

Example 17 and Example 18 N-tert-butoxycarbonyl-L- (4-methoxy) phenylalanyl {2- S-amino-2- [2- (1,3-dithiolano)]} - acetyl-4S-amino-3S- hydroxy-5-cyclohexylpentanoyl-N- (2-morpholinoethyl) amide (Example 17) N-tert-butoxycarbonyl-L- (4-methoxy) phenylalanyl {2- R-amino-2- [2- (1,3-dithiolano)]} acetyl-4S-amino-3S- hydroxy-5-cyclohexylpentanoyl-N- (2-morpholinoethyl) amide (Example 18)

* S = Example 17 (isomer A).
* R = Example 18 (isomer B).

The title compounds are analogous to Example I by PPA coupling of the compound of Example 16 and Aminoethylmorpholine prepared as amine component. The Crude product is separated by column chromatography, wherein a mixed fraction from Examples 17 and 18 occurs (analogously to Example 10 and Example 11), eluted first Isomer A (Example 17), then Isomer B (Example 18).

Analytical Data Isomer A (Example 17):
DC system I: R _f = 0.47.
HPLC system II: R _f = 10.36 min.
(+) FAB-MS: m / z 766 (M + H).

Analytical Data Isomer B (Example 18):
DC system I: R _f = 0.44.
HPLC system II: R _f = 9.96 min.
(+) FAB-MS: m / z 766 (M + H).

Example 19 N-tert-butoxycarbonyl-2-R-amino-2- [2- (1,3-dithiolano)] - acetyl-4S-amino-3S-hydroxy-5-cyclohexylpentanoyl- (2S- methyl) butylamide

To a solution of 650 mg (1.36 mmol) of the compound from Example 7 in 30 ml of dichloromethane are added Stir 483 μl (3 eq, 4.1 mmol) of 2-S-methyl-butylamine, 1.2 ml (5 eq, 6.8 mmol) of di-isopropylethyl-amine and - after cooling to -10 ° C - 1.2 ml (1.3 eq) of a 50% solution of propanephosphonic anhydride in Methylene chloride (Hoechst AG, Aldrich). The approach becomes Allow to come to room temperature overnight, with 20 ml Made up to dichloromethane and washed 3 times each with sat. sodium bicarbonate, 5% potassium hydrogen sulfate and sat. Saline shaken. The organic phase becomes dried over sodium sulfate, concentrated and by Column chromatography on silica gel (analogously to Example 10 and Example 11).

Yield: 460 mg (62% of theory).
DC system I: R _f = 0.52.
HPLC system II: R _f = 13.38 min.
(+) FAB-MS: m / z 546 (M + H).

Example 20 2-R-amino-2- [2- (1,3-dithiolano)] - acetyl-4S-amino-3S- hydroxy-5-cyclohexylpentanoyl- (2S-methyl) butylamide hydrochloride

The title compound is analogous to Example 2 by cleavage the Boc-protecting group from 4.20 mg (0.77 mmol) the compound of Example 19.

Yield: 350 mg (94% of theory).
DC system III: R _f = 0.41.
(+) FAB-MS: m / z 446 (M + H).

Example 21 N- (3-phenyl) propionyl {2-R-amino-2- [2- (1,3-dithiolano)]} acetyl-4S-amino-3S-hydroxy-5-cyclohexylpentanoyl- (2S- methyl) butylamide

100 mg (207 μmol) of the compound from Example 20 are dissolved in 10 ml of dichloromethane and successively while stirring with 303 .mu.l (1.74 mmol) of diisopropylethylamine and finally 27.4 μl (249 μmol) of 3-phenylpropionic acid chloride added. The approach will be added overnight Stirred room temperature, made up with ether and filtered with suction. The residue is analogous to Example 10 and 11 Chromatograph.

Yield: 63 mg (53% of theory).
DC system III: R _f = 0.69.
HPLC system II: R _f = 11.19 min.
(+) FAB-MS: m / z 578 (M + H).

