DD295377A5 - AMINOSAUTE DERIVATIVES WITH RENEWABLE PROPERTIES, PROCESS FOR THE PRODUCTION THEREOF, AGENTS AND THEIR USE THEREOF - Google Patents

Abstract

The invention relates to renin-inhibiting amino acid derivatives of the formula

Description

Amino acid derivatives having renin-inhibiting properties, processes for their preparation, agents containing them and their use

From EP-A-184055, EP-A-189203, EP-A-202571, EP-A-229667, EP-A-230266, EP-A-237202, EP-A-310071, EP-A-310072, WO -A-87/05302 and WO 88/05050 disclose renin-inhibiting aminodiol derivatives.

Furthermore, renin inhibitors are in Biochem. Biophys. Res. Comm. 132, 155-161 (1985), in Biochem. Biophys. Res. Comm. 146, 959-963 (1987) in FEBS Lett. 230, 38-42 (1988), J. Med. Chem. 30,976 (1987) and J. Med. Chem. 31,2277 (1988).

It has now been found that at the N-terminus azacyclic acyl-aminoacyl-substituted aminodiol derivatives with heterocyclic substitution at the C-terminus are surprisingly exceptionally potent and highly specific renin inhibitors which have a significantly improved absorption and significantly prolonged duration of action in vivo.

The invention therefore relates to compounds of the formula I.

R ² R ³ OH R ⁴

R ¹ ^ -XY-CH-CB-NH-CH-CH-CH-R ^{5 (I)}

Il 0

in which

R ^{1 is} a radical of the formula II, III or IV

10 _R 10

6 1 O 'I

ρ XZ Γηττ 1 Γ PtTl rr »Li 1 ΓγίιΊ

¹ V. ^K / l ^CH 2Jm " ^CH Jo \ l ^CH 2Jm" l ^CH Jo

N- <N- R ⁸

[CH ₂ J _n - [] ^ ⁹

(II) (III)

N-Z

(IV)

means, in which

R ⁶ and R ^{7 are} identical or different and represent hydrogen, an optionally substituted aliphatic radical having 1-21 C atoms,

an optionally substituted alicyclic radical having 3-20 C atoms,

an optionally substituted alicyclic-alilphatic radical having 4-20 C atoms, an optionally substituted aromatic radical having 6-12 C atoms, an optionally substituted araliphatic radical having 7-32 C atoms, an optionally substituted heteroaromatic or heteroaromatic (C , -C ₃ ) -aliphatic radical having in each case 5-12 ring atoms, or, if not already covered by the above definitions, for an optionally substituted alkanoyl radical having 1-18 C atoms,

an optionally substituted (C 1 -C ₈ ) -cycloalkyl- (C 1 -C ₈ ) -alkanoyl radical, an optionally substituted (CT-C 1 -C -royl radical,

an optionally substituted heteroaroyl radical,

an optionally substituted (C ₆ -C, ₂₎ aryl (C, -C ₈₎ -alkanoyl residue,

an optionally substituted heteroaryl (C, -C ₁₈ ) alkanoyl radical or an optionally substituted (Ce-Cul-Aryl-ICt-C ^ alkoxycarbonyl radical, or R ⁶ and R ⁷ together with the N-bearing radical Atom form a 4- to 8-membered ring which may be saturated or unsaturated and may contain another heteroatom selected from the group consisting of N, O and S;

R ^{6 is} as defined above and

R ⁷ for amino,

optionally substituted (C 1 -C 6 -alkylamino,

optionally substituted di- (C 1 -C ₄ ) -alkylamino,

hydroxy,

optionally substituted (C ₁ -C ₄ ) -alkoxy,

optionally substituted (C 1 -C ₄ ) -alkylsulfonyl,

optionally substituted (C ₆ -C ₂ ) arylsulfonyl or carbamoyl;

R ^{8 has} the meaning given for R ⁶ or R ⁷ ;

R ⁹ represents hydrogen, (C, -C _s) alkyl, _(Cr-C8) cycloalkyl, (Ca-Cgl-cycloalkyl-fC ^ Cl-alkyl, optionally substituted _{(C6, 2)} aryl,

optionally substituted (Cj-CnJ-aralkyl;

R ¹⁰ , R "and R ^{12 are the} same or different and are hydrogen or (C, -C ₆ ) -alkyl or R ¹⁰ and R" together form a (C ₂ -C ₄ ) -alkanediyl bridge, preferably ethylene bridge, and R ' ^{2 is} as defined above;

m is 0,1,2 or 3;

η = 1,2,3 or 4;

ο = 0,1,2 or 3;

ρ = 1, 2, 3 or 4;

X is -CO-, -CS-, -SOz or -SO-;

Y is - (CH ₂ Jq- (CR ¹³ R ¹ V.-O- or -S-, in which

q = 0,1,2 or 3,

r = 0,1 or 2,

Z is a branched or unbranched aliphatic radical having 1-6 C atoms, preferably (Ci-C _e ) -Alkapdiyl, and R ¹³ and R ' ^{4 are} identical or different and denote hydrogen or (J] -C ₆ ) alkyl ; R ² is hydrogen, (C ₁ -C ₁ O) -alkyl, (C ₆ -C ₁₂₎ -aryl, (C6-C, ₂₎ aryl (C, -C ₄₎ alkyl, (C ^ Cel Cycloalkyl, (C ₃ -C ₈ ) -cycloalkyl- (C, -C <) - alkyl, heteroaryl or heteroaryl-l ^ -C ^ -alkyl, wherein aryl or heteroaryl by one or two identical or different radicals from the Halogen, hydroxy, (C, -C ₄ ) alkoxy, amino, (Li-C ₄ ) alkylamino, di (C 1 -C ₄ ) alkylamino, CF ₃ and (C 1 -C ₄ ) alkyl may be substituted;

R ³ is hydrogen, (C, -C, ₀₎ alkyl, (Cj-Cai-cycloalkyl, (Cr-C _e) cycloalkyl (C, -C4) alkyl, (C ₆ -C ₁₂ aryl or I- (C <rC, ₂ ) -aryl (C, -C ₄ ) -alkyl;

R ⁴ is hydrogen, (C) -C, ₀₎ alkyl, (C _s -C, ₂₎ aryl, (C ₆ -C, ₂₎ aryl (C, -C ₄₎ alkyl, hydroxy or amino means; R ⁶ denotes a radical of the formula II

(CH ₂ ), - CHR ¹⁶ -Het (II)

R ¹⁵ is hydrogen, (C ₁ -C ₇ I--alkyl, (C, -C ₄₎ alkoxy, (C, -C ₄₎ alkylthio, (C, -C ₄₎ -alkylamino, hydroxyl, azido or halogen and Het is a 5- to 7-membered heterocyclic ring which may be benzannellated, aromatic, partially hydrogenated or fully hydrogenated containing, as heteroatoms, one or two identical or different radicals selected from the group consisting of N, O, S, NO, SO, SO ₂ and containing one or two identical or different radicals from the series (C 1 -C ₄ ) -alkyl, allyl, (C 1 -C ₄ ) -alkoxy, hydroxyl, halogen, amino, mono- or di- (C C 1 -C ₄ ) -alkylamino and CF ₃ may be substituted, and sO, 1, 2, 3 or 4;

B is the residue of an amino acid HB-OH, preferably from the series phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, β-2-thienylalanine, β-3-thienylalanine, β-2-furylalanine, β -3-furylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O -Benzyltyrosiri, O-tert.-butyltyrosine, phenylglycine, 1-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, beta-2-benzo | b] thienylalanine, beta-3-ol ⁷ Ben [b] thienylalanine, 2- Fluorophenylalanine, 3-fluorophenylalanine, 4-pyridylalanine, 4-fluorophenylalanine, norleucine, cysteine, S-methyl-cysteine, 1 ^, 5'-tetrahydroisoquinoline-S-carboxylic acid, homophenylalanine, DOPA, O-dimethyl-DOPA, N-. ' 3-thyl-histidine, 2-amino-4- (2-thienyl) -butyric acid, 2-amino-4- (3-thienyl) -butyric acid, 3- (2-thienyl) -serine, 2- or 4-thiazolylalanine, (Z) -dehydrophenylalanine, (E) -dehydrophenylalanine, 1,3-dioxolan-2-yl-alanine, N-pyrrolylalanine and 1-, 3- or 4-pyrazolylalanine and their physiologically acceptable SaI a.

The chiral centers in the compounds of formula I may have the R, S or R, S configuration. B is preferably in the S configuration or, in the case of cysteine and amino acids derived therefrom, in the R configuration

An aliphatic radical is preferably an alkyl radical or a corresponding unsaturated radical. The radical may be straight-chain or branched. The same applies to radicals derived therefrom, such as. Alkoxy, alkylthio, alkylamino, dialkylamino, alkanoyl and aralkyl.

An alicyclic radical is, for example, cycloalkyl or a radical derived therefrom (compare Alkyl). Cycloalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl are preferably understood to mean (C 1 -C 10 -cycloalkyl) If these cycles carry more than one substituent, they may be either in the form of an iron or a trans.

By an alicyclic-aliphatic radical is meant, for. B. cycloalkylalkyl and radicals derived therefrom (see alkyl).

An aromatic radical is preferably (C ₆ -C 12 ₎ -alkyl, such as, for example, phenyl, naphthyl or biphenylyl, preference being given to phenyl.

