DD296690A5 - RENIN-INHIBITING AMINOOLIGOHYDROXY DERIVATIVES - Google Patents

Abstract

The present invention relates to compounds of the formula I,

Description

Renin-inhibiting aminooligohydroxy derivatives

European Patent Applications EP-A 184855, 189203, 202577, 2229267, 230626 and 237202 and International Patent Application WO 87/05302 disclose renin-inhibiting aminodiol derivatives.

Furthermore, renin-inhibiting aminodiol derivatives are in Biochem. Biophys. Res. Commun.132, 155-161 (1985), in Biochem.

Biophys. Res. Commun. 146,959-963 (1987), FEBS Lett. 230, 38-42 (1988) and J. Med. Chem. 30,976-982 (1987).

Surprisingly, it has now been found that those compounds which differ from those described in the cited documents in that they contain additional hydroxyl function at the C-terminus are highly effective renin inhibitors in vitro and in vivo and have advantageous properties over the known compounds.

The invention relates to compounds of the formula I.

R ² R ³ R ⁴

AN-CH-CO-NH-CH- (CHOH) _n -CH ₂ OH ~~ (I)

in which A is a radical of the formulas II, III or IV

R ⁶ R ⁵ O R'-N-CH-C- (II)

R ⁷ R ⁵ OR ¹ -CH-CH-C- (III)

R ⁵ O R'-O-CH-C- (IV)

R 'ai) (C ₃ -C ₈₎ cycloalkyl, (C4-C _l o) bicycloalkyl, (C _g -C _l2) tricycloalkyl, _(C3-C8) -Cycloa! Alkyl- (C ₁ -C ₆₎ alkyl, (C ₄ -Cio) bicycloalkyl (Ci-C ₆₎ alkyl, (Cg-C ^ l-tricycloalkyl-tC-Cel-alkyl, (C ₃ -C _s) -Cycloalkylcarbonylund (C3- Cs) -cycloalkylsulfonyl, in which in each case the cycloalkyl, bicycloalkyl and tricycloalkyl substituent are represented by one or two identical or different radicals from the series F, Cl, Br, I, hydroxy, (C ₁ -C ₆ ) -alkoxy, ( C ₁ -C ₆ -alkenyl, carboxy, (C ₁ -C ₄ -alkoxycarbonyl, carbamoyl, carboxymethoxy, amino, (C ₁ -C ₄ -monoalkylamino, (C ₁ -C ₆ ) -dialkylamino, amino- (C ₁ -C ₆ ) - alkyl, (C ₁ -C ₆₎ alkylamino (C, -C ₆₎ alkyl, di-fCt-CeJ-alkylamino-fC ^ EJ-alkyl, amidino, hydroxyamino, Hydroximino.Hydrazono, imino, guanidino, (C , -C ₆ ) -Alkoxysulfonyl, (C ₁ -C ₆ ) alkoxysulfenyl, trifluoromethyl, (Ci-Cit-alkoxycarbonylamino, (Ce-C, 2) -aryl (C, -C ₄ ) alkoxycarbonyl-amino substituted may be hydrogen, hydroxy, (Ct-C ^ alkyl, _(Ci-Ce) alkoxy, (dC ₁₈₎ alkanoyl, (dC ₁₈₎ Alkoxycarbonyl, (C ₁ -C ₄ ) -alkylsulfonyl, (C ₁ -C ₈ ) -alkylsulfinyl, where the alkyl radicals are each protected by optionally protected amino, trimethylsilyl, hydroxy, mercapto, (C ₁ -C ₄ ) -alkylthio, halogen, ( C _t -C ₄ ) alkoxy, mono- or di- ^ -Csl-alkylamino, carboxy, carbamoyl, guanidino, (C ₁ -C ₄ ) alkoxycarbonyl, (d-CeJ-alkanoyloxy, phenyl (C, -C ₄ ) -alkoxy or a radical CONR ⁸ R ⁹ may be substituted; (C6-C ₁ 4) -aryl, _(C5-C14) -aryl- (Ci-C ₄₎ alkyl, (C _s -C ₄₎ -aryl- (C ₁ -C ₄₎ alkoxy, wherein the Aryl radical in each case by one, two or three identical or different radicals from the series (Ci-C ₆ ) alkyl, amino, mono- or di- (Ci-C ₄ ) -alkylamino, amino-iCH ^ l-alkyl.Hydroxy C 1 -C 6 -alkyl, mono- or di-C 1 -C ₆ -alkylamino-C 1 -C 5 -alkyl, hydroxy, C 1 -C ₄ -alkoxy, halogen, formyl, C 1 -C ₄ -alkoxycarbonyl, carboxamido Mono- or di- (C 1 -C ₄ ) -alkylaminocarbonyl and nitro;

Het, Het- (Cr-C ₄ ) alkyl, wherein Het represents a 5-, 6- or 7-membered heterocyclic ring, which may be additionally benzannellated and either aromatic, partially hydrogenated or fully hydrogenated and the heteroelement one or two identical or different Contains radicals from the series N, O, S, NO, SO and SO ₂ and by one or two identical or different radicals from the series (C ₁ -C ₄ I -AlkYl, (C ₁ -C ₄ I-AIkOXy, ( C ₁ -C ₄ -j-alkoxycarbonyl, hydroxy, halogen, amino, amino-tC, -C ₄ ) -alkyl, mono- or di- (C ₁ -C ₄ ) -alkylamino, or a radical NR ⁸ R ^9, where R ⁸ and R ⁹ are identical or different and are independently hydrogen; (C ₁ -C ₈ -alkyl-I, which (by amino, (C ₁ -C ₄₎ alkylamino, di- C ₁ -C ₄₎ -alkylamino, hydroxy or (C ₁ -C ₄ ) -alkoxy may be substituted; (C ₃ -C ₇ ) -cycloalkyl; mercapto; (C ₁ -C ₄ ) -alkylthio; phenylthio; (C ₁ -C ₄ ) -alkoxycarbonyl ; carboxy; _(C6-C14) aryl, substituted dasimArylrestwieoben described can be; Het or Het-td-Cd-alkyl, wherein Het is as defined above, mean or wherein

R ⁸ and R ⁹ form, together with the nitrogen atom carrying them, a 5 to 12-membered ring which may be mono- or bicyclic and may contain, as further ring members, 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom and is substituted by (C ₁ -C ₄ ) -alkyl may be substituted, or form

R ¹ a ₂ ) is a radical of the formula V.

R '' - W (V)

wherein R ¹ 'as R ^{1 is defined} under a,) and W is -CO -, - CS-, -O-S0-. -SO ₂ -, -SO-. -NH-SO ₂ -NH-CO-, -CH (OHh or -N (OH) -;

R 'and R ⁵ together with the nitrogen atom carrying them form a 5- to 12-membered ring which may be mono- or bicyclic, aromatic, partially hydrogenated or fully hydrogenated and contain, as further ring members, 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom and may be substituted by (C, -C ₄ ) -alkyl, R ² and R ⁶ independently of one another are hydrogen or (C 1 -C ₄ ) -alkyl, R ³ and R ^{5 are} independently of one another as R ^{1 is} defined under ai) ;

R ^{4 is} (C ₃ -C ₂ ) -alkyl; mono-, bi-odertricyclisches (Qj-C _1s) cycloalkyl, (C ₃ -C ₈₎ -Cycloal <ylmethyl, (C ₃ -C, el-Cycloalkylethyl, where the cycloalkyl moiety is optionally substituted by (C, _-C6) Dithiolanyl, (C ₆ -C ₄ ) arylmethyl, dithiolanylmethyl, dithiolanylethyl, dithianyl, dithianylmethyl or dithianylethyl; R ^{7 is} hydrogen or (C 1 -C ₈ ) -alkyl, or together with R 'or R ⁵ and the atoms carrying them form a mono- or bicyclic, saturated or partially unsaturated ring system having 5-12 ring members which, in addition to carbon, may also contain 1 sulfur atom, which may optionally be oxidized to the sulfoxide or sulfone, and

η 2-10 means

and their physiologically acceptable salts.

The chiral centers in the compounds of formula I may have the R, S or R-S configuration. Alkyl can be straight-chain or branched. The same applies to radicals derived therefrom.

Cyclohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl are understood as meaning (C ₃ -C ₈ ) -cycloalkyl or (C ₁ -C ₈ -cycloalkyl or (C 1 -C ₄ -tricycloalkyl) is an isocyclic aliphatic radical The non-aromatic radical which may optionally contain unsymmetrically distributed double bonds may optionally also be substituted by open-chain aliphatic side chains The two or three rings as components of such a radical are fused or spiro-linked and via a ring C atom or a side chain C Examples of these radicals are bornyl, norbornyl, pinanyl, norpinanyl, caranyl, norcaranyl, thiocyanyl, adamantyl, bicyclo (3.3.0) octyl, bicyclo (1.1.0) butyl , Spiro (3.3) heptyl substituents.

If the said cycles carry more than one substituent, these may be either in the form of ice or as trans. (C ₆ -C ₄ ) -aryl is, for example, phenyl, naphthyl, biphenylyl or fluorenyl; preferred is phenyl.

The same applies to radicals derived therefrom, such as e.g. Aryloxy, aroyl, aralkyl and aralkyloxy. By aralkyl is meant an alkyl-linked unsubstituted or substituted aryl radical, such as. B. benzyl, α- and ß-naphthylmethyl, halobenzyl and alkoxybenzyl, but aralkyl would not be limited to the radicals mentioned.

A radical Het within the meaning of the above definition is, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, .beta.-carbolinyl or a benzannellated, cyclopenta, cyclohexa or cyclohepta-fused derivative of these radicals. This heterocycle may be attached to a nitrogen atom by oxido, (C, -C ₆ ) -alkyl, e.g. Methyl or ethyl, phenyl or phenyl (C, -C ₄ ) alkyl, e.g. Benzyl, and / or on one or more carbon atoms by (C 1 -C ₄ ) -alkyl, for example methyl, phenyl, phenyl (C 1 -C ₄ ) -alkyl, for example benzyl, halogen, for example chlorine, hydroxyl, (C ₁ -C ₄ -alkoxy, ζ B. methoxy, phenyl- (C, -C ₄ ) -alkoxy, eg benzyloxy, or oxo substituted and partially saturated is η and is for example 2- or 3-pyrrolyl, phenyl -pyrrolyl, for example A- or ö-phenyl ^ -pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methylimidazolyl, for example i-methyl-2-, -A- or -5-imidazolyl, 1.3 Thiazol-2-yl, 2-, 3- or 4-pyridyl, 1-oxido-2-, 3- or 4-pyridyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, substituted 2-indolyl, for example 1-methyl, 5-methyl, 5-methoxy, 5-benzyloxy, 5-chloro or 4,5-dimethyl-2 indolyl, 1-benzyl-2- or 3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclohepta [b] -5-pyrrolyl, 2-, 3- or 4-quinolyl, 4-hydroxy 2-quinolyl, 1-, 3- or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzoxazolyl, 2-benz thiazolyl, benz [e] indol-2-yl or β-carbolin-3-yl. Partially hydrogenated or fully hydrogenated heterocyclic rings are, for example, dihydropyridinyl, pyrrolidinyl, e.g. B. 2-, 3- or 4-N-methylpyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino. Halogen is fluorine, chlorine, bromine or iodine, with fluorine, chlorine and bromine being preferred.