Table 1 Examples 22-43

The compounds listed in Table 1 are by Propanphosphonsäureanhydridkopplung the corresponding Obtained acids with the compound of Example 8 (analogously to Example 1). All connections will be after Standard workup purified by chromatography (analog Examples 10 and 11). The applied acids or derivatives are either commercially available or will be represented by known methods.  

Table 1

table 2 Examples 44-46

The examples listed in Table 2 are according to known Methods by reacting the compound from the Example 8 with the commercially available iso- or isothiocyanates (Aldrich) in dichloromethane with diisopropylethylamine as Auxiliary base, standard preparation and chromatography (Analogous to Example 10 and 11).  

Table 2

Table 3 Examples 47-69

The compounds listed in Table 3 are by Propanphosphonsäureanhydridkopplung the corresponding Acids X-OH with the compound of Example 8 obtained (analogously to Example 9). All connections will be after Standard workup purified by chromatography (analog Examples 10 and 11). The acids used are X-OH known or be known methods from the corresponding Esters X-OR (R = Me, Et, Bzl) by basic Saponification prepared (see Preparation Examples).  

Table 3

Examples 70-73

The compounds listed in Table 4 are by Propanphosphonsäureanhydridkopplung the corresponding Obtained acids with the compound of Example 12 (analogously to Example 9). All compounds are after standard workup purified by chromatography (analog Examples 10 and 11). The applied acids or derivatives are either commercially available or will be represented by known methods.  

Table 4

Examples 74-76

The compounds listed in Table 5 are by Propanphosphonsäureanhydridkopplung the corresponding Obtained acids with the compound of Example 13 (analogously to Example 9). All compounds are after standard workup purified by chromatography.

The added acids or derivatives are either commercial Available or are by known methods shown.

The compound of Example 75 will be out of the compound of Example 74 by basic saponification (analogously to Example 16).  

Table 5

Examples 77-88

The compounds listed in Table 6 are by Propanphosphonsäureanhydridkopplung the corresponding Obtained acids with the compound of Example 8 (analogously to Example 9). All compounds are after standard workup purified by chromatography.

The added acids or derivatives are either commercial Available or are by known methods shown.

The connection from Example 80 will be made from the example 78 obtained by cleavage of the Boc protective group (analogously to Example 2).

The compound of Example 81 will be apparent from the example 80 by reaction with phenylacetic acid / propanephosphonic anhydride obtained (analogously to Example 9).

The compound of Example 86 becomes the example 82 obtained analogously to Example 80.

The compound of Example 88 is converted by reaction of Example 8 with p-tolyl-sulfonyl chloride / triethylamine in dichloromethane and standard work-up.  

Table 6

Examples 89 to 93

The compounds listed in Table 7 are made the compound of Example 16 by propanephosphonic anhydride coupling with the corresponding amines, after standard work-up and subsequent chromatography obtained (analogously to Example 17 and 18).  

Table 7

example 94

The example listed in Table 8 is analogous to Example 9 by Propanphosphonsäureanhydridkopplung the Compound of Example 5 with phenylpropionic acid chloride (analogously to Example 21) standard workup and Chromatography obtained.  

Table 8

Claims (9)