The same applies to radicals derived therefrom, such as. B. aryloxy, aroyl, aralkyl and aralkyloxy.

Araliphatic radicals are, inter alia, aralkyl radicals, among which is preferably a (C ₁ -C ₆ ) -alkyl-linked, unsubstituted or substituted (C ₆ -C ₁₂ ) -aryl radical, such as, for example, benzyl, α- and However, aralkyl is not limited to the radicals mentioned.

By a heteroaromatic radical is meant, in particular, a radical containing a six-membered benzene-derived aromatic ring in which one or more CH groups are replaced by N, or which contains a five-membered benzene-derived aromatic ring in which two CH groups are replaced by S, NH or N and in which optionally further CH groups are replaced by N. This heteroaryl radical is preferably monocyclic or bicyclic. in the latter case, anneliiert with a benzene or a difined as above five- or six-membered ring

The same applies to radicals derived therefrom, such as the heteroaromatic-aliphatic radicals heteroaralkyl, heteroaroyl or heteroaryloxy.

A radical Het in the sense of definition is, for example, a heteroaryl radical such as 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 can be attached to a nitrogen atom by oxy, (C ₁ -C ₆ -alkyl, methyl, ethyl, phenyl or phenyl-C ₁ -C ₄ -alkyl, for example benzyl, and / or on a or more carbon atoms by (C 1 -C ₄ ) alkyl, e.g., methyl, phenyl, phenyl (C ₎ -C ₄ ) alkyl, e.g. Benzyl, halogen, e.g. B.

Chloro, hydroxy, (C, -C ₄ ) alkoxy, e.g. For example, methoxy, phenyl (C, -C ₄ ) alkoxy, z. B. benzyloxy, or oxo to trisubstituted and partially saturated and is for example 2- or 3-pyrrolyl, phenyl-pyrrolyl, z. 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl,

4-imidazolyl, methylimidazolyl, ζ. B. 1-methyl-2-, 4- or 5-imidazolyl, 1,3-tliiazol-2-yl, 2-, 3- or 4-pyridyl, 1 -oxy-2-, 3- or 4-pyridyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, e.g. 1-methyl, 6-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-i, 2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzoxazolyl, 2-benzthiazolyl, benz [e] indol-2-yl or β-carbolin-3-yl.

Partially hydrogenated or fully hydrogenated heterocyclic radicals are, for example, dihydropyridinyl, pyrrolidinyl, z. B. 2-, 3- or 4-N-methylpyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, tetrahydrothienyl. Halogen is fluorine, chlorine, bromine or iodine

 (m + n) is preferably> 2

 (o + p) is preferably s 1

 (q + r) is preferably, ie> 1

 s is preferably> 1.

Under the initially used term "optionally substituted" is understood to mean (if later in detail otherwise defined), in that the radical in question with one, two or three, preferably (one or two identical or different radicals from d ir series C, -C ₆ ) alkyl, (C) -C ₆ I -alkoxy, hydroxy, halogen, (C, -C ₆₎ alkanoyl, CF _3, amino, (C, -C _s) alkylamino, di-fC ^ alkylamino-Cel , Carbamoyl, (C 1 -C ₆ ) alkoxycarbonyl and sulfamoyl.

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. Carboxy, with alkali or alkaline earth metals, such as Na, K, Mg and Ca, as well as with physiologically acceptable organic amines, e.g. Triethylamine and tri- (2-hydroxyethyl) amine.

Compounds of formula I, which basic groups, for. As an amino group or a Gu jnidinogruppe contain, form salts with inorganic acids, such as. For example, hydrochloric acid, sulfuric acid or phosphoric acid and with organic 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 R ^e and R ^{7 are} identical or different and denote hydrogen, (C 1 -C ₁₈ ) -alkyl, an aliphatic acyclic radical of the formula C _a H [ _2a -b + u, in which double bonds, if their number exceeds 1, are not cumulative, a is an integer 2 to 18 and b is an even number 2 to a, a mono-, di- or tricyclic, non-aromatic, optionally branched hydrocarbon radical of the formula C _c H | _2c - d - ii. wherein c is an integer from 3 to 20, and d is an even number O to (c - 2), (C ₆ -C ₁₂ I-ArYl optionally substituted by one or two identical or different radicals from the series (C is -C ₄₎ alkylamino, di- (C ₁ -C ₄₎ alkylamino and substituted CF ₃ |, -C ₄₎ alkyl, (C, -C ₄₎ alkoxy, hydroxy, halogen, amino, (C , (Ce-C ^ l-aryl-fC ^ Cet-alkyl or (CT-Cnl-aroyl-ICt-CaJ-alkyl which may be substituted in the aryl part as described above, mono- or bicyclic, optionally partially hydrogenated heteroaryl, heteroaryl -fC ^ Ca) -alkanoyl with 5-7 or 8-10 ring atoms, of which up to 9 ring atoms are carbon and 1 to 2 ring atoms are sulfur or oxygen and / or 1 to 4 ring atoms nitrogen, which in the heteoaryl part as above for aryl (Ci-C _1B ) alkanoyl, (Cg-C ^ l-aryl-fC ^ cal-alkanoyl, which may be substituted in the aryl moiety as described above, (C ₇ -C ₁₃ ) -royl- ( C, -C ₈ ) -alkanoyl substituted in the aryl part as described above (C 1 -C ₆ ) -alkoxycarbonyl- (C ₁ -C ₈ ) -alkanoyl, (C 1 -C 12 -aryloxycarbonyl-fCr-Cg-alkdnoyl which may be substituted in the aryl part as described above (C _6- C ₁ J) -ArYl- (C ₁ -C ₈ ) -alkoxycarbonyl, (C ₁ -C 4 -alkoxy-tCt-cel-alkanoyUCg-Cnl-aryloxy-ld-cetalkanoyl described in the aryl part as described above for aryl (Ci -Cel acyl-t ^ -Cel alkanoyl, carboxy (C ₁ -C ₄ ) alkanoyl, carbamoyl (Ci-C ₄ ) alkanoyl, amino (C | -C ₄ ) alkyl, (Ct-C ^ -Alkanoylarnino FCT-CJ-alkyl, _(C7-C13) -Aroylamino- _(Cr-C4) alkyl, (C ₁ -C ₄₎ -alkoxycarbonylamino- (C, -C ₄₎ -alkyl, (C ₆ -C, ₂₎ aryl (C, -C ₄₎ -alkoxycarbonylamino- (C ₁ -C ₄₎ alkyl, (C _s -C, ₂₎ aryl (C, C ₄ ) alkylamino- (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkylamino, C 1 -C ₄ alkyl, di-C 1 -C 1 alkylamino, IC-O-alkyl, guanidino -fC ^ l-alkylMC ^ Cl-alkylthio-fC ^ Cl-alkyl, (Ce-C ₁₂ ) -arylthio (C 1 -C ₄ ) -alkyl which may be substituted in the aryl part as described above, carboxy (C _t -C ₄ ) -alkyl, carbamoyl (C ₁ -C ₄ ) -alkyl, (C) -C ₄ ) -alkoxycarbonyl- (C ₁ C ₄ ) -alkyl, (C ₆ -C ₁₂ ) -aryloxy- (C ₁ -C ₄ ) -alkyl which may be substituted in the aryl moiety as described above for aryl, or R ^e and R ⁷ together with the they bear the N atom forming a 5- or 6-membered ring which may be saturated or unsaturated and may contain another heteroatom selected from the group consisting of N, O and S; or R ^{6 is} as defined above, and

R ^{7 is} amino, (C 1 -C ₄ ) -alkylamino, di (C 1 -C ₄ ) -alkylamino, hydroxy, (C 1 -C ₄ ) -alkoxy, (C 1 -C ₄ ) -alkylsulfonyl, (Cg -Cul-arylsulfonyl or carbamoyl;

R ^{8 has} the meaning given for R ⁶ or R ⁷ ;

R ^{9 is} hydrogen, (C 1 -C ₆ ) -alkyl, (C ₄ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -cycloalkyl- (C 1 -C ₄ ) -alkyl, (C ₆ -C, ₂ ) aryl or (CrCJ-aryl-ICr-Ql-alkyl;

R ¹⁰ , R "and R ^{12 are the} same or different and are hydrogen or (C 1 -C ₄ ) -alkyl; m is 0,1,2 or 3, η is 1,2 or 3, ο is 0,1,2 or 3 ρ = 0,1,2 or 3; X is -CO- -CS -.-SOj- or -SO-; Y -:> I ₂ ) ^ - (CR ¹³ R ¹ V, -O- or- S- means in which q = 0,1,2 or 3, r = 0,1 or 2,