Salts of compounds of the formula I are understood in particular to be pharmaceutically usable or non-toxic salts.

Such salts are for example of compounds of formula I, which acidic groups, for. As carboxy, formed with alkali or alkaline earth metals, such as Na, K, Mg and Ca, and with physiologically acceptable organic amines, such as. For example, triethylamine and tri- (2-hydroxy-ethyl) amine.

Compounds of formula I which contain basic groups, e.g. an amino group or a guanidino group, form salts with inorganic acids, such as. As hydrochloric acid, sulfuric acid or phosphoric acid and with inorganic carboxylic or sulfonic acids, such as. As acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid. Preference is given to compounds of the formula I in which A is as defined on pages 1 and 2:

R ¹ is hydrogen or (C ₁ -C ₁ O) -AIkYh cyclopentyl; cyclohexyl; cyclopentyl; Cyclopentyl (C, -C ₆ ) alkyl; Cyclohexyl (C, -C ₆ ) alkyl; Phenyl (C 1 -C ₄ ) alkyl, wherein the phenyl radical is optionally substituted as indicated on pages 2 and 3; Thienyl or thienyl (C ₁ -C ₄ ) -alkyl, wherein the thiophene each by one or two identical or different radicals from the series (C, -C ₄ ) alkyl, (C, -C ₄ ) alkoxy or halogen may be substituted, 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl (C, -C ₄ ) alkyl, wherein the pyridine radical by one or two identical or different radicals from the (C ₁ -C ₄ alkyl group, (C ₁ -C ₄ alkoxy or halogen may be substituted; amino (C ₁ -C ₁₀ ) alkyl hydroxy (C ₁ -C 8) alkyl; (C ₁ -C ₄ ) alkyl; CJ-alkoxy-IC ^ C ^ l-alkyl; (C, -C ₄₎ alkoxycarbonyl (C ₁ -C ₁₀₎ alkyl; (C, -C _e) alkylsulfonyl; (C-Cei-alkylsulfinyl ( C ₁ -C ₈ ) -hydroxyalkylsulfonyl; (C ₁ -C ₈ ) -hydroxy-alkylsulfinyl; hydroxy-C ₁ -C 4 -alkanoyl; (C ₁ -C 4) alkanoyloxy-C ₁ -C 4 -alkyl; (C ₁ -C ₈ ) -alkyl; _1t ) alkanoyl; optionally protected AmJnO- (C ₁ -C ₁ ,) alkanoyl, such as (3-amino-3,3-dimethyl) propionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 4-N tert-butoxycarbonylaminobutyryl, SN-tert-butoxycarbonylaminopentanoyl or 6-N-tert-butoxycarbon ylaminohexanoyliDi - ^ - alkylamino Crj-ICR-CNJ-alkanoyl.MCj-CeJ-Cycloalkylcarbonyl.aminosubstituiertes (C3-C ₈₎ -cycloalkyl-carbonyl; amino-substituted (C 1 -C 12 -cycloalkyl-sulfonyl, (C 9 -C 14 -aryl-aryl-C 1 -C 12 -alkanoyl; 2-pyridyl *

(C 1 -C ₈ ) alkanoyl, 3-pyridyl (C 1 -C ₈ ) alkanoyl, 4-pyndyl- (C ₁ -C ₈ ) alkanoyl, optionally substituted by halogen, (C ₁ -C ₆ ) alkyl, ( C 1 -C ₄ -alkoxy or (C 1 -C ₆ -alkoxycarbonyl-substituted benzoyl, benzenesulfonyl, (C 1 -C ₁₀ ) -alkoxycarbonyl, if appropriate by means of trimethylsilyl, halogen, (C 1 -C ₆ ) -alkyl or halo (C 1 -C-C ₆ ) -alkvl substituted, (C ₆ -C ₄ ) aryl (CC ₆ ) alkoxycarbonyl, 4-amino-pipendino-1-carbonyl, 4-aminomethyl-pipendino-1-carbonyl, N (4-pipendinol-carbamoyl, or N methyl [2- (N (morpholino carbonyl) N methylamino) ethyl] aminocarbonyl

R 'and R ^5, together with the nitrogen atom bearing them, form a 5- to 12-membered ring which may be mono- or bicyclic, aromatic, partially hydrogenated or fully hydrogenated,

R ² and R ⁶ independently of one another denote hydrogen or (C 1 -C ₄ ) -alkyl, R ³ and R ⁵ independently of one another are as defined for R ¹ under a 1 of claim 1,

R ⁴ (C ₃ -C ₂₎ alkyl, mono, bi- or tricyclic (C _3-18) cycloalkyl or (C ₃ -C ₈₎ cycloalkylmethyl, said cycloalkyl optionally substituted by (C, -C ₄₎ -alkyl is, (Ce-C 1-6 arylmethyl, dithiolanyl, dithiolanylmethyl, dithianyl and dithianylmethyl,

R ^{7 is} hydrogen or methyl, or together with R 'or R ⁵ and the atoms carrying them, a mono- or bicyclic saturated or partially unsaturated ring system having 5-12 ring members, which may contain 1 carbon atom other than carbon, which may be sulfoxide or sulfone can be oxidized, forms, and

η 2-8, means

Particular preference is given to compounds of the formula I in which

R ^{1 is} hydrogen, (C ¹ -C ₈ ) alkylsulfonyl, (C ¹ -C ₈ ) alkylsulfinyl, 2 hydroxyethylsulfonyl, 2-hydroxypropylsulfonyl, 2-hydroxypropionyl, 3-hydroxypropionyl, 3-hydroxybutyryl, 2-hydroxy-3-methylbutyryl , (C 1 -C ₈ ) alkanoyloxy (C 1 -C ₆ ) alkyl, η decanoyl, formyl, acetyl, propionyl, pivaloyl, isovaleryl, isobutyryl, (3-amino-3,3-dimethyl-propionyl), 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, dimethylaminoacetyl, piperidino-4-carbonyl, morpholino-4-carbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, S-aminocyclobutylcarbonyl, 4-aminocyclohexylcarbonyl, S-aminocyclobutylsulfonyl, 4-aminocyclohexylsulfonyl, phenylacetyl, phenylpropanoyl, Phenyibutanoyl, 2-Pyndyl- (C 1 -C ₈ ) -alkanoyl, S-Pyndyl-iC-Celk-alkanoyl, 4-Pyndyl- (C 1 -C ₈ ) -alkanoyl, 4-Chlorobenzoyl, 4-methylbenzoyl, 2-methoxycarbonyl benzoyl, 4-methoxybenzoyl, pyrrolyl-2-carboryl, pyridyl, 3-carbonyl, benzenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, 2- (T. n-methylsilyl) ethoxycarbonyl, 2,2,2-Tnchlor-ethoxycarbonyl, ^1, 1-dimethyl-2,2,2-tnchlorethoxy-carbonyl, benzyloxy-carbonyl, 1-or 2-naphthylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl, 4-amino piperidino! -carbonyl, 4-aminomethylpiperidino-carbonyl, N-methyl- [2- (N- (morpholinocarbonyl) -N-methyl-amino) -ethyl] -aminocarbonyl, orN- (4-pipendino) -carbamoyl,

R ¹ and R ⁵ together with the nitrogen atom bearing them form an 8 to 12 g-ring acyclic ring which may be aromatic, partially hydrogenated or fully hydrogenated,

R ² and R ⁶ independently of one another denote hydrogen or methyl,

R ³ and R ⁵ independently of one another are hydrogen, methyl, ethyl, isopropyl, n-propyl, η-butyl, isobutyl, sec -butyl, 3-guanidinopropyl, carbamoylmethyl, 2-carbamoylethyl, carboxymethyl, 2-carboxylethyl, mercaptomethyl, 2- Methylthio) -ethyl, (1-mercapto-1-methyl) -ethyl, hydroxymethyl, 1-hydroxyethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, Ν, Ν-dimethylarmno, cyclohexylmethyl, imidazol-4-yl methyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, indol-3-yl-methyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl, (benzdioxolan-5-yl) -methyl, 2-thienyl, 2-thienylmethyl, 2- (2-thienyl) ethyl, 3-thienyl, 3-thienylmethyl, 2- (3-thienyl) ethyl, 4-chlorobenzyl, 2- (methylsulfmyl) ethyl, 2 (Methylsulfonyl) -ethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexyl, (1-methylimidazol-4-yl) -methyl, (3-methyl-imidazol-4-yl) -methyl, phenyl, 1- Naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-thiazolylmethyl, 4-thiazolylmethyl, 3-pyrazolylmethyl, 4-pyrimi dinylmethyl, indol-2-ylmethyl, 2-benzo [blothienylmethyl, 3-benzo [b] thienylmethyl, 2-furylmethyl, cyclohexyl or cyclopentyl,

R ⁴ is (C3-Ci ₂₎ -alkyl, mono- or bicyclic (Cr-C ^ cycloalkyl or (C3-Ci ₂₎ cycloalkylmethyl wherein the cycloalkyl moiety is optionally substituted by (CC ₄₎ alkyl, (Ce-Ciol -Aryl-methyl, dithiolanyl, dithiolanylmethyl, dithianyl or dithianylmethyl,

R ^{7 represents} hydrogen or, together with R ¹ and the atoms carrying them, a monocyclic or bicyclic saturated or partially unsaturated ring system having 5-12 ring members which, in addition to carbon, also contains 1 sulfur atom, which is particularly preferably oxidized to the sulphone, or together with R ⁵ and the atoms carrying them a thiochroman system whose sulfur atom is particularly preferably oxidized to sulfone forms, and

η 3-6 means

Furthermore, compounds of the formula I are particularly preferably mentioned, in which

R 'is hydrogen, (C 1 -C ₆ ) -alkylcarbonyl, (CC ₆ ) -alkylsulfonyl, amino-C 1 -C 5 -cycloalkylcarbonyl, 4-aminopipendino-icarbonyl, 4-aminomethyl-pipendino-1-carbonyl, N-methyl- [ 2- (N- (morpholinocarbonyl) -N-methylamino) ethyl] -aminocarbonyl,

R ¹ and R ⁵ together with the nitrogen atom indolyl,

R ² , R ⁶ and R ^{7 are} hydrogen,

R ^{3 is} (C ₁ -C ₆ ) -alkyl, imidazolyl- (C 1 -C ₄ ) -alkyl,

R ^{4 is} (C ₅ -C ₈ ) -cycloalkyl (C 1 -C ₄ ) -alkyl,

R ^{5 is} phenyl- (C 1 -C 6) -alkyl, thienylMC-C 1 -alkyl, and

mean η 2-4

The invention further relates to a process for the preparation of compounds of the formula I which is characterized in that a fragment having a terminal carboxyl group or its reactive derivative is coupled with a corresponding fragment having a free amino group, optionally to protect further functional groups (a) temporarily introduced protecting group (s) cleaved and the compound thus obtained optionally converted into their physiologically acceptable salt

Fragments of a compound of the formula I having a terminal carboxyl group have the following formulas Vl and VII

A-OH

R ² R ³

AN-CH-C-OH _(V11)

Fragments of a compound of the formula I having a terminal amino group have the following formulas VIII to X.