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 which is optionally substituted by an amino-protecting group,
R¹ is hydrogen or
represents a typical amino protecting group,
represents straight-chain or branched alkyl or acyl having in each case up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms,
- for a remainder of the formula stands,
wherein
a, a ', b, d, e, h and i are the same or different and are a number 0, 1, 2, 3, 4, 5, 6, 7 or 8, g is a number 1, 2, 3, 4 or 5 means that c and f are the same or different and denote a number 0, 1 or 2,
R³ and R ^{3 'are the} same or different and
- aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, nitro, hydroxy or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms,
straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 10 carbon atoms, which are optionally substituted by aryl having 6 to 10 carbon atoms,
a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 carbon atoms from the series N, S or O and their N-oxides,
R⁴ and R¹⁰ are the same or different and
Hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, nitro or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms,
R⁵ denotes straight-chain or branched alkyl having up to 8 carbon atoms,
R⁶ is halogen or straight-chain or branched alkyl or alkoxy having in each case up to 8 carbon atoms,
m is the <NH group, an oxygen atom, a sulfur atom or the SO₂ group,
R⁷ and R⁸ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,
R⁹ is aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen or by straight-chain or branched alkyl or alkoxy having in each case up to 8 carbon atoms,
a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S and its N-oxides,
Hydroxy or straight-chain or branched alkyl or alkoxy having in each case up to 10 carbon atoms, which is optionally substituted up to twice by hydroxy or by acyl having up to 8 carbon atoms or by pyrrolidinyl which is optionally substituted on the nitrogen by an amino-protecting group,
a radical of the formula R¹⁶-S (O) ₁ or R¹⁷-CO,
wherein
1 is a number 0, 1 or 2,
R¹⁶ 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 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S and the oxides thereof, which is optionally substituted by benzyl,
R¹⁷ represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms,
a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S, which is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms or benzyl,
or
a group of the formula -NR¹⁸R¹⁹ means
wherein
R¹⁸ and R¹⁹ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, optionally substituted by hydroxy, phenyl, a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, S or O, alkoxy of up to 6 carbon atoms, (C₁-C₆) dialkylamino, quaternary ammonium salts or a radical of the formula is substituted,
or
R¹⁸ or R¹⁹ cycloalkyl having 3 to 8 carbon atoms
or
R¹⁸ or R¹⁹ the rest of the formula or
R¹⁸ and R¹⁹ 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,
R¹¹ and R¹² are the same or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or an amino-protecting group,
R¹³ straight or branched alkoxy having up to 8 carbon atoms or hydroxy or
- a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, S or O means or
- 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 nitro, or
a group of the formula -NR¹⁸'R¹⁹ ',
wherein
R¹⁸ 'and R¹⁹' have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R¹⁴ is hydrogen or the group -NR²⁰R²¹,
wherein
R²⁰ and R²¹ are identical or different and denote hydrogen, an amino-protecting group or acyl having up to 8 carbon atoms,
R¹⁵ is aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, nitro or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
or
is straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl or by quaternary ammonium salts,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R¹⁶'-SO₂-, R²²R²³-N-SO₂- or R²⁴R²⁵-N-CO-,
wherein
R¹⁶ 'has the abovementioned meaning of R¹⁶ and is identical or different with this
and
R²², R²⁵, R²⁴ and R²⁵ have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R² is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or benzyl
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 (n = 1 or 2)
or or or or where the definitions given there apply,
n is the number 1 or 2,
Y is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or
- represents an amino protecting group or
- represents a radical of the formula -NHR²⁶, NR²⁷R²⁸, S (O) _k (NH) _r -R²⁹ or -OR³⁰,
R²⁶, R²⁷ and R²⁸ 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 10 carbon atoms, which may be polysubstituted by hydroxy, protected hydroxy, alkoxy or alkoxycarbonyl each having up to 6 Carbon atoms, carboxy, sulfo, phenyl or by a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S or by C₁-C₈-dialkylamino, C₁-C₆-Dihydroxydialkylamino or by a Remainder of the formula are substituted
or
R²⁷ and R²⁸ 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,
R²⁹ 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 or
R³⁰ is 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