Z is a branched or unbranched aliphatic radical having 1-4 C atoms, preferably _(C) -C ₄₎ alkanediyl, and R ¹³ and R ¹⁴ are identical or different and are hydrogen or (C] _-C4) alkyl mean; R ² is hydrogen, (C, -C ₆₎ alkyl, (C ₆ -C ₁₂ I-aryl, (C6-C, ₂₎ aryl (C, -C ₄₎ alkyl, (C ₄ -C ₆ ) -Cycioalky |, {C ₄ -C _e) -cycloalkyl- {C, -C ₂₎ alkyl, (C ₄ -C 7) -heteroaryl or (C ₄ -C 7) -heteroaryl- (C) -C2) - alkyl, wherein aryl or heteroaryl can be substituted as defined in claim 1 and wherein heteroaryl is as defined above for R ^e or R ⁷ ; R ^{3 is} isobutyl, benzyl or cyclohexylmethyl;

fl ⁴ is hydrogen, (dC ₆₎ alkyl, (Ce-C, ₀₎ aryl iCe-Cel-aryl-iC-CO-alkyl or hydroxy; R ⁶ is a radical of the formula II, worn i ^'s are hydrogen, (C, -C ₄₎ alkyl, (C, -C ₄₎ alkoxy, (C, -C ₄₎ alkylthio, (C ₁ - C ₄ ) alkylamino, hydroxy, azido or halogen, Het is as defined in claim 1 and s is 0,1 or 2; and B βι / ιηη residue of an amino acid HB-OH from the series phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, ß-2-thienylalanine, 6-3-thienylalanine, ß-2-furylalanine, β-3-furylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, mothionine sulfoxide, 2-pyridylalanine, 4-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine O-methyl tyrosine, O-benzyl tyrosine, O-tert-butyl tyrosine, phenyl glycine, 1-naphthyl alanine, 2-naphthyl alanine, 4-nitrophenyl alanine, norvaline, norleucine, cysteine, S-methyl cysteine, N-methyl histidine, II. SATetrahydroisoquinoline-S-carboxylic acid, 2- or 4-thiazolylalanine, homophenylalanine, 2-amino-4- (2-thienyl-butyric acid, 2-amino-4- (3-thienyl-butyric acid, 3- (2-thienyl) - serine, (Z) -dehydrophenylalanine, (E) -Deh / drophenylalanine, 1,3-dioxolan-2-yl-alanine, N-pyrrolylalanine and 1-, 3- or 4-pyrazolylalanine, in particular verbin compounds of the formula I, in which

R ⁶ and R ⁷ is hydrogen, (C, -C ₄₎ alkyl, _(Ci-Ce) cycloalkyl, (C ₄ -C ₆₎ cycloalkyl (C, -C ₄₎ alkyl, (C ₆ - C ₁₂ I-ArYl, which is optionally substituted by one or two identical or different radicals from the series methyl, ethyl, methoxy, ethoxy, halogen and amino, partially hydrogenated (C _e -C ₁₂ ) -aryl, (C ₆ -C ₁₂ ) Aryl- (C ₁ -C ₄ ) -alkyl which is optionally substituted in the aryl part as described above for aryl, (C ₁ -C ₄ -alkanoyl, (C ₁ -C ₄ -aryl-C ₁ -C ₄ -alkanoyl) optionally substituted in the aryl moiety as described above for aryl, (CH 2 -ol-heteroaryl-ICt-C 1 -alkanoyl, (C 1 -C ₄ ) -alkoxy- (C 1 -C ₄ ) -alkanoyl, CJ-alkoxycarbonyH ^ - C ₆ ) -alkanoyl, (C ₆ -C ₁₂ ) -aryloxycarbonyl- (C 1 -C ₆ ) -alkanoyl, which is optionally substituted in the aryl part as described above for aryl or (C _e -C ₁₂ ) - Aryl- (C ₎ -C ₄ ) alkoxycarbonyl which is optionally substituted in the aryl moiety as above for aryl, or R ^e and R ⁷ together with the supporting N atom of a piperidino-pyrroli dino, morpholino, piperazino or thiomorpholino residue; or

R ^{e is} as defined above, and

R ^{7 is} amino, methylamino, ethylamino, di- (C) -C ₂ ) alkylamino, hydroxy, methoxy, ethoxy, methylsulfonyl, ethylsulfonyl, phenylsulfonyl or carbamoyl;

R ^{8 has} the meaning given for R ⁶ and R ⁷ ;

R ^{9 is} hydrogen, (C ₁ -C ₃ ) -alkyl, (C ₄ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -cycloalkyl- (C ₁ -C ₂ ) -alkyl, (C _e -C ₁₂ ) -Aryl or (C ₆ -C, ₂ ) -aryl (C ₁ -C ₂ ) -alkyl;

R ¹⁰ , R "and R ^{12 are the} same or different and are hydrogen or (C ₁ -C ₃ ) -alkyl; m is 0,1 or 2;

η = 1,2 or 3;

ο = 0,1 or 2;

ρ = 1, 2 or 3;

X is -CO-or-SOj-;

Y is - (CH ₂ ) _q - (CR ¹³ R'Voder-O-, where q = 0,1 or 2,

r = 0,1 or 2,

Z -CH ₂ means and

R ¹³ and R ^{14 are the} same or different and are hydrogen or (C ₁ -C ₃ ) -alkyl; R ² (C, -C) alkyl, (C ₄ -C ₆₎ cycloalkyl, (Ci-Cel-cycloalkyl IC.-CJJ-alkyl, (C _e -C, ₀₎ aryl (C, - C ₂ ) -alkyl or (C ₄ -C _e ) -Heteroa: / 1- (C ₁ -C ₂ ) -alkyl, where aryl or heteroaryl is optionally substituted by one or two identical or different radicals from the series chlorine, fluorine, Methoxy, hydroxy and methyl is substituted;

R ^{3 is} isobutyl, benzyl or cyclohexylmethyl;

R ^{4 is} hydrogen or hydroxy;

R ^{5 is} a radical of the formula II in which R ^{16 is} hydrogen or fluorine, Het is a 2-, 3- or 4-pyridyl radical, a 2-, 4- or 5-imidazole radical or a 2-oxazolinyl radical, wherein said heterocycles may each be substituted by one or two identical or different radicals selected from the group methyl, ethyl, propyl, allyl, fluorine, chlorine, bromine, CF ₃ and methoxy, and s is 0, 1 or 2; and

B is a residue of an amino acid HB-OH from the series phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, β-2-thienylalanine, β-3-thienylalanine, β-2-furylalanine, lysine, ornithine , Valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, mththione sulfoxide, 2-pyridylalanine, 3-pyridylalanine, 4-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O-benzyltyrosine , O-tert-butyl-tyrosine, phenylglycine, 1-naphthyl-alanine, 2-naphthyl-alanine, 4-nitrophenyl-alanine, norvaline, norleucine, 1-methyl-5-tetrahydro-isoquinoline-S-carboxylic acid, 2- or 4-thiazolyl-alanine, homophenylalanine, 2- Amino-4- (2-thienyl) -butyric acid and 1-, 3- and 4-pyrazolylalanine; Histidine or norvaline is preferred.

Very particular preference is given to compounds of the formula I in which

R ⁶ , R ⁷ and R ^{8 are the} same or different and are hydrogen, (C 1 -C ₄ ) -alkyl, (C 1 -C ₄ ) -alkanoyl, such as acetyl, (Ce-C, ₂ ) -aryl (C | -C ₄ ) -alkyl, such as benzyl, (C ₇ -C ₃ ) -aryl, such as benzoyl, (C ₄ -C ₁₀ ) heteroaroyl, such as nicotinyl, (C 1 -C ₄ ) -alkoxycarbonyl, such as tert-butoxycarbonyl, or benzyloxycarbonyl mean;

R ^{3 is} as defined above, but in particular as defined in claim 3;

R ¹⁰ , R "and R ^{12 are the} same or different and are hydrogen, methyl or ethyl; m is 0.1 or 2;

η = 1,2 or 3;

ο = 0,1 or 2;

ρ = 1, 2 or 3;

X is -CO-or-SOr-;

Y - (CH ₂ J ₁₁ - (CR ¹³ R ¹ V or -O- means where q = list,

Z -CH ₂ means and

R ¹³ and R ' ^{4 are the} same or different and are hydrogen, methyl or ethyl; R ^{2 is} cyclohexylmethyl, benzyl, 1- or 2-naphthylmethyl, 2-, 3- or 4-thienylmethyl, p-mothoxybenzyl or p-fluorobenzyl, but in particular benzyl; and

R ³ , R ⁴ , R ⁵ and B are as defined in claim 3.

The invention further relates to a process for the preparation of compounds of the formula I, which comprises coupling a fragment having a terminal carboxyl group or its reactive derivative with a corresponding fragment having an amino group, if appropriate for protecting further functional groups (a) temporarily introduced protective group (s) cleaves off and the resulting compound optionally converted into its physiologically acceptable salt.

Fragments of a compound of the formula I with a terminal carboxyl group have the following formula IVa or

R ² R ²

R'-X-Y-CHC-OH R'-X-Y-CHC-B-OH

ο o

(IVa) (IVb)

Fragments of a compound of the formula I having a terminal amino group have the following formula Va or Vb:

R ³ OH R ⁴ HB-NH-CH-CH-CH-R ⁵ Va

R ³ OH R ⁴ H ₂ N-CH-CH-CH-R ⁵ Vb

The connection of the components takes place only in the combination IVa with Va and IVb with Vb. 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 or 1-hydroxybenzotriazole as ester component, coupling with a carbodiimide such as dicyclohexylcarbodiimide or with propanephosphonic anhydride or methylethylphosphinic anhydride and the mixed anhydride method with pivaloyl chloride (M.Zaoral, Coll. Chem. Commun., 1962, 27, 1273). The reaction is carried out in an inert solvent or solvent mixture at a temperature between -20 ° C and the boiling point of the reaction mixture.