R ⁶ R ⁵ OR ² R ³ OR ⁴

I ι Il I I U ι

HN-CH-CN-CH-C-HN-CH- (CHOH) -CH ₂ OH _(ν , _Μ)

R ² R ³ OR ⁴ II II HN-CH-C-HN-CH- (CHOH) _n -CH ₂ OH ₍ I _X)

R ⁴ -.

H ₂ N - CH - (CHOH) _n --CH ₂ OH _(X)

Methods which are suitable for the preparation of an amide bond, z. In Houben-Weyl, Methods of Organic Chemistry, Vol. 15/2; Bodanszky et al., Peptide Synthesis, 2nd Ed. (Wiley & Sons, New York 1976) or Gross, Meienhofer, The Peptides: Analysis, Synthesis, Biology (Academic Press, New York 1979). Preferably, the following methods are used:

Active ester method with N-hydroxy-succinimide, 1-hydroxybenzotriazole or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine as the alcohol component, coupling with a carbodiimide such as dicyclohexylcarbodiimide, with propanephosphonic anhydride or methylethylphosphinic anhydride and the mixture Anhydride method with pivaloyl chloride or ethyl chloroformate or isobutyl ester, or coupling with phosphonium reagents such as benzotriazole-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), or uronium reagents such as 2- ( 1 H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) or 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate ( Chem. Ber. 103 [1970] 788 and 2034, Z. Naturforsch. 21b [1966] 426; Angew. Chem. Int. Ed. 19 [1980] 133; US Patent 4,426,325).

 Fragments of the formula VI, provided they are

a) Formula II are synthesized according to the generally known methods for the preparation of amino acids;

b) Formula III are synthesized either starting from the corresponding α-amino acids, with their chiral center retained. Diazotization at -20 ° C to 50 ° C in digested mineral acids leads to a-bromocarboxylic acids or via the lactic acid to a-trifluoromethanesulfonyloxy carboxylic acids, which can be reacted with a nucleophile bearing R ¹ and R ⁷ ;

c) Formula IV are synthesized starting from the corresponding α-amino acids, their chiral center being obtained. Diazotization at -20 ⁰ C to 50 ⁰ C in dilute mineral acids leads to lactic acids, which can be reacted with an R 'carrying electrophile.

Fragments of formula VII are synthesized according to well-known methods for the production of amino acids and peptides.

Fragments of formula X are prepared from suitable carbohydrates via the corresponding protected γ-lactones.

First, reaction takes place with a C nucleophile such as a Grignard compound or an alkyl lithium compound, followed by aminoglycosidation and reductive ring opening with complex hydrides such as LiAlH ₄ or catalytic hydrogenation.

Alternatively, fragments of formula X may be prepared from the appropriate protected aralkylaminoglycosides.

Here, the aralkyl radical is expediently chosen so that a hydrogenolytic removal is possible before the amide coupling.

Reaction with a C nucleophile such as an alkyl lithium compound in a solvent inert to these nucleophiles, such as diethyl ether, tetrahydrofuran, tetrahydropyran, formaldehyde dimethyl acetal or 1,2-dimethoxy ethane, at a temperature between -30 ° C and the boiling point of the solvent, preferably between 0 ° C and the boiling point of the solvent is provided by the aralkyl derivative of the protected fragment of formula X. This can be released by catalytic hydrogenation with hydrogen or catalytic transfer hydrogenation with ammonium formate for amide coupling.

The pre and post operations required for the preparation of compounds of the formula I, such as introduction and removal of protective groups, are known from the literature and are described, for example, in US Pat. In T.W. Greene "Protective Groups in Organic Synthesis" (Johne Wiley & Sons, New York, 1981) Salts of compounds of the formula I having salt-forming groups are prepared in a manner known per se, for example by reacting a compound of the formula I with a basic group with a stoichiometric amount of a suitable acid or compounds of the formula I having an acidic group with a ♦

Stoichiometric amount of a suitable base reacts stereoisomer mixtures, especially mixtures of diastereomers, which may be obtained in the synthesis of compounds of formula I, can be separated in a conventional manner by fractional crystallization or by chromatography

The compounds of the formula I according to the invention have enzyme-inhibiting properties, in particular they inhibit aspartyl proteases, such as renin

Renin is secreted by the juxtaglomerular cells of the kidney into the bloodstream as a result of various stimuli (volume depletion, sodium deficiency, ß-receptor disruption). The angiotensinogen secreted from the liver cleaves the decapeptide angiotensin I which is converted by the angiotensin converting enzyme ( Angiotensin II plays an essential role in regulating blood pressure by directly increasing blood pressure through vascular constriction. In addition, it stimulates the secretion of aldosterone from the kidney, thus increasing the extracellular fluid volume by inhibiting sodium excretion inhibitors of the enzymatic activity of the renin cause a reduced production of angiotensin I, which results in a reduced formation of angiotensin II. The lowering of the concentration of this active peptide hormone is the direct cause of the Antihypertensive effects of renin inhibitors The efficacy of renin inhibitors can be tested by in vitro tests. The reduction of angiotensin I formation in various systems (human plasma, purified human renin) is measured

1 test principle

For example, human plasma containing both renin and angiotensinogen is incubated at 37 ° C with the compound to be tested. Angiotensinogen is released under the action of renin angiotensin I, which can then be measured by a commercial radioimmunoassay This angiotensin release is performed by Inhibited renin inhibitors

2 recovery of the plasma

The blood is collected by volunteers (ca 0.51 per person, Bluko-Abnahmegerat the Fa ASID Bonz and Sohn Unterschleißheim) and partially evacuated bottles under ice cooling collected The gain is prevented by addition of EDTA (final concentration 1OmM) After centrifugation (rotor HS4 [Sorvall repeat] 3 500 rpm, 0-4 ⁰ C, 15 min, if necessary) the plasma is carefully aboipettiert Fur and frozen in suitable portions at -30 ° C the test plasmas will only be of sufficiently high Reninaktivitat uses plasmas with lower Reninaktivitat be a Cold treatment (-4 "C, 3 days) activated (Prorenin -> Renin)

3 Carrying out the test

Angiotensin I is determined with the Renin Maia® kit (Serono Diagostics SA, Coinsins, Switzerland) Incubation of the plasma is carried out according to the instructions given there. A JJJpI plasma (thawed at 0-4 ⁰ C) 100μΙ phosphate buffer (pH7,4)

Addition of 10 ⁴ MRamipnlat ^ IPMSF solution 10μΙ 0.1% Genapol PFIC 12plDMS0bzw test preparation

The Testpraparate be ι a 10 ^"2 M in 100% dimethyl sulfoxide (DMSO) dissolved and diluted with water containing the incubation max 1% DMSO

The batches are mixed in ice and incubated for 1 hour in a water bath (37 ° C) from an additional batch without inhibitor without further incubation a total of 6 samples (100μΙ each) to determine the starting angiotensin I content of the plasma used withdrawn

The concentrations of the test preparations are chosen so that the range of 10-90 ⁰ C enzyme inhibition is covered (at least five concentrations) At the end of the incubation period, three 100 μΙ samples are frozen in pre-cooled Eppendorf vessels on dry ice from each approach and at approx. 25 ° C stored for angiotensin I determination (mean of three individual samples)

4 angiotensin I radioimmunoassay (RIA)

The instructions for use of the RIA kits (Renin Maia® kit, Serono Diagnostics SA, Coinsins, Switzerland) are followed exactly. The calibration curve covers the range from 0.2 to 25.0 ng angiotensin I per ml. The base angiotensin I content of the Plasma is subtracted from all measured values Plasma renin activity (PRA) is given as ng Ang l / ml χ hour. PRA values in the presence of the test substances are based on an approach without inhibitor (= 100%) and as% residual activity against the concentration ( M) of the Testpraparates (logarithmic scale), the IC ₅₀ value read the compounds of general formula I described in the present invention show in the in vitro test inhibitory effects at concentrations of about 10 ^"6 to 10" ¹⁰ moles / l

In detail, the following values were determined: TABLE 1

example ICsoIM] IC ₆₀ [M] No. human plasma renin purified human secretin 1 4.2-10 " ⁷ 1,2-10 " ⁷ 2 4.0 10 " ⁹ 4.0-10 " ⁹ 3 2.2x10 " ⁸ 1.2 x 10 " ⁸ 4 1.6 10 " ⁹ 2.4 · 10 " ⁹ 5 1.1 · 10 " ⁸ 1.4-10 " ⁸ 7 2.2 · 10 " ⁷ 3.0 · 10 " ⁷ 9 1.8-10 " ⁸ 1,2-10 " ⁸ 10 1.1 · 10 " ⁷ 5.0-10 " ⁸ 11 1.9 -10 " ⁶ 3.6x10 " ⁶ 12 > 10 " ⁶ 1.0-10 " ⁵

Renin inhibitors cause blood pressure reduction in salt-depleted animals. Since human renin is different from the renin of other species, primates such as rhesus monkeys are used for in vivo testing of renin inhibitors.

1st test principle

Primate renin and human renin are largely homologous in their sequence. Intravenous injection of furosemide stimulates endogenous renin release. Subsequently, the test compounds are administered and their effect on blood pressure and heart rate is measured.

2. Carrying out the test

6 rhesus monkeys were pretreated orally on 10 mg / kg · d furosemide on 6 consecutive days. On the 7th day, about 10 minutes before the start of the experiment, another 10 mg / kg Furosemide i. v. administered. Subsequently, the anesthesia with 20 mg / kg ketamine i.m. initiated and with 40 mg / kg pentobarbitone i.v. continued. A lateral branch of the femoral artery was dissected free and cannulated for blood pressure measurement by means of a blood pressure transducer (P23ID). Blood samples for determination of plasma renin activity were taken via a Braunüle in the saphenous vein.

The title compound of Example 2 shows the following result: 2 mg / kg i.d. (in 0.1 η citric acid 2 mg / ml)

t [min] blood pressure Pulse- Change PRA Modification [%] Modification [%] [%] 1 - 0.72 -1.16 3 - 8,21 -1.61 5 -11.53 -2.42 10 -11.82 -2.51 15 -12.68 -3.49 -20 20 -13.48 -1.97 30 -16.43 -1.61 -62 45 -12.82 +0.09 -53 60 -13.98 -0.09 -58 75 - 8,79 + 1.16 90 - 6.77 +3.04 -51 120 -47

The compounds of the present invention are effective in a dose range of about 0.1-5 mg / kg i.v., when administered intraduonally by gastroscope in the dose range of about 0.5-50 mg / kg.

The compounds of the general formula I described in the present invention can be used as antihypertensives as well as for the treatment of heart failure.

The invention further relates to the use of compounds of the formula I for the preparation of medicaments for hypertension therapy and the treatment of congestive heart failure.