a remainder of the formula means
wherein
R³¹ and R³² are the same or different and denote 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. 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,
for Prolein (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-naphthylalanine (1-Nal, 2-Nal), 4-methoxyphenylalanine, (3-thionaphthyl) glycine, homophenylalanine or O-benzyl-serine stand,
R¹ is hydrogen or tert-butoxycarbonyl (Boc), ethoxycarbonyl, (Etoc), methoxycarbonyl (Metoc) benzyloxycarbonyl (Z), allyloxycarbonyl (Alloc), isopropoxycarbonyl, isopentoxycarbonyl (= 3,3-dimethylpropoxycarbonyl), N-fluorenyloxy-carbonyl ( F-Moc), phenoxyacetyl, acetyl, formyl, pivalolyl, isovaleroyl, phenylacetyl, phenylpropionyl, cinnamoyl, 3,3-dimethylpropionyl, toluenesulfonyl, phenylsulfonyl or tert-butyl-sulfonyl,
represents straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, which is optionally substituted by phenyl or naphthyl,
- for a remainder of the formula stands,
wherein
a, a ', b, d, e, h and i are the same or different and are a number 0, 1, 2, 3, 4, 5, 6 or 7, g is a number 1, 2, 3, 4 or 5 c and f are the same or different and denote a number 0, 1 or 2,
R³ and R³ 'are the same or different and
Phenyl or naphthyl, which are optionally substituted by fluorine, chlorine, bromine, nitro, hydroxy or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 8 carbon atoms, which are optionally substituted by phenyl or naphthyl,
Morpholino, morpholino-N-oxide, pyridyl, pyridyl-N-oxide, pyrrolidinyl or piperidinyl,
R⁴ and R¹⁰ are identical or different and are hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or naphthyl, the latter being optionally substituted by fluorine, chlorine, bromine, nitro or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms are substituted
R⁵ denotes straight-chain or branched alkyl having up to 6 carbon atoms,
R⁶ is fluorine, chlorine 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,
R⁷ and R⁸ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
R⁹ is phenyl or naphthyl, which is optionally substituted by fluorine, chlorine, bromine or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
Morpholino, morpholino-N-oxide, piperidinyl, pyrrolidinyl, pyridyl or pyridyl-N-oxide,
Hydroxy or straight-chain or branched alkyl or alkoxy having in each case up to 8 carbon atoms, which is optionally substituted up to twice by hydroxy or by acyl having up to 6 carbon atoms or by pyrrolidinyl- (N-BOC),
a radical of the formula R¹⁶-S (O) ₁ or R¹⁷-CO,
wherein
l is a number 0, 1 or 2,
R¹⁶ represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or naphthyl, or
Morpholino, morpholino-N-oxide, pyridyl, pyridyl-N-oxide, pyrrolidinyl or piperidinyl, which are optionally substituted by benzyl,
R¹⁷ represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or naphthyl,
- Morpholino, morpholino-N-oxide, pyridyl, pyridyl-N-oxide, pyrrolidinyl or piperidinyl, which are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms or benzyl, or
a group of the formula NR¹⁸R¹⁹, in which
R¹⁸ and R¹⁹ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, optionally substituted by hydroxy, phenyl, pyridyl, morpholino, piperidinyl, alkoxy having up to 4 carbon atoms, (C₁-C₄) dialkylamino,
- or a remainder of the formula is substituted,
or
R¹⁸ or R¹⁹ cyclopropyl mean
or
R¹⁸ and R¹⁹ together with the nitrogen atom form a morpholino or piperidinyl ring,
R¹¹ and R¹² are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or one of the amino-protecting groups listed above,
R¹³ represents straight-chain or branched alkoxy having up to 6 carbon atoms or hydroxyl,
Morpholino, pyridyl, piperidinyl or pyrrolidinyl,
- 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 or nitro, or
a group of the formula -NR¹⁸'R¹⁹ ',
wherein
R¹⁸ 'and R¹⁹' have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R¹⁴ is hydrogen or the group -NR²⁰R²¹,
wherein
R²⁰ and R²¹ are identical or different and denote hydrogen, one of the abovementioned amino-protecting groups or acyl having up to 6 carbon atoms,
R¹⁵ phenyl or naphthyl, which is optionally substituted by fluorine, chlorine, nitro or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, or
represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl or by a radical of the formula (CH₃) ₃N⊕Cl⊖,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R¹⁶'-SO₂, R²²R²³N-SO₂ or R²⁴R²⁵N-CO,
wherein
R¹⁶ 'has the abovementioned meaning of R¹⁶ and is identical or different thereto and
R²², R²³, R²⁴ and R²⁵ have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R² is hydrogen, straight or branched alkyl having up to 6 carbon atoms or benzyl
or
in the case that A and B simultaneously signify a bond,
R¹ and R² together with the nitrogen atom form one of the rings mentioned in claim 1,
n is the number 1 or 2,
Y is hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cyclopropyl,
- represents one of the above-listed amino protecting groups or
- represents a radical of the formula -NHR²⁶, -NR²⁷R²⁸ or -OR³⁰,