The preparation of the optically active amines of the formula Vb used as starting compounds, in which R ² , R ³ and R ^{4 are} as defined above, takes place starting from optically active α-amino acids, the center of their asymmetry being retained. For this purpose, an N-protected amino aldehyde is prepared in a known manner, which is coupled in an aldol-analogous addition to a corresponding heteroarylalkyl moiety and after cleavage of the N-protecting group amino alcohols of formula Vb results. When R ⁴ = OH also serves as an N-protected amino aldehyde as starting material, which is converted, for example by aldol analogous addition of unsaturated compounds, introduction of suitable protecting groups and subsequent epoxidation in the required intermediates. Diastereomer mixtures are obtained with respect to the OH-carrying center which are separated in a manner known per se, for example by fractional crystallization or by chromatography.

The review of the diastereomeric purity is carried out by HPLC, the enantiomeric purity can be checked in a known manner by conversion into Mosher derivatives (H.S. Mosheret, al., J. Org. Chem.34.2543 [1969]).

The preparation of N-protected amino aldehydes is carried out according to B. Castro et al. (Synthesis 1983, 376).

The aldol-analogous addition to N-protected amino aldehydes (preferably N-tert-butoxycarbonyl and benzyloxycarbonyl protective groups) takes place in a countercurrently inert solvent, such as ether, THF, toluene, DMF, DMSO or dimethoxyethane.

Suitable bases for the deprotonation of the heteroarylalkyl component are alkali metal alkoxides, such as potassium O-tert-butylate, sodium methoxide, alkali metal hydrides, such as sodium or potassium hydride, organometallic bases, such as n-butyllithium, s-butyllithium, methyllithium or phenyllithium, sodium amide and alkali metal salts of organic nitrogen bases, such as lithium diisopropylamide.

The preparation of Carbcxy-protected succinic acid derivatives in enantiomerically pure form is carried out according to J. J. Plattner et al. (J. Med.

Chem 31, 2277 [1988J] and D.A. Evans et al. (J. Am. Chem. Soc., 104, 1737 (1982)).

Carbamoyl-substituted α-hydroxypropionic acid derivatives are prepared by reacting enantiomerically pure or racemic α-hydroxypropionic acid derivatives and the N-containing ring systems as defined with reactive carbonic acid derivatives, such as, for example, Phosgene, diphosgene, triphosgene, carbonyldiimidazole or di- (1-benzotriazolyl) carbonate with the addition of suitable bases such. For example, triethylamine, pyridine or ethyl-diisopropylamine in an inert solvent.

Aminosulfonyl derivatives are prepared by condensation of the corresponding substituted amines with ω-chlorosulfonylalkylcarboxylic acid derivatives using bases, and then after appropriate removal of temporarily introduced protecting groups by the method described above with fragments of the general amino-terminated formula I (such as Vb) coupled by suitable activation methods. Among others, the Chlorsulfonylpropionsäurederivate z. B. obtained by Michael addition of suitable sulfur-containing nucleophiles to substituted acrylic acid derivatives followed by oxidation at the S atom.

The preparatory and postoperative operations 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".

Salts of compounds of formula I with salt-forming groups are prepared in a conventional manner by z. B.

reacting a compound of formula I with a basic group with a stoichiometric amount of a suitable acid.

Stuffy isomer mixture · insbesondoro diastereomer mixtures, which are obtained using racemic carboxylic acid derivatives and raceiiiischer amino acids H-B-OH, can be separated in known per se by fractional crystallization or by chromatography.

The compounds of the formula I according to the invention have enzyme-inhibiting properties; In particular, they inhibit the action of the natural enzyme renin. Renin is a proteolytic enzyme from the aspartyl protease class which is secreted by the juxtaglomerular cells of the kidney into the bloodstream as a result of various stimuli (volume depletion, sodium deficiency, β-receptor stimulation). There it separates the decapeptide angiotensin I from the angiotensinogen excreted from the liver. This is converted into angiotensin II by the angiotensin converting enzyme (ACE), which plays an essential role in regulating blood pressure by directly increasing blood pressure through vascular contraction, and by stimulating and elevating the secretion of aldosterone from the adrenal gland By inhibiting sodium excretion, extracellular fluid volume increases, which in turn contributes to blood pressure increase Inhibitors of renin enzymatic activity cause decreased formation of angiotensin I, resulting in reduced formation of angiotensin II Peptide hormone is the direct cause of the hypotensive effect of renin inhibitors.

The efficacy of renin inhibitors can be checked by in vitro tests. Here, the reduction of the formation of angiotensin I in various systems (human plasma, purified human renin) is measured.

1st test principle

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

2. Recovery of the plasma

Fresh human blood to be withdrawn (about 0.51 per person, Bluko removal device of the company ASID Bonz and son, Unterschleißheim) is collected in partially evacuated bottles under ice cooling. Coagulation is prevented by addition of EDTA (final concentration 10 mM). After centrifugation (rotor HS 4 [øorvall, 3500μm ₁ O- ^{0 0} C, 15 min, repeat if necessary), the plasma is carefully pipetted off and frozen in appropriate portions at -30X. For the test only plasmas with sufficiently high renin activity are used. Plasmas with low renin activity are by a cold treatment (-4 ⁰ C, 3 days) on (prorenin -> renin).

3. Execution of the test

Angiotensin I is determined using the Renin-Maia® kit (Serono Diagnostics SA, Coinsins, Switzerland). The incubation of the plasma is carried out according to the instructions given there: Incubation batch: 1000 μΙ plasma (emerged at 0-4 ⁰ C)

100 μΙ phosphate buffer (pH 7.4) Addition of 1 0 '* M Ramiprilat 10MlPMSF-Lösi / ng

10 μΙ 0.1% Geneva pole PFIC

12 μΙ CMSO or test preparation

The test preparations are generally dissolved in 10% ² M in 100% dimethyl sulfoxide (DMSO) and diluted with DMSO, the incubation mixture contains a maximum of 1% DMSO.

The salts are mixed in ice and incubated for 1 hour in a water bath (37 ⁰ C). From an additional batch without inhibitor, a total of 6 samples (100 μΙ each) are taken without further incubation to determine the starting angiotensin I content of the plasma used.

Concentrations of the test preparations are chosen to cover approximately the range of J-90% enzyme inhibition (at least five concentrations). At the end of the incubation period, three ΙΟΟμΙ samples are frozen in pre-cooled Eppendorf tubes on dry ice from each batch and stored at -25 ° C for angiotensin I determination (middle word from three individual samples).

Angiotensin I Radiolum Immunoassay (RIA)

The instructions for use of the RIA kit (Renin-Maia * kit, Serono Diagnostics SA, Coinsins, Switzerland) are followed exactly. The calibration curve covers the range of 0.2 to 25.0 ng angiotensin I per ml. The plasma base angiotensin I content is subtracted from all measurements. Plasma renin activity (PRA) is reported 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 indicated as% residual activity. From the plot of% residual activity against the concentration (M) of the test preparation (logarithmic scale), the IC ₅ O-WeTt is 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 b is 10 ~ '° mol / l.

Renin inhibitors cause blood pressure reduction in salt-depleted animals. Because human renin is different from the renin of other species, primates (marble sets, rhesus monkeys) are used for in vivo testing of renin inhibitors. Primate renin and human renin are largely homologous in their sequence. By i. v. Injection of furosemide stimulates endogenous renin secretion. Subsequently, the test compounds are administered and their effect on blood pressure and heart rate is measured. The compounds of the present invention are here in a dose range of about 0.1-5 mg / kg i.V. effective, with intraduodenal administration by gastroscope in the dose range of about 1-50mg / kg. The compounds of general formula I described in the present invention can be used as antihypertensives, as well as for the treatment of heart failure.

The HIV protease autocatalytically cuts out of the GAG-POL polypeptide and then cleaves the precursor peptide ρ55 into the core antigens ρ 17, p24 and ρ 14. It is thus an essential enzyme whose inhibition interrupts the life cycle of the virus and its Propagation prevents.

Biological tests showed that the compounds according to the invention have enzyme-inhibiting activity and also inhibit viral enzymes such as the HIV protease. Of particular importance is the HIV protease-inhibiting activity, which qualifies the compounds according to the invention in particular for the therapy and prophylaxis of diseases caused by infection with HIV. The erf indiingsgemäßen compounds of general formula I show in in vitro tests used inhibitory effects at concentrations of otwa 10 " ⁴ to 10" ⁹ mol / l.

The invention further relates to the use of compounds of the formula I for the production of medicaments for hypertension therapy and the treatment of congestive heart failure and for the therapy and prophylaxis of viral diseases, in particular diseases caused by HIV and the said medicines.

Pharmaceutical preparations contain an effective amount of the active ingredient of formula I together with an inorganic or organic pharmaceutically acceptable carrier. The application may be intranasal, intravenous, subcutaneous or peroral. The dosage of the active ingredient depends on the species of warm-blooded animals, body weight, age and method of administration.

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

For an oral application form, the active compounds are mixed with the customary additives such as carriers, stabilizers or inert diluents and brought by conventional methods into 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 carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, especially corn starch. The preparation can be carried out both as dry and moist granules. As oily carriers or solvents are, for example, vegetable or animal oils in Betraccht, 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 mannitol solutions, or a mixture of the various solvents mentioned.