Pharmaceutical preparations contain an effective amount of the active ingredient of formula I together with an organic pharmaceutically acceptable carrier.

The application may be intranasal, intravenous, subcutaneous, peroral or intraduodenal. The dosage of the active ingredient depends on the species of warm-blooded animals, body weight, age and method of administration.

The pharmaceutical compositions of the present invention are prepared by conventional solution, mixing, granulation or coating techniques.

For oral use, the active compounds are mixed with the conventional additives such as carriers, stabilizers or inert diluents and brought by conventional methods in suitable dosage forms, such as tablets, dragees, capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. As inert carrier can z. Gum arabic, magnesia, magnesium carbonates, potassium phosphate, lactose, glucose, magnesium stearate fumarate or starch, especially corn starch. The preparation can be carried out both as a dry and as a wet granules. As oily carriers or solvents come

For example, vegetable or animal oils, such as sunflower oil and cod liver oil. *

For subcutaneous or intravenous administration, the active compounds or their physiologically acceptable salts, if desired with the conventional substances such as solubilizers, emulsifiers or other auxiliaries in solutions, suspensions or emulsions. As a solvent come z. B. in question: water, physiological saline or alcohols, eg. As ethanol, propanediol or glycerol, besides sugar solutions such as glucose or Mannitlösunge, or a mixture of the various solvents mentioned.

List of abbreviations used:

Ac acetyl Boc tert-butoxycarbonyl BOP Benzotriazol-1-yl-oxy-tris- (dimethylamino) phosphonium BuLi n-butyllithium DC TLC DCC dicyclohexylcarbodiimide DCI Desorption Chemical Ionization DIP diisopropylether DNP 2,4-dinitrophenyl DME 1,2-dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide EE ethyl acetate El Electron Impact etoc Ethoxy carbonyl FAB Fast atom bombardment H hexane Hep n-heptane HOBt 1-hydroxybenzotriazole Iva isovaleryl M molecular peak MeOH methanol MS mass spectrum MTB Methyl tert-butyl ether NEM N-ethylmorpholine Nva norvaline Never norleucine PPA n-propanephosphonic R. T. room temperature Mp. melting point Sdpxx Boiling point at xx Torr TBTU 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyl uronium Thi 2-thienyl alanine THF tetrahydrofuran Z benzyloxycarbonyl

Short list of selected C terms

HN

HN

ohh

(D) -Manno-pentol (XX)

(D) -Manno-Pento1

HN

Ό4-

(L) -glomo-pentol (XX)

⁰ X ⁶

(L) -Gulo-Pentol

ce

ce ce

(D) -TaIo-pentol (XX)

ce

OH

CH C (D) -Talo-pentol

\ __ Ace oh

OH CH (L) -allo-pentol

The other abbreviations used for amino acids correspond to the usual in peptide chemistry three-letter code as ore. In Eur. J. Biochem. 38, 9-37 (1984). Unless otherwise stated, they are always L-configuration amino acids. ~~~

The following examples serve to illustrate the present invention without being limited thereto.

example 1

Iva-Phe-Nva - [(L) -Gulo-Pentol]

200 mg of Iva-Phe-Nva - [(L) -glomo-pentol (XX) J are dissolved in 10 ml of 85% aqueous trifluoroacetic acid and left for 2.5 hours at R.T.

touched. The solvents will be i.Vak. removed and on silica gel with CH ₂ Cl ₂ / MeOH 10: 1 chromatographies. This gives 140 mg of the title compound as a colorless amorphous powder.

(L) -AlIo-pentol (XX)

R, (Ch ₂ Cl ₂ / MeOH 10: 1) = 0.26

MS (FAB + LiJ): 614 (M + Li)

a) Iva-Phe-Nva - [(L) -glomo-pentol (XX)]

578 mg Iva-Phe-Nva-OH, N-ethylpiperidine and 229 μΙ 230μΙ triethylamine are dissolved in 25 ml of anhydrous CH ₂ CI ₂ and treated at -15 ° C with pivaloyl chloride 204μΙ. Stirred for 10 minutes at RT, cooled to -10 ⁰ C and treated with a solution of 599 mg of H- (L) -glulopentol (XX) in 10 ml of anhydrous CH ₂ Cl ₂ . Stirred at RT for 20 hours, the solvent i.Vak. removed and taken up in 150 ml of EE. Wash three times with 50 ml of KH ₂ PO ₄ solution each time and three times with 50 ml of NaHCO ₃ solution each time, the EA phase dried over K ₂ CO ₃ and the solvent i.Vak. away. Chromatography on silica gel with DIP / MTB 1: 1 yields 200 mg of the title compound as a colorless amorphous powder.

R, (MTB / DIP1: 1) = 0.10

MS (FAB): 688 (M + 1)

b) [H- (L) -glomo-pentol (XX)]

740 mg of [N-benzyl- (L) -glomo-pentol (XX)] are dissolved in 20 ml of anhydrous MeOH and admixed under argon with 150 mg of Pd / C (10%) and 1.1 g of HCO ₂ NH ₄ . The mixture is refluxed for 1.5 hours, filtered from the catalyst and the solvent i.Vak. away. 600 mg of the title compound are obtained as a pale yellow oil, which is used further without purification.

R, (MTB) = 0.05

c) [N-benzyl- (U-gulo-pento1 (XX)]

880 mg of 2-benzylamino, 2-cyclohexylmethyl, (3,4-isopropylidene) -3 (S), 4 (S) -dihydroxy, 5- (R) - [(1,2-isopropylidene) -1 (S), 2 -dihydroxyethylj-tetrahydrofuran are dissolved in 25 ml of anhydrous THF and mixed with 188 mg LiAlH ₄ . Stirred for 20 hours at RT, mixed with 50ml NaHCO ₃ solution and extracted three times with 100ml EE. About Na ₂ SO ₄ is dried and the solvent i.Vak. away. 690 mg of the title compound are obtained as a colorless oil.

R, (MTB / Hep 1: 5) = 0.31

MS (DCI): 448 (M + 1)

2-hydroxyethyl] -tetrahydrofuran

4.65 g of Z-cyclohexylmethyl.O.-isopropylideneK.SiSi ^ tSJ-trihydroxy.S-iRJ-Ki ^ -isopropylideni-KSl ^ -dihydroxyethyl] -tetrahydrofuran and 5.7 ml of benzylamine are dissolved in 150 ml of anhydrous toluene and - in 20 ° C with 91 ΟμΙ TiCI ₄ added. The mixture is stirred for 3 hours at RT, mixed with 100 ml of saturated aqueous Na ₂ CO ₃ solution, diluted with 300 ml of EA and washed with KH ₂ PO ₄ solution until pH 5 is reached. The organic phase is dried with Na ₂ SO ₄ and the solvent i.Vak. away. Chromatography on silica gel with MTB / Hep 1: 5 provides 1.0 g of the title compound as a colorless oil.

R _f (MTB / Hep 1: 5) = 0.24

MS (DCI): 446 (M + 1)

e) 2-Cyclohexylmethyl, (3,4-isopropylidene) -2,3 (S) .4 (S) -trihydroxy, 5- (R) - [(1,2-S-isopropylidene) -1 (S), 2-dihydroxyethyl] -tetrahydrofuran

5.16 g (2,3-, ö ^ -Diisopropylidenl-L-Gulonsaure-y-lactone is suspended in 300 ml of diethyl ether and added dropwise under argon at reflux temperature 1.1 equivalents of cyclohexylmethyl-magnesium bromide in 50 ml of diethyl ether over 2 hours then being treated with 100 ml of saturated aqueous NaHCO ₃ solution, extracted twice with 100 ml of EA, the organic phase dried over Na ₂ SO ₄ and the solvent ν Vak removed to give 4.9 g of the title compound as a colorless oil, slightly contaminated with bisadduct

R, (DIP) = 0.40 MS (DCI). 357 (M + 1)

f) (2,3-, 5,6-diisopropylidene) L-guilonic acid-y-lactone

42 g of L-gulonic acid γ lactone and 100 mg of p-toluenesulfonic acid are refluxed in 300 ml of 2,2-dimethoxypropane for 5 hours. After 1 hour, a clear solution is obtained. The volatile constituents are removed in vacuo and recrystallised from DIP. 45 g of the title compound are obtained as colorless crystals, m.p. 144 ° C

R ₁ (DIP) = 0.12 MS (DCI). 259 (M + 1)

Example 2 (2 (S) -benzyl, 3-t-butylsulfonyl) propionyl-His - [(D) -manno-pentol]

960 mg (2 (S) -benzyl, 3-t-butylsulfonyl) propionyl-His - [(D) -manno-pentol (XX)] are dissolved with 722 mg of ρ-toluene-sulfonic acid in 100 ml of methanol and 2 drops of water are added Hours at RT, then with NaHC0 ₃ solution to pH = 7, the methanol removed in vacuo, extracted three times with 100 ml of MTB and dried over Na ₂ SO ₄ The solvent is removed in vacuo with the residue on silica gel with acetone / water 10.1 chromatographed 120 mg of the title compound are obtained as white crystals

Mp 100-110 ° C (decomposition)

R, (acetone / water 10 1) = 0.46 MS (FAB) 681 (M + 1)

a) (2 (S) -benzyl, 3-t-butylsulfonyl) propionyl-His - [(D) -manno-pentol (XX)]

850mg of (2 (S) -benzyl, 3-t-butylsulfonyl) -propionyl-His (DNP) - [(D) -manno-pentol (XX)] and 0.94ml of thiophenol are dissolved in 15ml of acetonitrile and stirred at RT for 2 hours Solvent is removed in vacuo, the residue is digested with DIP and the residue on silica gel with MeOH / MeOH 5.1 Chromatography 400mg of the title compound are obtained as pale yellow crystals

M.p. = 160 ⁰ C (decomposition)

R, (toluene / MeOH 5 1) = 0.39 MS (FAB) 761 (M + 1)

b) (2 (S) -benzyl, 3-t-butylsulfonyl) propionyl-His (DNP) - [(D) -manno-pentol (XX)]

1.3 g (2 (S) -benzyl, 3-t-butylsulfonyl) -propionyl-His (DNP) -OH, 0.31 ml N-ethylpiperidine and 0.31 ml triethylamine are dissolved in 30 ml CH ₂ Cl ₂ and at -15 0.28 ml pivaloyl chloride added dropwise under argon for 10 minutes, stirred at RT, cooled to -10 ⁰ C and a solution of 400mg H- (D) -Manno-PentoKXX) in 5ml CH ₂ Cl _{2 was} added dropwise 18 hours at RTgerger , diluted with 100 ml of MTB and extracted once each with 100 ml of 0.66 M KH ₂ PO ₄ and 100 ml of saturated NaHC0 ₃ solution over Na ₂ SO ₄ is dried and the solvent is removed in vacuo to give 850 mg of the title compound as an amorphous powder, which is further reacted without purification