wherein
R²⁶, R²⁷ and R²⁸ are identical or different and denote hydrogen, cyclopropyl or straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, which are optionally substituted by hydroxyl, pyridyl or morpholino,
R³⁰ is hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,
and their physiologically harmless salts. 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 , p-Cl-phenylalanine, p-nitrophenylalanine, 2-naphthylalanine (2-Nal), 4-methoxyphenylalanine, (3-thionaphthyl) glycine, homophenylalanine or O-benzyl-serine,
R¹ is hydrogen or
for tert-butoxycarbonyl (Boc), ethoxycarbonyl, (Etoc), methoxycarbonyl (Metoc), benzyloxycarbonyl (Z), isopropoxycarbonyl, allyloxycarbonyl (Alloc), phenoxyacetyl, acetyl, pivaloyl, isovaleroyl, phenylpropionyl, tosyl, tert -butylsulfonyl or 3 , 3-dimethylpropionyl,
represents straight-chain or branched alkyl or acyl each having up to 4 carbon atoms, which is optionally substituted by phenyl or naphthyl,
- for a remainder of the formula stands,
wherein
a, a ', b, d, e, h and i are the same or different and are a number 0, 1, 2, 3, 4, 5 or 6, g is a number 1, 2, 3 or 4, c and f are the same or different and denote a number 0, 1 or 2,
R³ and R³ 'are the same or different and
Phenyl or naphthyl, which are optionally substituted by fluorine, chlorine, methyl, nitro or methoxy,
straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, which are optionally substituted by phenyl or naphthyl,
- morpholino, pyridyl or piperidinyl,
R⁴ and R¹⁰ are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or naphthyl, the latter optionally being substituted by fluorine, chlorine, nitro, methyl or methoxy,
R⁵ represents straight-chain or branched alkyl having up to 4 carbon atoms,
R⁶ is fluorine, chlorine or straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
m is the <NH group or an oxygen atom,
R⁷ and R⁸ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R⁹ is phenyl or naphthyl, which is optionally substituted by fluorine, chlorine, methyl or methoxy,
Morpholino, pyridyl or piperidinyl,
- hydroxy or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, which may be up to 2 times by hydroxy or by a radical of formula a radical of the formula R¹⁶-SO₂- or R¹⁷-CO,
wherein
R¹⁶ represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or naphthyl,
Is morpholino, piperidinyl or pyridyl, which is optionally substituted by benzyl,
R¹⁷ represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or naphthyl,
Morpholino, pyridyl or piperidinyl, which is optionally substituted by methyl or benzyl,
a group of the formula -NR¹⁸R¹⁹,
wherein
R¹⁸ and R¹⁹ are the same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, optionally substituted by phenyl, hydroxy, pyridyl, morpholino, piperidinyl, methoxy, ethoxy, dimethylamino or a radical of the formula is substituted,
or
R¹⁸ and R¹⁹ together with the nitrogen atom form a morpholino or piperidinyl ring,
R¹³ represents straight-chain or branched alkoxy having up to 4 carbon atoms or hydroxy,
Morpholino, pyridyl or piperidinyl,
- 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 or nitro,
a group of the formula -NR¹⁸'R¹⁹ ',
wherein
R¹⁸ 'and R¹⁹' have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R¹⁴ is hydrogen or the group -NR²⁰R²¹,
wherein
R²⁰ and R²¹ are identical or different and denote hydrogen, one of the abovementioned amino-protecting groups or acyl having up to 4 carbon atoms,
R¹⁵ is phenyl or naphthyl, which is optionally substituted by fluorine, chlorine, nitro, methyl or methoxy,
is straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl or by a radical of the formula (CH₃) ₃N⊕Cl⊖,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R¹⁶'-SO₂-, R²²R²³N-SO₂- or R²⁴R²⁵N-CO,
wherein
R¹⁶ 'has the abovementioned meaning of R¹⁶ and is identical or different thereto and
R²², R²³ and R²⁵ have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R 2 is hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or benzyl,
n is the number 1 or 2,
Y is hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms,
- represents one of the above-listed amino protecting groups or
- represents a radical of the formula -NHR²⁶, -NR²⁷R²⁸ or -OR³⁰,
wherein
R²⁶, R²⁷ and R²⁸ are the same or different and are hydrogen, cyclopropyl or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, which are optionally substituted by hydroxyl, pyridyl or morpholino,
R³⁰ is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
and their physiologically acceptable salts. 4. Process for the preparation of compounds 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 which is optionally substituted by an amino-protecting group,
R¹ is hydrogen or
represents a typical amino protecting group,
represents straight-chain or branched alkyl or acyl having in each case up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms,
- for a remainder of the formula stands,
wherein
a, a ', b, d, e, h and i are the same or different and are a number 0, 1, 2, 3, 4, 5, 6, 7 or 8, g is a number 1, 2, 3, 4 or 5 means that c and f are the same or different and denote a number 0, 1 or 2,