List of abbreviations used:

Boc tert-butyloxycarbonyl BuLi n-butyl-lithium DCC dicyclohexylcarbodiimide DCI Desorption Chemical Ionization DNP 2,4-dinitrophenyl DME dimethoxyethane DMF dimethylformamide EE ethyl acetate FAB Fast atom bombardment Fmoc fluorenylmethoxycarbonyl H hour HOBt Ί-hydroxybenzotriazole M Mülekularpeak MS mass spectrum min minutes NEM N-ethylmorpholine THF tetrahydrofuran Trt triphenylmethyl

The following examples are intended to illustrate the preparation of the compounds of the invention without the invention being restricted to them.

example 1

N- [N- (2 (R) -benzyl-3- (4- (tert-butyloxycarbonyl) amino-1-piperidinyl-carbonyl) propionyl-L-histidinyll- (2S, 3R, 4S) -1-cyclohexyl -3,4-dihydroxy-6- (2-pyridyl) -2-hexylamide

0.12 g of the compound from Example 1a are mt 60mg thiophenol ind4ml abs. Acetonitrile for 2 hours at room temperature. After concentration and twice codistilling with toluene is on silica gel with CH ₂ Cl ₂ / MeOH / sat. NH ₃ (10: 1: 0.1) chromatographies. This gives 72 mg of the title compound as a yellow amorphous solid.

R, (SiO ₂ , CH ₂ Cl ₂ / MeOH / saturated NH ₃ 10: 1: 0.1): 0.33

MS (FAB): 802 (M + H)

a) N- [N- (2 (R) -Benzyl-3- (4- (tert-butyloxycarbonyl) amino-1-piperidinylcarbonyl) -propionyl) L-histidinyl (DNP)] - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6- (2-pyridyl) -2-hexylamide

0.4 g of BOC-L-His (DNP) - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide (compound from Example 1 f) are mixed with 6 ml Trifluoroacetic acid in 6ml abs. CH ₂ Cl ₂ stirred for 2 hours at room temperature. The resulting residue after concentration is taken up in 1 M NaHCO ₃ solution, the mixture extracted three times with EA and the EE phase over Na ₂ SO ₄

dried. After concentration, the residue in 6 ml abs. DMF dissolved, 224.5 mg of the compound from Example 1b, 118.6 mg of N, N'-dicyclohexylcarbodiimide and 89.3 mg of 1-hydroxybenzotriazole was added, the pH of the solution was adjusted to 9 with N-ethylmorpholine and allowed to stand for 48 hours. After filtration, it is diluted with EA and washed once each with saturated NaHCO ₃ solution, water and saturated sodium chloride solution, dried over Na ₂ SO ₄ and concentrated. Chromatography on silica gel (CH ₂ Cl ₂ / MeOH 20: 1) gives 140 mg of the title compound as a yellow resin. R, | SiO ₂ , CH ₂ Cl ₂ / MeOH 10: 1): 0.42 MS (FAB): 968 (M + H), 974 (M + Li)

1.3 g of the compound from Example 1 c are abs. 60 ml. Dissolved ethanol and hydrogenated with 200mg Pd / C (10% Pd) for 1 hour at room temperature (1.1 bar H ₂ ). After filtration and removal of the solvent in vacuo, 0.74 g of the title compound crystallize from cold diethyl ether.

R, (SiO ₂ , CH ₂ Cl ₂ / MeOH 9: 1): 0.3

Mp: 135-136 ⁰ C

MS (DCI): 391 (M + H)

c) 2 (R) -Benzyl-3- [4- (tert-butyloxycrabonyl) amino-1-piperidinylcarbonyl] -propionic acid benzyl ether

1, Og (23) -2- (carboxymethyl) -3-phenyl-propionic acid benzyl ester (prepared according to J. Med Chem.31 [1988] 2277) are dissolved in 50 ml abs. CH ₂ Cl ₂ at ⁰ ° C. with 0.31 ml of oxalyl chloride and 0.5 ml of abs. Stirred for DMF1 hour. After concentration, the residue in 25ml abs. CH ₂ Cl _{2 was} added, the solution was adjusted to pH 7 with triethylamine and 0.71 g of the compound from Example 1 d and 0.47 ml of triethylamine, dissolved in 50 ml of abs. CH ₂ Cl ₂ , added dropwise. After stirring for 3 hours at ⁰ ° C., the mixture is concentrated, the residue is taken up in EA, washed once each with cold 2N HCl and saturated NaHCO ₃ solution and dried over MgSO ₄ . Removal of the solvent gave 1.35 g of the title compound as a pale yellow oil. Ri (SiO ₂ , CH ₂ Cl ₂ / MeOH 9: 1): 0.5 MS (DCI): 481 (M + H)

d) 4- (tert-butyloxycarbonyl) amino-piperidine

10.0 g of the compound from Example 1 e are hydrogenated in 60 ml of ethanol / glacial acetic acid 9: 1 with 1.0 g Pd / C (10% Pd) for 1 hour at room temperature (1.1 bar H ₂ ). After filtration, concentration, 2-times Codestillieren with toluene, uptake in EE, shaking with sat. NaHCO ₃ and saturated brine, dried over MgSO ₄ and concentrated to give a beige residue, from which 5.5 g of the title compound were obtained as white crystals by recrystallization from EA.

R, (SiO ₂ , CH ₂ Cl ₂ / MeOH 9: 1): 0.11

Mp 159-161 ⁰ C

MS (DCI): 201 (M + H)

e) 1-Benzyl-4 - ((tert-butyloxycarbonyl) amino] -piperidine

10.0 g of 4-amino-N-benzyl-piperidine are dissolved in 100 ml of abs. Dissolved CHjCl ₂ , treated with 11.5 g of di-tert-butyl dicarbonate, the solution stirred for 2 hours at room temperature and allowed to stand for 12 hours. Concentration and recrystallization of the residue from EA yield 12.9 g of the title compound as white crystals.

R, (SiO ₂ , CH ₂ Cl ₂ / MeOH 8: 2): 0.23

MS (DCI): 291 (M + H)

f) BOC-L-His (DNP) - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6- (2-pyridyl) -2-hexylamide

0.5 mmol of the (2S, 3R, 4S) -isomer from Example 1 g with 5 ml of HCl in DME (saturated) for 2 hours. After concentration, the residue in 3ml abs. DMF solved. Each 0.5 mmole of BOC-His (DNP) -OH, N, N'-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole are added. The solution is adjusted to pH 9 with N-ethylmorpholine and stirred for 24 hours. After filtration, it is diluted with EA, washed once each with saturated NaHCO ₃ solution, water and saturated brine, dried over MgSO ₄ and concentrated. Chromatography on silica gel (CH ₂ Cl ₂ / MeOH 20: 1) gives the title compound as a yellow resin. MS (FAB): 696 (M + H)

g) (2S, 3R, 4S) -2- (tert -butyloxycarbonyl) amino-1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -hexane

93.0 mg of 2-picoline in 1 OmITHF are mixed at ~ 78 ° C with 1.4 ml of n-butyllithium. After warming to room temperature, the mixture is stirred for 30 minutes, then cooled to -4O ⁰ C. 1 mmol (2RS, 3R, 4S) -3-tert-butyldimethylsilyloxy-4- (tert-butyloxycarbonylaminol-S-cyclohexyl-1-oxopentane (known from EP-A 189203, Example 6) are added (dissolved After stirring at room temperature for 10 hours, the mixture is diluted with water and extracted with methyl tert-butyl ether, the crude product is dissolved in THF after concentration and 5 ml of a 1 M solution of tetrabutylammonium fluoride in THF at ⁰ ° C. for 1 hour After dilution with water, extraction with EA and concentration, 0.15 g of the (2S, 3R, 4S) -isomer (MS (FAB): 391 (M + H)) and 0.12 g of the (23.3S, 4S) -isomers (MS (FAB): 391 (M + H)).

Example 2

N-LN- (3- (4-Amino-1-piperidinyl-carbonyl) -2 (R) -benzylpropionyl-L-histidinyl] - (2R, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexalamid acetate

70.0 mg of the compound from Example 1 are in 4 ml of abs. CH ₂ Cl ₂ with 4 ml of trifluoroacetic acid for 2 hours at room temperature. After concentration, it is taken up twice in toluene and concentrated again. The residue is dissolved in a little water, the pH of the solution is adjusted to 5 by the addition of Amberlite ion exchanger (acetate form), the ion exchanger is filtered off and the filtrate is freeze-dried. This results in 63.8 mg of the title compound in the form of a pale yellow, amorphous solid.

MS (FAB): 702 (M + H)

Example 3

N- | N- (2 (S) - (4- (tert -butyloxycarbonyl) amino-1-piperidinyl-carbonyl-oxy) -3-phenyl-propyl-ylyl) -L-histidinyl] - (2S, 3R, 4S) -1-cyclohexyl-3,4-aihydroxy-6 (2-pyridyl) -2-hexylamide

This compound is prepared from the compound from ^Ex: manufactured el 3a as described in the Example 1; yellow amorphous solid.

MS (FAB): 804 (M + H)

a) N- [N- (2 (S) - (4- (tert -butyloxycarbonyl) amino-1-piperidinylcarbonyl-oxy) -3-phenylpropionyl) -L-histidinyl (DNP)] - (2S, 3R , 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide

This compound is prepared by the procedure given in Example 1a from the compounds of Examples 1 f and 3b; yellow resin.