Rf (EE / MeOH 10 1) = 0.53 MS (FAB). 927 (M + 1)

c) (2 (S) -benzyl, 3-t-butylsulfonyl) propionyl-His (DNP) -OH

10.7 g of (2 (S) -benzyl, 3-t-benzylsulfonyl) propionic acid N-hydroxy-succinimide ester and 11.3 g of H-HiS (DNP) -OH hydrochloride are dissolved in 500 ml of THF / ethanol 1 L and treated with 470 ml saturated aqueous NaHCO ₃ solution is stirred for 5 hours, the organic solvents are removed in vacuo and adjusted to pH = 1-2 with NaHSO ₄ solution, extracted three times with 500 ml of EA each, dried over Na ₂ SO ₄ and The solvent is removed in vacuo. It is taken up in 350 ml acetone / EA 1 l and precipitated with diethyl ether in the ultrasound bath. 12.5 g of the title compound are obtained as a yellow powder

R, (MeOH / CH ₂ Cl ₂ 1 5) = 0.11 MS (FAB) 588 (M + 1)

d) (2 (S) -Benzyl, 3-t-butylsulfonyl) propionic acid N-hydroxy-succinimide ester

8.0 g (2 (S) benzyl, 3 t-butylsulfonyl) -propionic acid (J Med Chem 31.1839 [1988]) una 3.3 g of N-hydroxysuccinimide are dissolved in 200 ml of 1,2-dimethoxyethane and at 0 ⁰ C, a solution of 5.8 g of DCC in 50 ml of 1,2-dimethoxyethane is allowed to stand for 18 hours at 6 ° C, at 20 ⁰ C, the solvent is removed in vacuo and taken up in 100 ml acetonitrile From urea is filtered off and the solvent at 20 ° C in vacuo Removes 10.7 g of the title compound as a colorless oil, which is reacted further without purification

e) H- (D) -manno-pentol (XX)

The compound is prepared analogously to Example 1 b from N-benzyl- (D) -Manno-PentoKXX)]

f) [N-benzyl- (D) -manno-pentol (XX) l

8,8g2-benzylamino, (3,4-isopropylidene) -3 (S), 4 (S) -dihydroxy, 5 (R) - [(1,2-isopropylidene) -1 (R), 2-dihydroxyethyl] - tetrahydrofuran and 7.1 ml of cyclohexylmethyl bromide are dissolved in 250 ml of THF and reacted with 0.7 g of lithium wire (3.2 mm 0, about 1% Na) under argon in an ultrasonic bath at RT. After 6 hours, the solvent is removed in vacuo, with 500ml 0.67M KH ₂ P0 ₄ solution

taken and extracted three times with 300ml MTB. About Na ₂ SO ₄ is dried, the solvent was removed in vacuo and the residue on silica gel with MTB / Hep 1: 1 chromatographed. This gives 3.3 g of the title compound as a colorless oil.

R, (MTB / Hep 1: 1) = 0.39 MS (DCI): 448 (M + 1)

g) 2-Benzylamino, (3,4-isopropylidene) -3 (S), 4 (S) -dihydroxy, 5 (R) - [(1,2-isopropylidene) -1 (R), 2-dihydroxyethyl] - tetrahydrofuran 31.5 g of 2,3-, 5,6-diisopropylidene-D-mannofuranoside and 20.0 ml of benzylamine are heated in 250 ml of toluene on a water separator. After 7 hours, the water separator is replaced by a Soxhlet extruder filled with 4A molecular sieve and refluxed for a further 16 hours. The solvent is then removed in vacuo, taken up with 500 ml of EA and washed three times with 250 ml of 0.67 M KH ₂ PO ₄ solution. About Na ₂ SO ₄ is dried and the solvent is removed in vacuo. This gives 41.5 g of the white, crystalline title compound.

R, (toluene / EE2: 1) = 0.29 MS (DCI): 350 (M + 1)

Alternatively, syntheses

h) (2 (S) -benzyl, 3-t-butyl-isulfonyl) -propionyl-His - [(D) -manno-pentol (XX)] (2a)) 785 mg (2 (S) -benzyl, 3-t butylsulfonyl) propionic acid and 382μΙ triethylamine are dissolved in 20 ml of DMF and added at RT 1.1g 0-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate and stirred for 5 min at RT. Then a solution of 1.6 g of H-His - [(D) -manno-pentol (XX)] in 15 ml of DMF is added dropwise and stirred at RT for 20 h. The solvent will be i.Vak. removed, taken up with 500 ml of EA and washed three times with 100 ml of Na ₂ CO 3 solution. About Na ₂ SO ₄ is dried, the solvent i.Vak.

removed and chromatographed on silica gel with EA / MeOH 5: 1. This gives 1.1 g of the title compound of Example 2a).

i) H-His - [(D) -manno-pentol (XX)]

3 g of Z-His - [(D) -manno-pentol (XX)] and 3 g of ammonium formate are dissolved in 50 ml of methanol, 2 g of Pd / C (10%) are added and the mixture is stirred at RT under argon for 5 h. Then the catalyst is filtered off, the solvent i. Vak. removed, taken up in 500 ml of EA and washed three times with 50 ml of Na ₂ CO ₃ solution. About Na ₂ SO ₄ is dried and the solvent i.Vak. away. This gives 1.8 g of the title compound as a foam, which is stored under argon and reacted as quickly as possible.

k) Z-His - [(D) -manno-pentol (XX)]

500 mg of H- (D) -manno-pentol (XX) and 405 mg of Z-His-OH are dissolved under argon in 20 ml of DMF, followed by the addition of 303 μl of diphenylphosphoryl azide at 0 ° C. followed by 208 μl of diethylamino-2-propanol. Stirred for 2h at 0 ⁰ C and then 4d at RT. The reaction mixture is diluted with 200 ml of EA and washed once each with 100 ml of 0.7M KH ₂ PO ₄ solution and 100 ml of saturated NaHCO ₃ solution. About Na ₂ SO ₄ is dried and chromatographed on silica gel with EA / MeOH 10: 1. This gives 530 mg of the title compound, colorless foam.

R, (EE / MeOH 10: 1) = 0.17 MS (FAB): 629 (M + 1)

I) H- (D) -manno-pentol (XX)

410 mg of N-benzhydryl- (D) -manno-pentoKXX) and 490 mg of ammonium formate are dissolved in 15 ml of anhydrous methanol, admixed with 82 mg of Pd / C (10%) and stirred at RT under argon for 6 h. The solvent will be i.Vak. removed, taken up in 100 ml of EA and washed three times with 50 ml of Na ₂ CO ₃ solution. The organic phase is dried with Na ₂ SO ₄ and the solvent i. Vak. away. After gentle vacuum drying to remove the diphenylmethane, 275 mg of the title compound of Example 2e) are obtained.

m) N-Benzhydryl- (D) -Manno-PentoKXX)

1.8 g of 2-benzhydrylamino, (3,4-isopropylidene) -3 (S), 4 (S) -dihydroxy, 5 (R) - [1,2-isopropylidene] -1 (R), 2-dihydroxyethyl] - tetrahydrofuran and 1,2ml Cyclohexylmethylbromid be in 40ml Formaldehyddimethylaceta! (distilled from K / Na alloy) and reacted with 115 mg of lithium wire (3.2 mm 0, about 1% Na) under argon in an ultrasonic bath at 20-40 ° C 3.5 h. Then again 115 mg lithium wire and 1.2 ml Cyclohexylmethylbromid is added and reacted for 1 h at 40-60 ° C. The reaction mixture is poured into 200 ml of NaHCO ₃ solution and extracted three times with 100 ml of MTB. About Na ₂ SO ₄ is dried, the solvent i. Vak. removed and chromatographed on silica gel with DIP / toluene 1: 3. 1.1 g of the title compound are obtained as a colorless oil.

R, (DIP / toluene 1: 3) = 0.28 MS (DCI): 524 (M + 1)

n) 2-Benzhydrylamino, (3,4-isopropylidene) -3 (S), 4 (S) -dihydroxy, 5 (R) - [1,2-isopropylidene] -1 (R), 2-diyhdroxy-ethyl] -tetrahydrofuran

10 g of D (+ (- mannose and about 10 mg of p-toluenesulfonic acid are suspended in 40 ml of 2,2-dimethoxypropane and stirred for 1 h at 40 ° C. A clear solution is obtained 10 ml of benzhydrylamine are added and the mixture is refluxed for 24 h 10 ml of 2,2-dimethoxypropane and 2 ml of benzhydrylamine are added and the mixture is refluxed for a further 18 hours. Volatiles are removed in vacuo, taken up in 100 ml of EA and washed three times with 100 ml of NaHCO ₃ solution, dried over Na ₂ SO ₄ , the solvent and then chromatographed on silica gel with DIP / toluene 1: 5, giving 17 g of the title compound as pale yellow crystals, mp: 82-84 ° C.

R, (DIP / toluene 1: 3) = 0.41 MS (DCI): 426 (M + 1)

Analogously, the title compound of Example 2g) can be prepared in a one-pot process from D (-t -! - mannose.

Example 3

cis-4-aminocyclohexylcarbonyl-Phe-His - [(D) -Manno-Pentoll

180 mg (N-tert-butoxycarbonyl-cis-4-amino-cyclohexylcarbonyl) -Phe-His-1 (D) -manno-pentol (XX)] are dissolved in 5 ml of CH ₂ Cl ₂

and added at 0 ⁰ C 5 ml of trifluoroacetic acid. Stirred for 24 hours at RT, 100 ml of saturated Na ₂ CO ₃ solution was added and 3 χ

extracted with 100ml EE. About Na ₂ SO ₄ is dried, the solvent was removed in vacuo and the residue on silica gel with acetone / H ₂ O / conc. NH ₃ 100: 10: 5 chromatographed. 24 mg of the toe compound are obtained as a colorless powder.

R ₁ (ACeUnnZH ₂ CVkOnZ-NH ₃ lOOnO ^) = 0.12 MS (FAB): 687 (M + 1)

a) (N-tert-butoxycarbonyl-cis-4-aminocyclohexylcarbonyl-Phe-His - [(D) -IVIanno-pentol (XX)]

The title compound is prepared analogously to Example 2 a), 2 b) from (N-tert-butoxycarbonyl-cis-4-aminocyclohexylcarbonyl) -Phe-His (DNP) -OH and H (D) -manno-PentoKXX).

R, (EE / MeOH 5: 1) = 0.43 MS (FAB): 868 (M + 1)

b) (N-tert-butoxycarbonyl-cis-4-aminocyclohexylcarbonyl) -Phe-His (DNP) -OH

The title compound is prepared analogously to Example 2 c), 2d) from (N-tert-butoxycarbonyl-cis-4-aminocyclohexylcarbonyl) -Phe-OH and H-HiS (DNP) -OH.

R, (EE / MeOH3: 1) = 0.20 MS (FAB): 694 (M + 1)

c) N- (N-tert-butoxycarbonyl-cis-4-aminocyclohexylcarbonyl) -L-phenylalanine

5.5 g of N- (N-tert-butoxycarbonyl-cis-4-aminocyclohexylcarbonyl) -L-phenylalanine benzyl ester are hydrogenated in 230 ml of ethanol over 1 g of Pd / carbon under atmospheric pressure. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off. After recrystallization from n-heptane / ethyl acetate, 4.1 g of colorless product are obtained.