R³ and R³ 'are the same or different and
- aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, nitro, hydroxy or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms,
straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 10 carbon atoms, which are optionally substituted by aryl having 6 to 10 carbon atoms,
a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 carbon atoms from the series N, S or O and their N-oxides,
R⁴ and R¹⁰ are the same or different and
Hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, nitro or by straight-chain or branched alkyl or alkoxy having in each case up to 8 carbon atoms,
R⁵ denotes straight-chain or branched alkyl having up to 8 carbon atoms,
R⁶ is halogen or straight-chain or branched alkyl or alkoxy having in each case up to 8 carbon atoms,
m is the <NH group, an oxygen atom, a sulfur atom or the SO₂ group,
R⁷ and R⁸ are the same or different and denote hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,
R⁹ is aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen or by straight-chain or branched alkyl or alkoxy having in each case up to 8 carbon atoms,
a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S and its N-oxides,
Hydroxy or straight-chain or branched alkyl or alkoxy having in each case up to 10 carbon atoms, which is optionally substituted up to twice by hydroxy or by acyl having up to 8 carbon atoms or by pyrrolidinyl which is optionally substituted on the nitrogen by an amino-protecting group,
a radical of the formula R¹⁶-S (O) ₁ or R¹⁷-CO,
wherein
l is a number 0, 1 or 2,
R¹⁶ 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 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S and the oxides thereof, which is optionally substituted by benzyl,
R¹⁷ represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms,
a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, O or S, which is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms or benzyl,
or
a group of the formula -NR¹⁸R¹⁹ means
wherein
R¹⁸ and R¹⁹ are the same or different and are hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, optionally substituted by hydroxy, phenyl, a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, S or O, alkoxy having up to 6 carbon atoms, (C₁-C₆) dialkylamino, quaternary ammonium salts or by a radical of the formula is substituted,
or
R¹⁸ or R¹⁹ cycloalkyl having 3 to 8 carbon atoms
or
R¹⁸ or R¹⁹ the rest of the formula or
R¹⁸ and R¹⁹ 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,
R¹¹ and R¹² are the same or different and denote hydrogen or an amino-protecting group,
R¹³ straight or branched alkoxy having up to 8 carbon atoms or hydroxy or
- a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series N, S or O means or
- 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 nitro, or
a group of the formula -NR¹⁸'R¹⁹ ',
wherein
R¹⁸ 'and R¹⁹' have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R¹⁴ is hydrogen or the group -NR²⁰R²¹,
wherein
R²⁰ and R²¹ are identical or different and denote hydrogen, an amino-protecting group or acyl having up to 8 carbon atoms,
R¹⁵ is aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, nitro or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
or
is straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl or by quaternary ammonium salts,
L and L 'are the same or different and represent an oxygen or a sulfur atom,
W is a radical of the formula R¹⁶'-SO₂-, R²²R²³-N-SO₂- or R²⁴-R²⁵-N-CO-,
wherein
R¹⁶ 'has the abovementioned meaning of R¹⁶ and is identical or different with this
and
R²², R²⁵, R²⁴ and R²⁵ have the abovementioned meaning of R¹⁸ and R¹⁹ and are identical or different therefrom,
R² is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or benzyl
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 (n = 1 or 2)
or or or or where the definitions given there apply,
n is the number 1 or 2,
Y is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or
- represents an amino protecting group or
- represents a radical of the formula -NHR²⁶, NR²⁷R²⁸, S (O) _k (NH) _r -R²⁹ or -OR³⁰,
R²⁶, R²⁷ and R²⁸ 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 10 carbon atoms, which may be polysubstituted by hydroxy, protected hydroxy, alkoxy or alkoxycarbonyl each having up to 6 Carbon atoms, carboxy, sulfo, phenyl, or by a 5- to 7-membered, saturated or unsaturated 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 the formula are substituted
or
R²⁷ and R²⁸ 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,
R²⁹ 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 a bonded via N 5- to 7-membered saturated heterocycle having up to 3 heteroatoms from the series N, O or S.
or
R³⁰ is hydrogen or straight or branched alkyl of 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
a remainder of the formula means
wherein
R³¹ and R³² are the same or different and denote 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, characterized in that