RF, (SiO ₂ , CH ₂ Cl ₂ / MeOH 10: 1): 0.35

MS (FAB): 970 (M + H);

b) 2 (S) - | 4- (tert-Butyloxycarbonyl) amino-1-piperidinyl-carbonyl-oxy] -3-phenyl-propionic acid

Methanol at 0 ⁰ C 3c 465,0mg the compound from Example stirred with 5 ml 1 N sodium hydroxide solution for 3 hours in 5 ml. After concentrating and taking up the residue in water, the solution is adjusted to pH 5 with 2N hydrochloric acid and extracted several times with EA. The organic phase is washed with saturated brine, dried over MgSO ₄ and concentrated.

Recrystallization of the residue from EA / n-heptane gives 242, viz the title compound.

R, (SiO ₂ , CH ₂ Cl ₂ / MeOH 9: 1): 0.29

Mp .: 100-103 ⁰ C

MS (DCI): 293 (M-BOC + 2H), 201 (MC ₁₀ H ₉ O ₄ + 2H)

c) 2 (S) - [4- (tert-Butyloxycarbonyl) amino-1-piperidinylcarbonyl-oxy] -3-phenyl-propionic acid ethyl ester

500.0 mg of ethyl 2 (S) -hydroxy-3-phenyl-propionate (prepared from L-3-phenyl-lactic acid and ethanolic HCl solution) are dissolved in 10 ml of abs. CH ₂ Cl ₂ with 1.1 g di- (I-benzotriazolyll carbonate (70%) and 332,7mg ethyldiisopropylamine. The resulting solution is stirred first for 7 hours at room temperature and then allowed to stand for 12 hours. After addition of 512 5 mg of the compound from Example 1 d and 332.7 mg of ethyldiisopropylamine are stirred for a further 7 hours at room temperature The reaction solution is diluted with 30 ml of EA, washed with saturated Na ₂ CO ₃ and saturated brine and dried over Na ₂ SO ₄ Chromatography on silica gel (n-heptane / EA 2: 1) gives 480.0 mg of the title compound as a colorless oil

R, (SiO ₂ , n-heptane / EE 2: 1): 0.20 MS (DCI): 421 (M + H), 321 (M-BOC + H)

Example 4

N- [N- (2 (S) - (4-Amino-1-piperidinyl-carbonyl-oxy) -3-phenylpropionyl) -L-histidinyl] - (2S, 3R, 4S) -1-cyclohexyl-3,4 dihydroxy-6- (2-pyridyl) -2-hexylamide acetate

This compound is prepared by the procedure given in Example 2 from the compound of Example 3; beige, amorphous solid.

MS (FA3): 704 (M + H)

Examples

N- | N- (2 (R) -benzyl-3- (N-benzyl-piperidinyl-4-amino-carbonyl) propionyl) -L-histidinyl] - (2S, 3R, 4S) -1-cyclohexyl-3, 4-dihydroxy-6- (2-pyridyl) -2-hexylamide

This compound is prepared according to the procedure given in Example 1 from the compound of Example 5a; yellow

MS (FAB): 792 (M + H)

a) N- [N- (2 (R) -Benzyl-3- (N-benzyl-piperidinyl-4-amino-carbonyl) -propionyl) -L-histidinyl (DNP)] - (2S, 3R, 4S) -1 cyclohexyl-3,4-dihydroxy-6- (2-pyridyl) -2-hexylamide

This compound is prepared according to the procedure given in Example 1 a from the compounds of Examples 1 g and 5b.

MS (FAB): 958 (M + H), 964 (M + Li)

b) 2 (R) -Benzyl-3 (N-benzyl-piperidinyl-4-amino-carbonyl) -propionic acid

345.0 mg of the compound from Example 5c are hydrogenated in 30 ml of ethanol with 70 mg of Pd / C (10% Pd) for 10 minutes at room temperature (1.1 bar H ₂ ). Filtration and concentration gives 269.0 mg of the title compound in the form of a light brown oil. R, (SiO ₂ , CH ₂ Cl ₂ / MeOH 1: 1): 0.21 MS (DCI): 381 (M + H)

c) Benzyl 2 (R) -Benzyl-3- (N-benzyl-pipsridinyl-4-amino-carbonyl) -propionate

This compound is prepared from 4-amino-N-benzylpiperidine according to the method described in Example 1 c, which here by the use of 2 equivalents of base, waiving the extraction with 2 N HCl solution and the chromatographic workup on silica gel (CH ₂ CI ₂ / EE 7: 3) is modified. R, (SiO ₂ , CH ₂ Cl ₂ / EE 7: 3): 0.25 MS (DCI): 471 (M + H)

Examples

N- [N- (2 (R) -benzyl-3- {piperidinyl-4-amino-carbonyl) propionyl) -L-histidinyll- (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 - (2-pyridyD-2-hexylamide acetate

40.0 mg of the compound from Example 5 are hydrogenated in 10 ml of ethanol / glacial acetic acid 9: 1 with 10 mg Pd / C (10% Pd) for 1 hour at room temperature (1.1 bar H ₂ ). After filtration, concentration and 2 times codistillation with toluene, the residue is taken up in water and the solution is freeze-dried. This results in 22.3 mg of the title compound as a beige, amorphous solid.

MS (FAB): 702 (M + H)

Example 7

N- [N- (2 (S) - (N-benzyl-piperidinyl-4-amino-carbonyl-oxy) -3-phenyl-propionyl) -! .- histidinyl] - (2S, 3R, 4S) -1- cyclohexy'-3,4-clihydroxy-6- (2-pyridyl) -2-hexylamide

This compound is prepared from the compound of Example 7a according to the procedure given in Example 1; yellow, amorphous solid

MS (FAB): 794 (M + H)

a) N- [N- (2 (S) -N-benzyl-piperidinyl-4-amino-carbonyl-oxy) -3-phenyl-propionyl) -Lh-idinyl (DNP)) - (2S, 3R, 4S) - 1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide

This compound results from the compounds of Examples 1 g and 7 b according to the procedure indicated in Example 1 a; yellow resin.

MS (FAB): 960 (M + H); 966 (M + Li)

b) 2 (S) - (N-Benzyl-piperidinyl-4-amino-carbonyl-oxy) -3-phenyl-propionic acid

400.0 mg of the compound from Example 7c are stirred in 5 ml of ethanol with 1 ml of 1 N sodium hydroxide solution at ⁰ ° C. for 3 hours and left to stand at about 8 ° C. for 12 hours. After concentration, the residue is dissolved in water, neutralized with 2 N hydrochloric acid and extracted after addition of sodium chloride several times with EA. Drying over Na ₂ SO _4, concentration and chromatography on silica gel (CH ₂ CI ₂ / Me0H 2: 1) affords the title compound 224,0mg

 MS (DCI): 383 (M + H)

c) 2 (S) - (N-Benzyl-piperidinyl-4-amino-carbonyl-oxy) -3-phenyl-propionic acid ethyl ester

This compound is prepared from 4-amino-N-benzylpiperidine according to the procedure given in Example 3c, wherein here pyridine is used as the auxiliary base and in the chromatographic work-up the eluent n-heptane / EE 1: 1; white crystals.

Ri (SiO ₂ , n-heptane / EE 1: 1): 0.25

Mp 72-74 ° C

MS (DCI): 411 (M + H)

Example 8

N- [N- (3-phenyl-2 (S) - (piperidinyl-4-amino-carbonyl-oxy) propionyl) -L-histidinyl] - (2S, 3R, 4S) -1-cyclohexyl-3,4 dihydroxy-6- (2-pyridyl) -2-hexylamide acetate

This compound is prepared from the compound of Example 7 following the procedure set forth in Example 6; light brown, amorphous solid.

MS (FAB): 702 (M + H)

Example 9

N- [N- (2 (R) -benzyl-3- (4- (tert-butyloxycarbonyl) amino-1-piperidinyl-carbonyl) propionyl) -L-histidinyll- (2S, 3S) -1-cyclohexyl- 3-hydroxy-6- (2-pyridyl) -2-hexylamide

80 mg of the compound from Example 9a are stirred in 1 ml of 90% acetic acid for 3 hours at 60 ° C. After concentration, the residue is taken up in EA, washed twice each with saturated NaHCO ₃ and common salt solution and dried over Na ₂ SO ₄ . Concentration and chromatography on silica gel (CH ₂ Cl ₂ / MeOH 9: 1) gives 31.2 mg of the title compound.