Melting point 160-161 ⁰ C. (decomposition) MS (DSI): 391 (M + 1)

d) N- (N-tert-butoxycarbonyl-cis-4-aminocyclohexylcarbonyl) -L-phenylalanine benzyl ester

6.0 g of N-tert-butoxycarbonyl-cis-1,4-aminocyclohexanecarboxylic acid and 6.3 g of L-phenylalanine benzyl ester were dissolved in 75 ml of DMF and mixed with 24 ml of n-PPA and 15.7 ml of NEM at 0 ° C and overnight reacted at RT. The solution is diluted with CH ₂ CI ₂ and each washed with semisaturated NaHC03 solution, 10% citric acid and water, dried over MgSO ₄ and concentrated in vacuo. Flash chromatography gave 5.7 g of pure product.

Ia] g °: -14.6 ° (c = 1.1 in CH ₃ OH)

Example 4

2 (S) - {N-methyl-N- (2- [N- (morpholinocarbonyl) -N-methylamino] ethyl> -3-phenylpropionyl} -aminocarbonyloxy-His - [(D) -Manno-pentol]

The title compound is prepared analogously to Example 2 a), 2b), 2c) and 2d) from 2 (S) - {N-methyl-N- (2- [N- (morpholinocarbonyl) -N-methylamino] ethyl) aminocarbonyloxy} - Prepared 3-phenylpropionic acid.

R, (EE / MeOH 1: 1) = 0.22 MS (FAB): 790 (M + 1)

a) 2 (S) - {N-methyl-N- (2- [N- (morpholinocarbonyl) -N-methylamino] ethyl) -aminocarbonyloxy} -3-phenylpropionic acid 840g 2 (S) - {N-methyl-N- (2- [N- (morpholinocarbonyl) -N-methylamino] ethyl) -aminocarbonyloxy} -3-phenylpropionäureethylester are dissolved in 100 ml of methanol and treated with 20 ml of 0.1 N sodium hydroxide solution. After 16 hours at RT, the methanol is distilled off and the residue is adjusted to pH 1-2 with hydrochloric acid. Extraction 3 times with EA gives, after drying with Na ₂ SO ₄ and concentration, the title compound (24%), which is used without further purification for the next reactions.

MS (DCI): 394 (M + 1)

b) 2 (S) - {N-Methyl-N- (2- [N- (morpholinocarbonyl) -N-methylamino] ethyl) -aminocarbonyloxy} -3-phenylpropionic acid ethyl ester

To 2g di (4-benzotriazolyl) carbonate and 0,23ml pyridine in CH ₂ CI ₂ (20 ml) are added dropwise at RT0,9g Phenylmilchsäureethylester in CH ₂ Cl ₂ (10ml). After 6 hours, 900 mg of N-methyl-N, -IN-morpholine-carbonyl-N-methylaminol-ethylamine in 10 ml of CH ₂ Cl _{2 are} added dropwise. After 16 hours, 100 ml of ethyl acetate are added and then washed twice with saturated Na ₂ CO ₃ solution, twice with saturated NaHSO ₄ and 1 χ with saturated NaCl solution. After drying with Na ₂ SO ₄ and concentration, a yellow oil is obtained which, after chromatography on SiO ₂ (eluant EE), gives the title compound.

R, (EE) = 0.3 MS (DCI): 422 (M + 1)

c) N-methyl-N-2- [N- (morpholinocarbonyl) -N-methylamino] -ethylamine

2.1 g of Boc-N-methyl-N, -lN-tmorpholinocarbonyl-N-methylaminolethylamine are stirred in 75 ml of ~ 6N solution of HCl in DME at RT for 3 hours. After concentration 50 ml of saturated Na ₂ CO ₃ solution are added and extracted three times mrt EE. After drying and concentration, the title compound is obtained, which is used without further purification for the further reactions.

d) Boc-N-methyl-N-Z-tn-fmorpholinocarbonylO-N-methylaminolethylamine

The title compound is obtained analogously to Example 4 b) from 2.1 g of morpholine, 10 g of di- (I-benzotriazoly-dodecarbonate, 2 ml of pyridine and 4.7 g of Boc-N-methyl-2- (methylamino) ethylamine.

R, (EE) = 0.25 MS (OCI): 302 (M + 1)

e) Boc-N-methyl-1-methylaminoethylamine

12.5 g of di-t-butyl dicarbonate in 25 ml of CH ₂ Cl _{2 are} added dropwise at 10 ° C. to N, N'-dimethylethylenediamine at 5 ° C. After 4 hours at RT, the excess diamine is distilled off. The residue is taken up in EA (100 ml) and washed with saturated Na ₂ CO ₃ solution and saturated NaCl solution. After drying with Na ₂ SO ₄ and concentration, the title compound is obtained, which is used crude for further reactions.

MS (DCI): 189 (M + 1)

Example 5 S-tA-amino-i-piperidinyl-carbonyl-O-ZfRl-benzylpropionyl-His-HDJ-manno-pentol] The title compound is prepared analogously to Example 3 from 3- [4- (tert-butoxycarbonyl) amino-1-piperidinylcarbonyl ) -2 (R) -benzylpropionic acid.

R, (AcCtOnZH ₂ OZkOnZ, NH ₃ 100: 10: 5) = 0.15 MS (FAB): 687 (M + 1)

a) S - tert-Butoxycarbonylamino-i-piperidinylcarbonyl-1RI-benzylpropionic acid

1.3 g of 3- [4- (tert-butoxycarbonyl) amino-1-piperidinylcarbonylj-2 (R) -benzylpropionic acid benzyl ester are hydrogenated in 60 ml of EtOH with 200 mg of PdZC for 1 hour at RT. After filtration and removal of the solvent in vacuo, the title compound crystallized from cold diethyl ether.

Schmp.:135-136°C

Rf (CH ₂ Cl ₂ Z MeOH 9: 1) = 0.30 MS (DCI): 391 (M + 1)

b) S-K-tert-Butoxycarbonyl-l-amino-i-piperidinyl-carbonyl-1-yl-benzyl-propionic acid benzyl ester

1, Og 2 (R) - (carboxymethyl) -3-phenyl-propionic acid benzyl ester (J. Med. Chem. 31 2277 [1988]) are dissolved in 50 ml of CH ₂ Cl ₂ at 0 ° C. with 0.31 ml of oxalyl chloride and 1 ml of DME stirred for 1 hour. The solvent is removed in vacuo, taken up in 25 ml of CH ₂ QA ₂ , adjusted to pH = 7 with 2 drops of triethylamine and to this solution 0.71 g of 4- (tert-butoxycarbonyl) -amino-piperidine and 0.47 ml of triethylamine in 50 ml of CH ₂ Cl ₂ , stirred for 3 hours at 0 ° C, the solvent was taken up in vacuo removed 50 ml of EA and washed once each with 50 ml of 2 N HCl and saturated NaHCO ₃ solution. The mixture is dried over MgSO ₄ , the solvent is removed in vacuo and 1.3 g of the title compound are obtained as a colorless oil.

R, (CH ₂ Cl ₂ ZMeOH 9: 1) = 0.50 MS (DCI): 479 (M + H)

c) 4- (tert-butoxycarbonyl) amino-piperidine

10.0 g 1 -BenzyM-Ktert.-butoxycarbonyDaminoI-piperidine are dissolved in 60 ml of ethanol, 9: 1 with 1 g of PdZC at RT for 1 hour

1 bar pressure hydrogenated. The catalyst is filtered off, the solvent is removed in vacuo (residues of glacial acetic acid are distilled off azeotropically with toluene) and taken up in 100 ml of EA. The mixture is then washed once each with 100 ml of saturated NaHCO ₃ solution and saturated NaCl solution, dried over MgSO 4 and the solvent is removed in vacuo. The residue is recrystallized from EA, giving 5.5 g of the title compound as white crystals.

M .: 159-161 ⁰ C

R _f (CH ₂ Cl ₂ ZMeOH 9: 1) = 0.11 MS (DCI): 201 (M + 1)

d) 1-Benzyl-4 - [(tert-butoxycarbonyl) amino] -piperidine

10.0 g of 4-amino-N-benzylpiperidine are dissolved in 100 ml CH ₂ CI ₂ and treated with di-tert-butyl dicarbonate 11.5 g, the solution

Stirred for 2 hours at RT and allowed to stand overnight. The solvent is removed in vacuo and recrystallized from EA. This gives 12.9 g of the title compound as white crystals.

M.p .: 123 ° C

R ₍ (CH ₂ Cl ₂ / MeOH 8: 1) = 0.23 MS (DCI): 291 (M + 1)

Example 6

2 (S) - (4-Amino-1-piperidinocarbonyloxy) -3-phenylpropionyl-His - [(D) -manno-pentol] The title compound is prepared analogously to Example 3 from 2 (S) - [4- (tert-butoxycarbonyl ) amino-1-piperidinocarbonyloxyl-3-phenylpropionic acid.

R, (acetoneZH ₂ OZ conc NH ₃ 100: 10: 5) = 0.15 MS (FAB): 689 (M + 1)

a) 2 (S) - [4- (tert-Butoxycarbonyl) amino-1-piperidinocarbonyloxy] -3-phenylpropionic acid

1.8 g of ethyl (2 (S) - [4-tert-butoxycarbonyl) amino-1-piperidinocarbonyloxy) -3-phenylpropionate and 5.1 ml of 1 N NaOH are dissolved in 30 ml of ethanol and stirred at RT for 18 hours. It is then diluted with 50 ml H ₂ O. Ethanol in vacuo and adjusted to pH = 1-2 with NaHSO ₄ solution. It is extracted three times with 100 ml of EA, dried over Na ₂ SO ₄ and the solvent is removed in vacuo. The title compound, which crystallized from ether-zn-heptane, gives 1.0 g of white crystals.

M .: 100-101 ⁰ C

R f (CH ₂ Cl ₂ Z MeOH) = 0.29 MS (DCI): 393 (M + 1)

b) 2 (s) - [4- (tert-Butoxycarbonyl) amino-1-piperidinocarbonyloxy] -3-phenylpropionic acid ethyl ester

825 mg of ethyl phenylmethylate and 1.8 g of di- (I-benzotriazoly-O-carbonate (70%) are dissolved in 40 ml of CH ₂ Cl ₂ 386μΙ _¥

Ethyldiisopropylamin added and stirred at RT18 hours. Then 850 mg of 4- (tert-butoxycarbonyl) aminopiperidine

(Example 5c)), dissolved in 10 ml of CH ₂ Cl ₂ , added dropwise and added a further 386μΙ ethyldiisopropylamine. Stirring is continued for 2 hours at RT, the solvent is removed under reduced pressure and taken up in 100 ml of MTB. With 100 ml Na ₂ CO ₃ solution and 100 ml NaHSO ₄ solution is washed, dried over Na ₂ SO ₄ and the solvent removed in vacuo. 1.8 g of the title compound are obtained as a colorless oil, which is used further without purification.