• [A] Compounds of the general formula (II) in which
  D, E, R² and Y have the meaning given above
  and
  Z is an amino protecting group,
  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 R 2 are as defined above,
  and
  Z 'has the abovementioned meaning of Z and is identical or different with it,
  with activation of the carboxylic acid by conventional methods in inert solvents to give compounds of the general formula (Ia) in which
  Z ', R², n, D, E and X have the abovementioned meaning,
  converts the protective group Z 'according to the usual method and in a further step with compounds of general formula (IV) R¹-AB · OH (IV) in which
  R¹, A and B have the abovementioned meaning,
  optionally condensed under the above-mentioned carboxylic acid activation,
  and optionally saponifying the corresponding esters by the customary method or first reacting the compounds of the general formula (III) and (IV) by the method indicated above and then adding a further peptide bond with the compounds of the general formula (II) or by
• [B] Compounds of the general formula (Ib) in which
  A, B, R¹, R², n, D and E have the abovementioned meaning and
  Y 'is alkoxy having up to 8 carbon atoms or benzyloxy,
  saponified according to the usual method first to the corresponding acids and in a further step in the presence of excipients with amines of the general formula (V) or (VI) H₂NR '(V) orNHR'R''(VI) in which
  R, R 'and R "are identical or different and correspond to the scope of meaning of the respective amino groups listed under Y,
  condenses, or by
• [C] either compounds of the general formula (Ic) in which
  A, B, R¹, R² and n are as defined above, and
  R³³ is alkyl having up to 6 carbon atoms or benzyl,
  or compounds of the general formula (Id) in which
  Z ', n, R² and R³³ have the abovementioned meaning,
  first saponified to the corresponding acids by the usual method and then with the fragment of the general formula (VII) DEY (VII) in which
  D, E and Y are as defined above,
  in inert solvents, if appropriate in the presence of auxiliaries,
  and in the case of the compounds of the general formula (Id) in a next step according to the method described under process [A] with gradual cleavage of the respective protective group Z 'with compounds of the general formula (IV) or (IVa) R¹-A-OH ( IVa) or R¹-AB-OH (IV) in which
  R¹, A and B have the abovementioned meaning,
  implements,
  and the substituent Y optionally derivatized by customary methods, for example by substitution.

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 compounds of the general formula (I) according to claim 1 optionally using standard auxiliary and Carriers in a suitable application form transferred. 8. Compounds of the formulas (Ia) (Ib) and (Id) in which the substituents have the meaning given in claim 4. 9. Use of compounds of general (I) according to claim 1 in the fight against circulatory diseases.