MS (FAB): 786 (M + H)

a) N- [N- (2 (R) -Benzyl-3- (4- (tert-butyloxycarbonyl) -amino-1-piperidinylcarbonyl) -propionyl) -L-histidinyl (Trt)) - (2S, 3S) -1-cyclohexyl-3-hydroxy-6- (2-pyridyl) -2-hexylamide

375 mg of the compound from Example 9b are in 4ml abs. DMF dissolved, 225 mg of the compound from Example 1 b, 120 mg of N, N'-dicyclohexylcarbodiimide and 90 mg of 1-hydroxybenzotriazole added and adjusted with N-ethylmorpholine, the solution to pH9. After standing at room temperature for 48 hours, it is filtered, the filtrate is diluted with EA and washed once each with saturated NaHCu ₃ solution, water and saturated brine. Drying, concentration and chromatography on silica gel give 298 mg of the title compound

 MS (FAB): 1028 (M + H)

b) H-His (Trt) - (2 S, 3 S) -1-cyclohexyl-3-hydroxy-6- (2-pyridyl) -2-hexylamide

600 mg of the compound described in Example 9c are in GmI abs. DMF with 0.65 ml of diethylamine for 1 hour at room temperature. Concentration and chromatography on silica gel (CH ₂ Cl ₂ / MeOH 9: 1) gives 380 mg of the title compound. MS (FAB): 656 (M + H)

c) Fmoc-His (Trt) - (2S, 3S) -1-cyclohexyl-3-hydroxy-6- (2-pyridyl) -2-hexylamide 1.0g Fmoc-His (Trt) -OH, 283mg 1-hydroxybenzotriazole , 370 mg of tyN'-dicyclohexylcarbodiimide and 0.25 ml of N-ethylmorpholine are dissolved in 10 ml of abs. Dissolved DMF and stirred for 1 hour at room temperature. To this mixture is added dropwise a solution of 483 mg of (S) -amino-1-cyclohexyl-3 (S) -hydroxy-6 (2-pyridyl) -hexane (known from EP-A 0255082) in 4 ml of DMF and 12 hours stirred at room temperature. After addition of 5 ml of water is filtered from the 'urea formed and taken up with EA. The organic phase is washed repeatedly with saturated NaHCO ₃ and saturated brine, dried over MgSO ₄ and concentrated after filtration in vacuo. Chromatography on silica gel provides 880 mg of said compound. Melting point: 85 ^° C. MS (FAB):

Example 10

N- [N- (3- (4-Amino-1-piperidinyl-carbonyl) -2 (R) -benzylpropionyl) -L-histidinyl] - (2S, 3S) -1-cyclohexyl-3-hydroxy-6- ( 2-pyridyl) -2-hexylamide-acetate 25 mg of the compound from Example 9 are in 2 ml abs. CH ₂ Cl ₂ stirred with 2 ml of trifluoroacetic acid for 2 hours at room temperature. After concentration, 2-times codistilling with toluene, the residue is dissolved in water, adjusted by addition of Amberlitelonenaustauscher (acetate form), the solution to pH5, filtered and the filtrate is lyophilized. The title compound is obtained in a yield of 20 mg.

MS (FAB): 686 (M + H)

b: play 11 N- (N- (2 (S) - (4- (tert -butyloxycarbonyl) amino-1-piperidinyl-carbonyl-oxy) -3-phenyl-propionyl) -L-histidinyl-1- (2S, 3S ) -1-cyclohexyl-3-hydroxy-6- (2-pyridyl) -2-hexylamide This compound is prepared from the compound of Example 11a by the method given in Example 9.

MS (FAB): 788 (M + H)

a) N- [N (2 (S) - (4- (tert -butyloxycarbonyl) amino-1-piperidinyl-carbonyl-oxy) -3-phenylpropionyl) -L-histidinyl (Trt)] - (2S, 3S) -1-cyclohexyl-3-hydroxy-6- (2-pyridyl) -2-hexylamide

This compound is prepared from the compounds of Examples 3b and 9b according to the procedure given in Example 9a. MS (FAB): 1030 (M + H)

Example 12

N- [N- (2 (S) - (4-Amino-1-piperidinyl-Cjrbonyl-oxy) -3-phenyl-propionyl) -L-histidinyl] - (2S, 3S) -1-cyclohexyl-3-hydroxy -6- (2-pyridyl) -2-hexylamide-acetate The title compound is prepared according to the procedure described in Example 2 from the compound described in Example 11.

MS (FAB): 688 (M + H)

Example 13

N- [N- (2 (R) -Benzyl-3- (N-benzyl-piperidinyl-4-amino-carbonyl) -propion / 1) -L-histidinyl-{2 S, 3 S) -1-cyclohexyl-3 -hydroxy-6- (2-pyridyl-2-hexyl-amide The title compound is prepared according to the procedure described in Example 9 from the compound indicated in Example 13a.

MS (FAB): 776 (M + H)

a) N- [N- (2 (R) -Benzyl-3- (N-benzyl-piperidinyl-4-amino-carbyl) -propionyl) -L-histidinyl (Trt)] - (2S, 3S) -1-cyclohexyl -3-hydroxy-6- (2-pyridyl) -2-hexylamide

This compound is prepared from the compounds of Examples 5 b and 9 b by the method described in Example 9 a. MS (FAB): 1018 (M + H)

Example 14

N- [N- (2 (R) -benzyl-3- (piperic '; nyl-4-amino-carbonyl !! - propionyl) -L-histidinyll- (2S, 3S) -1-cyclohexyl-3-hydroxy- 6- (2-pyridyl) -2-hexylamide-acetate The title compound is prepared from the compound of Example 13 according to the procedure given in Example 6.

MS (FAB): 686 (M + H)

Example 15

N- [N- (2 (S) - (N-benzyl-piperidinyl-4-amino-carbonyl-oxy) -3-phenyl-propionyl) -L-histidinyl] - (2S, 3S) -1-cyclohexyl-3 -hydroxy-6- (2-pyridyl) -2-hexylamide The title compound is prepared from the compound indicated in Example 15a by the method described in Example 9.

MS (FAB): 778 (M + H)

a) N- [N- (2 (S) - (N-Benzyl-piperidinyl-4-amino-carbonyl-oxy) -3-phenylpropionyl) -L-histidinyl (Trt)] - (2S, 3S) - 1-cyclohexyl-3-hydroxy-6- (2-pyridyl) -2-hexylamide

The title compound is prepared from the compounds listed in Examples 7b and 9b by the method described in Example 9a. MS (FAB): 1020 (M + H)

Example 16

N-IN- (3-phenyl-2 (S) - (piperidinyl-4-amino-carbonyl-oxy) propionyl) -L-nistidinyl] - (2S, 3S) -1-cyclohexyl-3-hydroxy-6- (2-pyridyl) -2-hexylamide acetate The title compound is prepared from the compound of Example 15 following the procedure described in Example 6.

MS (FAB): 688 (M + H)

Example 17

N- [N- (2 (R) -benzyl-3- (4- (tert-butyloxycarbonyl) amino-1-piperidinyl-carbonyl) propionyl) -L-notvalinyll- (2S, 3R, 4S) -1- cyclohexyl-3,4-dihydroxy-6- (2-pyridyl) -2-hexylamici The title compound is prepared from the compounds of Examples 1 b and 17 a by the procedure given in Example 1 a.

a) BOC-Nva- (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide The title compound is prepared from BOC-norvaline and the compound of Example 1g according to the prepared in Example 1 a.

MS (FAB): 492 (M + H)

Example 18

N- | N- (3- (4-Amino-1-piperidinyl-carbonyl) -2 (R) -benzylpropionyl) -L-norvalinyl] - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy -6- (2-pyridyl) -2-hexylamide-acetate The title compound is prepared from the compound of Example 17 according to the procedure given in Example 2.

MS (FAB): 664 (M + H)

Example 19

N- [N- (2 (S) - (4- (tert-butyloxycarbonyl) amini-1-piperidinyl-carbonyl-oxy) -3-phenyl-propionyl) -L-norvalinyl] - (2S, 3R, 4S) 1-cyclohexyl-3,4-dihydroxy-6- (2-pyridyl) -2-hexylamide The title compound is prepared from the compounds of Examples 3 b and 17a by the procedure given in Example 1a.

MS (FAB): 766 (M + H)

Example 20

N- (N- (2 (S) - (4-Amino-1-piperidinyl-carbonyl-oxy) -3-phenyl-propionyl) -L-norvalinyl) - (2S, 3R, 4S) -1-cyclohexyl-3 , 4-Dihydroxy-6- (2-pyridyl) -2-hexylamide-acetate. The title compound was prepared wild from the compound of Example 19 according to the procedure given in Example 2.

MS (FAB): 666 (M + H)

Example 21

N- [N- (2- (R) -benzyl-3- (N-benzyl-piperidinyl-4-amino-carbonyl) propionyl) -L-norvalinyl] - (2S, 3R, 4S) -1-cyclohexyl-3 , 4-Dihydroxy-6- (2-pyridyl) -2-hexylamide The title compound is prepared from the compounds of Examples 5 bund 17a according to the procedure given in Example 1a.

MS (FAB): 754 (M + H)

Example 22

N- [N- (2 (R) -benzyl-3- (piperidinyl-4-amino-carbonyl) propionyl) -L-norvalinyl | - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy- 6- (2-pyridyl-2-hexylamide-acetate. The title compound is prepared from the compound of Example 21 following the procedure described in Example 6.

MS (FAB): 664 (M + H)

Example 23

N- (N- (2 (S) - (N-Benzyl-piperidinyl-4-amino-carbonyl-oxy) -3-phenylpropionyl) -L-norvalinyl-J- (2S, 3R _/ 4S) -1-cyclohexyl- 3,4-Dihydroxy-6- (2-pyridyl) -2-hexylamide The title compound is prepared from the compounds of Examples 7b and 17a by the method described in Example 1a.