R, (Hep / EE 2: 1) = 0.2 MS (DCI): 421 (M + 1)

Example 7 2 (S) - (4-Aminomethyl-1-piperidinocarbonyloxy) -3-phenylpropionyl-His - [(D) -manno-pentol] The title compound is synthesized analogously to Example 6.

R, (acetone / H ₂ O / conc NH ₃ 100: 10: 5) = 0.15 MS (FAB): 703 (M + 1)

Example 8

(3-t-Butylsulfonyl, 2-thienylmethyl) propionyl-His - [(D) -manno-pentol] The title compound is synthesized analogously to Example 2.

R, (acetone / water 10: 1) = 50 MS (FAB): 687 (M + 1)

Example 9 (2 (S) -benzyl, 3-t-butylsulfonyl) propionyl-His-4 (S) - (5-cyclohexyl-1, 3-trihydroxy) -pentylamide 240mg (2 (S) -benzyl, 3 t-butylsulfonyl) propionyl His (DNP) -OH is dissolved with 69 mg HOBt, 93 mg DCC and 0.3 ml NEM in 8 ml DMF (absolute) and cooled to 0 ° C. This is followed by the addition of the described under 9 a) solution of 4 (S) - (5-cyclohexyl-1,2,3-trihydroxy) pentylamine. After warming, the solution remains at RT for 48 hours. The reaction solution is treated with 0.5 ml of H ₂ O, then filtered off from the resulting dicyclohexylurea and the filtrate taken up in 25 ml of EA. This solution is washed with 10% NaHCO ₃ solution, water and saturated NaCl solution, filtered through cotton wool and concentrated in vacuo. This oily crude product thus obtained is purified over silica gel with CH ₂ Cl ₂ / CH ₃ OH 20: 1 chromatographies. The product with an Rf of 0.5 (CH ₂ Cl ₂ ZCH ₃ OH 9: 1 on silica gel) is obtained in a yield of 60 mg as a glassy solid.

MS (FAB): 787 (M + 1)

The product is dissolved in 5 ml of CH ₂ Cl ₂ (absolute) and stirred at RT with 0.2 ml of thiophenol for 4 hours at RT. After filtering off the solvent in vacuo, the crude mixture with CH ₂ Cl ₂ Z ¹ CH ₃ OH 20: 1 is chromatographed on silica gel. 16mg of the title compound are obtained.

R, (CH ₂ Cl ₂ / MeOH 9: 1) = 0.25 MS (FAB): 621 (M + 1)

a) 4 (S) - (5-Cyclohexyl-1,2,3-trihydroxy) -pentylamine

130 mg (2RS, 3RS, 4S) -4-tert-butoxycarbonylamino-5-cyclohexyl-1,2,3-trihydroxypentane (Example 9b) are dissolved in 2 ml of DME and saturated with 4 ml. HCI / DME solution and 30 min. stirred at 0 ⁰ C. After warming to RT, the solution is concentrated in vacuo and concentrated three times in each case after addition of toluene (absolute). This oil thus obtained is used immediately in the subsequent reaction step as a solution in DMF.

b) (2RS, 3RS, 4S) -4-tert-butoxycarbonylamino-5-cyclohexyl-1,2-trihydroxypentane

293 mg of the pentenol obtained in Example 9c) are dissolved in 10 ml of THF (absolute) together with 240 mg of trimethylamine-N-oxide and admixed with 11 mg of osmium tetroxide. The solution turns green-brown after a few minutes and is stirred overnight at RT. The solution is mixed with 10% NaHSO ₃ solution, stirred for 30 minutes, then concentrated in vacuo, taken up with 50 ml of ethyl acetate and separated from the aqueous phase. The organic phase is dried with 1 N HCl, 10% Na ₂ SO ₄ and concentrated in vacuo. There remains an amorphous solid of 140mg.

MS (DCI): 318 (M + 1)

c) 4S-tert-butoxycarbonylamino-5-cyclohexyl-cis-2-pentenol

In 20 ml of absolute methylene chloride, 0.98 g of 4-tert-butoxycarbonylamine-5-cyclohexyl-cis-2-pentenoic acid (prepared according to WCStill et al., Tetrahedron Lett., 1983, 4405) at -78 ° C. with 5.5 ml of a 1.2M Solution of diisobutylaluminum hydride in toluene. After 1 hour, allow to warm to RT. Addition of 1 ml of methanol terminates the reaction and, after dilution with 80 ml of CH ₂ Cl ₂ , the solution is shaken once each against 10% K-Na tartrate solution, 10% citric acid solution and saturated NaCl solution. The solution is dried over MgSO ₄ , concentrated in vacuo and the crude oily product obtained is chromatographed on silica gel (cyclohexane / ethyl acetate). 480mg of a slightly yellow oil is obtained.

Example 10 Iva-Phe-Nva - [(D) -Manno-Pentoll

The compound is prepared analogously to Example 1) and 1 a) from Iva-Phe-Nva-OH H- (D) -Manno-PentoKXX).

R, (CH ₂ Cl ₂ / MeOH) = 0.06 MS (FAB + LiI): 614 (M + Li)

The title compounds of Examples 11 and 12 are prepared analogously to Example 2:

Example 11 Indolyl ^ -carbonyl-His-ffDl-manno-pentol

Ri (CH ₂ CH ₂ -MeOHlkOnZ-WaBr. NH ₃ = 50: 10: 1) = 0.10 MS (FAB): 558 (M + 1)

Example 12 2 (S) -hydroxy, 3-phenylpropionyl-His - [(D) -manno-pentol]

R, (acetone / H ₂ O 10: 1) = 0.25 MS (FAB): 563 (M + 1)

Claims (4)

-1- 296 69 Claims: 1. A process for the preparation of a compound of the formula I. R ² R ³ R ⁴ AN-CH-CO-NH-CH- (CHOH) _n -CH ₂ OH (I) in which A is a radical of the formulas II, IM or IV R ⁶ R ⁵ O I I Il R 1 N-CH-C- (II) R ⁷ R ⁵ O I I Il R ^ CH-CH-C- (111) R ⁵ O R ¹ -O-CH-C- (IV) R ¹ ad (C 1 -C 5 -cycloalkyl, (C 1 -C 4) -cycloalkyl, (C 1 -C 4 -cycloalkyl) (Cs-CsJ-cycloalkylsulfonyl, wherein each of the cycloalkyl, '~~ Bicycloalkyl and tricycloalkyl substituent by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxy, (C ₁ -Ce) -alkoxy, (C ₁ -C ₆ I--alkyl, carboxy, (d -CeJ-alkoxycarbonyl, carbamoyl, carboxymethoxy, amino, (d-CeJ-monoalkylamino, l, amidino, hydroxyamino, hydroximino, hydrazono, imino, guanidino, (C ₁ -Ce) -alkoxy sulfonyl, (C ₁ -C ₄ ) -alkoxysulfenylmifluoromethyl, (C ₁ -C ₄ ) -alkoxycarbonylamino, (C ₆ -C ₁₂ ) -aryl (C ₁ -C ₄ ) alkoxycarbonyl-amino, may be substituted; Hydrogen, hydroxy, (dC ₁₈ ) -alky], (C ₁ -Ce) -alkoxy, (dC ₁₈ ) -alkanoyl, (d-dsl-alkoxycarbonyl, (d-dsJ-alkylsulfonyl, (d-CsJ-alkylsulfinyl, wherein the alkyl radicals in each case by optionally protected amino, trimethylsilyl, hydroxy, mercapto, (C ₁ -C ₄ ) -alkylthio, halogen, (C ₁ -C ₄ ) -alkoxy, mono- or di (C ₁ -C ₈ ) -alkylamino, carboxy, carbamoyl, guanidines (Ci-CJ-alkoxycarbonyl, (d-CsJ-alkanoyloxy, phenyl (C _n -C ₄ ) -alkoxy or a radical CONR ⁸ R ⁹ may be substituted;
(C ₁ -C ₄ -alkoxy; _(C6-C14) -aryl, (Ce-d ^ -AryMd-QJ-alkyl, (C ₆ -C ₁₄₎ -aryl- (C ₁ -C ₄₎ alkoxy, wherein the aryl radical in each case by one, two or three identical or different radicals from the series (C ₁ -C 6) -alkyl, amino, mono- or di- (C ₁ -C ₄ ) -alkyl-amino, amino- (C ₁ -C ₄ ) -alkyl, hydroxyl (C ₁ -C ₄ ) -alkyl, mono- or di-QJ-alkylamino ^ d-CJ-alkyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, halogen, formyl, (C ₁ -C ₄ -alkoxycarbonyl, carboxamido, Mono- or di- (C 1 -C ₄ ) -alkylaminocarbonyl and nitro may be substituted; Het, Het- (Ci-C ₄ ) -alkyl, wherein Heteinen represents 5-, 6- or 7-membered heterocyclic ring, which may be additionally benzannellated and either aromatic, partially hydrogenated or fully hydrogenated and the heteroelement as one or two identical or different radicals from the series N, O, S, NO, SO or SO ₂ and by one or two identical or different radicals from the series (C, -C ₄ ) alkyl, (CC ₄ ) alkoxy, (dC ₄ ) alkoxycarbonyl, hydroxy , Halogen, amino, amino-id-CJ-alkyl, mono- or di (C ₁ -C ₄ ) -alkylamino; or a group NR ⁸ R ⁹ , where R ⁸ and R ^{9 are the} same or different and independently hydrogen; (C ₁ -C) -alkyl which may be substituted by amino, (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxy or (d "-C ₄ ) -alkoxy, (Qr-CyJ-cycloalkyl; mercapto; (C ₁ -C ₄ ) -alkylthio; phenylthio; (C ₁ -C ₄ -alkoxycarbonyl; carboxy, (C ₆ -C ₁₄ ) -aryl which may be substituted in the aryl radical as described above; Het or Het (dC ₄ ) alkyl, wherein Het is as defined above, mean or wherein
R ⁸ and R ⁹ together with the nitrogen atom carrying them have a 5- to 12-membered Ri form, which may be mono- or bicyclic and as further ring members may contain 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom and may be substituted by (C ₁ -C ₄ alkyl group AI)
or
R ¹ a ₂ ) is a radical of the formula V. R ¹ '-W (V) in which R ¹ 'is defined as R ¹ under a, and W is -CO -, - CS -, - O- 80 -, - SO ₂ -, - SO-, -NH-SO ₂ -, - NH-CO- , -CH (OH) -steht -or-N (OH); R ¹ and R ⁵ together with the nitrogen atom they carry form a 5- to 12-membered ring which may be mono- or bicyclic and contain, as further ring members, 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom and (Cy-C ₄ ) Alkyl may be substituted, R ² and R ⁶ independently of one another denote hydrogen or (C ₁ -C ₄ -alkyl, R ³ and R ⁵ independently of one another are defined as R ¹ under a ^; R ^{4 is} (C ₃ -C ₁₂ ) -alkyl; mono-, bi- or tricyclic (C ₃ -C ₁₈ ) -cycloalkyl, (C ₃ -C ₈ ) -cycloalkylmethyl, (C ₃ -C ₁₈ ) -cycloalkylethyl, where the cycloalkyl part is optionally substituted by (C ₁ -Cg) -alkyl ; dithiolanyl; _(C6-C14) arylmethyl; Dithiolanylmethyl; Dithiolanylethyl; dithianyl; Dithianylmethyl or dithianylethyl; R ^{7 is} hydrogen or (C ₁ -C ₈ ) -alkyl or, together with R ¹ or R ⁵ and the atoms carrying them, forms a mono- or bicyclic, saturated or partially unsaturated ring system having 5-12 ring members which, apart from carbon, still forms May contain 1 sulfur atom, which may optionally be oxidized to the sulfoxide or sulfone, and η 2-10 means and their physiologically acceptable salts, characterized in that one couples a fragment with terminal carboxyl group or its reactive derivative with a corresponding fragment having a free amino group, optionally to protect further functional groups (a) temporarily introduced protecting group (s) cleaves off and the compound thus obtained optionally converted into their physiologically acceptable salt. Process according to Claim 1, characterized in that a compound of the formula I is prepared in which A as defined in claim 1; R ^{1 is} hydrogen or (C ¹ -C ₁₀ ) -alkyl; cyclopentyl; cyclohexyl; Cyclopentyl (C 1 -C ₆ ) alkyl; CyclohexyHCv-C ^ alkyl; Phenyl (C ₁ -C ₄ ) alkyl, wherein the phenyl radical is optionally substituted as indicated in claim 1; Thienyl or thienylMCT-Cjl-alkyl, where the thiophene radical may each be substituted by one or two identical or different radicals from the series (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy or halogen, 2, 3- or 4-pyridyl or 2-, 3- or ^ pyridyl-iC-iC ^ -alkyl, wherein the pyridine radical by one or two identical or different radicals from the series (C ₁ -CJ-AIkYl, (C ₁ -C ₄ J -alkoxy or halogen may be substituted; amino (C- | -C ₁₀₎ alkyl; hydroxy-I ^ oJ-alkyl; (^ -CJ-alkoxy-fCH ^ oJ-alkyl; (C ₁ - C ₄ ) alkoxycarbonyl-C ₁ -C ₈ alkyl; (C ₁ -C ₈ ) alkylsulfonyl; (C ₁ -C ₈ ) alkylsulfinyl; (C ₁ -C ₈ ) hydroxyalkylsulfonyl; (C ₁ -C ₅ ) -hydroxyalkylsulfinyl; Hydroxy-C ₁ -C 3 -alkanoyl, (C ₁ -C ₈ ) -alkanoyloxy-F C! -C ₁₀ ) -alkyl, (C ₁ -C 5) -alkanoyl, optionally protected Am-Jan-O (C ₁ -C ₁₁ ) - alkanoyl such as (3-amino-3,3-dimethyl) -propionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, ^ N-tert-butoxycarbonylaminobutyryl, 5-N-tert-butoxycarbonylaminopentanoyl or 6-N- tert-Butoxycarbon ylaminohexanoyl; Di (C ₁ -C ₇ ) alkylamino (C ₂ -C ₁₁ ) alkanoyl; (C ₃ -C ₈ ) cycloalkylcarbonyl; amino substituted (C ₃ -C ₈ ) cycloalkylcarbonyl; amino substituted (C ₃ -C ₈ ) cycloalkylsulfonyl, (C ₆ -C ₁ 0) aryl (C ₂ -C ₁₁ ) alkanoyl; 2-pyridyl (C ₁ -C ₈ ) alkanoyl; S-pyridyl-t ^ -CaJ alkanoyl; ^ PyridyMCr-CsI alkanoyl; benzoyl optionally substituted by halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) -alkoxy or (C ₁ -C ₄ ) -alkoxycarbonyl; benzenesulfonyl; (C ₁ -C ₁ 0) -alkoxycarbonyl, optionally substituted by trimethylsilyl, halogen, (C ₁ -C ₆ ) alkyl or haloK ^ -CgJ-alkyl; (C ₆ -Cu) aryl (C ₁ -C ₆ ) alkoxycarbonyl; 4-amino-piperidino-i carbonyl; 4-aminomethylpiperidino-i-carbonyl; N- (4-piperidino) carbamoyl; or N-methyl- [2- (N- (morpholino carbonyl) -N-methylamino) ethyl] aminocarbonyl; R ¹ and R ⁵ together with the nitrogen atom bearing them form a 5 to 12 membered ring which may be mono- or bicyclic, aromatic, partially hydrogenated or fully hydrogenated; -3- 296 69 R ² and R ^{6 are} independently hydrogen or (C ₁ -C ₄ alkyls; R ³ and R ^{5 are} independently defined as in claim 1; R ^{4 is} (C ₃ -C ₁₂ ) alkyl; mono-, bi - or tricyclic (C ₃ -C ₁₈ ) -cycloalkyl or (C ₃ -C ₁₈ ) -cycloalkylmethyl, wherein the cycloalkyl moiety is optionally substituted by (C ₁ -C ₄ ) -alkyl, (Ce-C 1 to 3-arylmethyl; dithiolanyl; Dithiolanylmethyl; Dithianyl and dithianylmethyl; R ^{7 is} hydrogen or methyl, or together with R ¹ or R ⁵ and the atoms carrying them, a mono- or bicyclic saturated or partially unsaturated ring system having 5-12 ring members, which may contain 1 carbon atom in addition to carbon, which may be sulfoxide or Sulfone can be oxidized forms; and
η 2-8, means. 3. The method according to claim 1 and / or 2, characterized in that one prepares a compound of formula I, in which R ^{1 is} hydrogen, (C ¹ -C ₈ alkylsulfonyl; (C ¹ -C ₈ ) alkylsulfinyl; 2-hydroxyethylsulfonyl; 2-hydroxypropylsulfonyl; 2-hydroxypropionyl; 3-hydroxypropionyl; 3-hydroxybutyryl; 2-hydroxy-3-methylbutyryl; (C 1 -C 12) alkanoyloxy-fCi-C 1-6 -alkyl; n-decanoyl; formyl; acetyl; propionyl; pivaloyl; isovaleryl; isobutyryl; (3-amino-3,3-dimethyl) -propionyl); 4-aminobutyryl; 5-aminopentanoyl; 6-aminohexanoyl; dimethylaminoacetyl; piperidino-4-carbonyl; iviorpholino-4-carbonyl; cyclopropylcarbonyl; cyclobutylcarbonyl; cyclopentylcarbonyl; cyclohexylcarbony; S-aminocyclobutylcarbonyl; 4-aminocyclohexylcarbonyl; S-aminocyclobutylsulfonyl; 4-aminocyclohexylsulfonyl; phenylacetyl; phenylpropanoyl; Phenylbutanoyl; 2-pyridyl (C ₁ -C ₈ ) alkanoyl; S-pyridyl-C ₁ -C ₅ alkanoyl; 4-pfridyl (C ₁ -C ₈ ) alkanoyl; 4-chlorobenzoyl; 4-methylbenzoyl; 2- Methoxycarbonylbenzoyl; 4-methoxybenzoyl; pyrrolyl-2-carbonyl; pyridyl-3-carbonyl; benzenesulfonyl; methoxycarbonyl; ethoxycarbonyl; isobutoxycarbonyl; tert-butoxycarbonyl; 2- (tri methylsilyl) -ethoxycarbonyl; 2,2,2-trichloroethoxycarbonyl; benzylcarboxylyl; 1- or 2-naphthylmethoxycarbonyl; 9-fluorenylmethoxycarbonyl; 4-amino-piperidino-1-carbonyl; 4-aminomethylpiperidino-1-carbonyl; N-methyl - [2- (N- (morpholino-carbonyl) -N-methylamino) -ethyl] -aminocarbonyl; or N- (4-piperidino) -carbamoyl; R ¹ and R ^5, together with the nitrogen atom bearing them, form an 8 to 12 membered bicyclic ring which may be aromatic, partially hydrogenated or fully hydrogenated; R ² and R ⁶ independently of one another are especially hydrogen or methyl; R ³ and R ⁵ independently of one another are hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, 3-guanidinopropyl, carbamoylmethyl, 2-carbamoylethyl, carboxymethyl, 2-carboxyethyl, mercaptomethyl, 2 (Methylthio) -ethyl, (i-mercapto-i-methyl) -ethyl, hydroxymethyl, 1-hydroxyethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, Ν, Ν-dimethylamino, cyclohexylmethyl, imidazole-4 yl-methyl, benzyl-2-methylbenzyl, 3-methylbenzyl, indol-3-ylmethyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl, (benzdioxolan-5-yl ) -methyl, 2-thienyl, 2-thienylmethyl, 2- (2-thienyl) -ethyl, 3-thienyl, 3-thienylmethyl, 2- (3-thienyl) -ethyl, 4-chlorobenzyl, 2- (methylsulfinyl) - ethyl, 2- (methylsulfonyl) ethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexyl, (1-methyl-imidazol-4-yl) -methyl, (3-methyl-imidazol-4-yl) - methyl, phenyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-thiazolylmethyl, 4-thiazolylmethyl, 3-pyrazolylmethyl, 4-pyrimidine ylmethyl, indol-2-ylmethyl, 2-benzo [b] thienylmethyl, 3-benzo [b] thienylmethyl, 2-furylmethyl, cyclohexyl or cyclopentyl; R ^{4 is} (C ₃ -C ₁₂ ) -alkyl; mono- or bicyclic (C 3 -C ₁₂ ) -cycloalkyl or (cy-C 1 -C 6 -cycloalkylmethyl, wherein the cycloalkyl moiety is optionally substituted by (C 1 -C ₄ ) -alkyl; (C 1 -C 4 -j-arylmethyl; dithiolanyl; dithiolanylmethyl; Dithianyl or dithianylmethyl; R ^{7 is} hydrogen or together with R ¹ and the atoms carrying them a mono- or bicyclic saturated or partially unsaturated ring system having 5-12 ring members, which contains 1 carbon atom in addition to carbon, which is particularly preferably oxidized to sulfone forms, or together with R ⁵ and the atoms carrying them "a" thiochroman system whose sulfur atom is particularly preferably oxidized to sulfone forms, and η 3-6 means. 4. The method according to any one of claims 1 to 3, characterized in that one prepares a compound of formula I, in which R ^{1 is} hydrogen; (C 1 -C ₆ -alkylcarbonyl; (C 1 -C ₆ ) -alkylsulfonyl, -amino- (C ₅ -C ₈ ) -cycloalkylcarbonyl, A-amino-piperidino-1-carbonyl, -benzenomethyl-piperidino-1-carbonyl; Methyl [2- {N- (morpholinecarbonyl) -N-methylamino) -ethyl] -aminocarbonyl; R ¹ and R ⁵ together with their supporting nitrogen atom indolyl; R ² , R ⁶ and R ^{7 are} hydrogen;
R ³ (C ₁ -Ce) -Alkyl; Imidazolyl-f ^ -CJ-alkyl; 5. A process for the preparation of a pharmaceutical preparation comprising a compound according to any one of claims 1 to 4, characterized in that bringing the active ingredient together with a physiologically acceptable carrier and optionally further additives, auxiliaries and / or preservatives in a suitable dosage form ,