MS (FAB): 756 (M + H)

Example 24

N- [N- (3-phenyl-2 (S) - (piperidinyl-4-amino-carbonyl-oxy) propionyl) -L-norvalinyl] - (2S, 3R, 4S) -1-cyclohexyl-3,4 -dihydroxy-6- (2-pyridyl-D-2-hexylamide-ac-stat The title compound is prepared from the compound of Example 23 according to the procedures given in Example 6.

Example 25

N- [N- (3- (4- (tert -butyloxycarbonyl) amino-1-piperidinyl] arbonyl) -2 (R) - (1-naphthylmethyl) propionyl) -L-histidinyl) - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6- (2-pyridyl) -2-hexylamide The title compound is prepared from the compound of Example 25a according to the procedure given in Example 1.

MS (FAB): 852 (M + H)

a) N-IN-Ol-tert-butyloxycarbonyl-diamino-i-piperidinyl-carbonyl-D-IRI-d-naphthylmethy-propionyl-L-histidinyl-IDNP)] - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy -6- (2-pyridyl) -2-hexylamide

The title compound is prepared from the compounds of Examples 1 fund 25b by the method given in Example 1a.

MS (FAB): 1018 (M + H)

b) S-t'l-tert-butyloxycarbony-diamino-i-piperidinyl-carbonyl-1-IR-1-naphthylmethyD-propionic acid

The title compound is prepared from the compound of Example 25c by the procedure given in Example 1b. MS (DCI): 441 (M + H)

c) S-H-tert-Butyloxycarbonyl-din-amino-1-piperidinyl-1-phenyl-1-naphthyl-ethyl-propionate

The title compound is prepared from 2 (R) - (carboxymethyl) -3- (1-naphthyl) -propionic acid benzyl ester (prepared according to J. Med. Chem. [1988] 2277-22d8) and the compound from Example 1d after that in Example 1 c specified method. MS (DCI): 531 (M + H)

Example 26

N- [N- (3- (4-Amino-1-piperidinyl-carbonyl) -2 (R) - (1-naphthylmethyl) propionyl) -L-histidinyl | - (2S, 3R, 4S) -1-cyclohexyl- 3,4-dihydroxy-6- (2-pyridyl) -2-hexylamide acetate

The title compound is prepared from the compound of Example 25 according to the procedure given in Example 2.

MS (FAB): 752 (M + H)

Example 27

N- [N- (3- (N-Ben7yl-piperidinyl-4-amino-carbonyl) -2 (R) - (1-naphthylmethyl) propionyl) -L-histidinyl] - (2S, 3R, 4S) -1 cyclohexyl-3,4-dihydroxy-6- (2-pyridyl) -2-hexylamide

The title compound is prepared from the compound of Example 27a by the method given in Example 1.

MS (FAB): 842 (M + H)

a) N- [N- (2 (R) - (3- (N-Benzyl-piperidinyl-4-amino-carbonyl) -1-naphthylmethyl) -propionyl) -L-histidinyl (DNP)] - (2S, 3R , 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide

The title compound is prepared from the compounds of Examples 1 and 27b according to the procedure given in Example 1a.

MS (FAB): 1008 (M + H)

b) 2 (R) - [3- (N-Benzyl-piperidinyl-4-amino-carbonyl) -1-naphthylmethyl] -propionic acid

The title compound is prepared from the compound of Example 27c according to the procedure given in Example 5b. MS (DCI): 431 (M + H)

c) 2 (R) - [3- (N-Benzyl-piperidinyl-4-amino-carbonyl) -1-naphthylmethyl) -propionic acid benzyl ester

The title compound is prepared from 4-amino-N-benzylpiperidine and 2 (R) - (carboxymethyl) -3- (1-naphthyl) -propionic acid benzyl ester according to the procedure given in Example 1c

 MS (DCI): 521 (M + H)

Example 28

N- [N- (2 (R) - (1-naphthylmethyl) -3- (4-amino-piperidinyl-carbonyl) propionyl) -L-histidinyl] - (2S, 3R, 4S) -1-cycloiiexyl-3, 4-dihydroxy-6- (2-pyridyl) -2-hexylamide acetate

The title compound is prepared from the compound of Example 27 according to the procedure given in Example 6.

MS (FAB): 752 (M + H)

Example 29

N- [N- (2 (S) -benzyl-3- (4-tert-butyloxycarbonyl) amino-1-piperidinyl-sulfonyl) propionyl) -L-histidinyl] - (2S, 3R, 4S) -1- cyclohexyl-3,4-dihydroxy-6- (2-pyridyl) -2-hexylamide

The title compound is prepared from the compound of Example 29a analogously to the procedure described in Example 1.

MS (FAB): 838 (M + H)

a) N-IN- (2 (S) -benzyl-3- (4- (tert-butyloxycarbonyl) -nmino-1-piperidinylsulfonyl) -propionyl) -L-histidinyl (DNP)] - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6- (2-pyridyl) -2-hexylamide

The title compound is z. Example by the method of Example 1 a from 2 (R, S) -Benzyl-3- [4- (tert-butyloxycarbonyl) amino-1 piperidinyl-sulfonylj-propionic acid. The two resulting diastereomers are separated by column chromatography on silica gel with the solvent mixture of methylene chloride and methanol 96/4 to 9/1. The product eluted first has an optical rotation of [α] "= -35.9 ° (c = 1, CHaOH) and the subsequently eluted product has a rotation of [α] o = -24.8 ° (c = 1, . CH ₃ OH) Eino of the two diastereomers is the title compound MS (FAB). 1004 (M + H)

b) 2 (R, S) -Benzyl) -3- [4- (tert -butyloxycarbonyl) amino-1-piperidinylsulfonyl] -propionic acid 2- (R, S) -benzyl-3-chloroisulfonyl-propionic acid benzyl ester becomes analogous of EP-A 236734. Instead of Benzylmalonsäuremonoethylesters Benzylmalonsäuremonobenzylester is used. To the chlorosulfonyl compound (2 mmol) in methylene chloride (3.2 ml) is added at -10 ° C 4-tert-butyloxycarbonyl-amino-piperidine (2 mmol) and triethylamine (2 mmol) in 5.4 ml of methylene chloride. After the reaction (15min at -15 ⁰ C) and workup 715mg sulfonamide derivative can be obtained. M.p .: 115-1 I7 ° C This substance is catalytically hydrogenated at room temperature with Pd / C in methanol to give the title compound. Mp .: 161-163 ⁰ C MS (FAB): 1004 (M + H)

Example 30

N- (N- (3- (4-Amino-1-piperidinyl-sulfonyl) -2 (R) -benzylpropionyl) -L-histidinyll- (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy- 6- (2-pyridyl) -2-hexylamide acetate The title compound is prepared from the compound of Example 29 following the procedure of Example 2.

MS (FAB): 738 (M + H)

Example 31

N- [N- (2 (R) -benzyl-3- (4- (tert-butyloxycarbonyl) aminomethyl-1-piperidinylcarbonyl) propionyl) -L-histidinyll- (2S, 3R, 4S) -1-cyclohexyl- 3,4-Dihydroxy-6 (2-pyridyl) -2-hexylamide The title compound is prepared from the compound of Example 31a by the method of Example 1.

MS (FAB): 816 (M + H)

a) N- [N- (2 (R) -Benzyl-3- (4- (tert -butyloxycarbonyl) aminomethyl-1-piperidinylcarbonyl) -propionyl) -L-histidinyl (DNP)] - (2S, 3R, 4S ) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide

The title compound is prepared from the compounds of Examples 1f and 31b by the method of Example 1a. MS (FAB): 982 (M + H)

b) 2 (R) -Benzyl-3- [4- (tert -butyloxycarbonyl) aminomethyl-1-piperidinylcarbonyl] -propionic acid

The title compound is prepared from the compound of Example 31c by the procedure given in Example 1b. MS (DCI): 405 (M + H)

c) 2 (R) -Benzyl-3- [4- (tert-btityloxycarbonyl) aminomethyl-1-piperidinylcarbonyl] -propionic acid benzyl ester

The title compound is prepared from (2R) -2 (carboxymethyl) -3-phenylpropionic acid benzyl ester and the compound from Example 31d by the procedure given in Example 1c. MS (DCI): 495 (M + H)

d) 4- (tert-butyloxycarbonyl) aminomethylpiperidine

10.8 g of 4- (aminomethyl) piperidine are dissolved in 100 ml CH ₂ CI _2, 25g di- (tert-butyloxycarbonyl) carbonate added and the resulting solution stirred for 3 hours at room temperature. After concentration, the residue is taken up in diisopropoyl ether, extracted twice with 100 ml of 5% NaHSO ₄ solution each time, the combined extracts are adjusted to pH 9 with Na ₂ COa and extracted three times with 250 ml of EA. Drying over Na ₂ SO ₄ and rotary evaporation yields 6 g of the title compound as a colorless oil. R ₁ (SiO ₂ , CH ₂ Cl ₂ / MeOH 9: 1): 0.12 MS (DCI): 215 (M + H)

Example 32

N- [N- (3- (4-aminomethyl-1-piperidinyl-carbonyl) -2 (R) -benzylpropionyl) -L-histidinyl) - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy -6 (2-pyridyl) -2-hexylamide-acetate This compound is prepared from the compound of Example 31 according to the procedure given in Example 2; white, amorphous solid.

MS (FAB): 716 (M + H)

Example 33

N- [N- (2 (S) - (4- (tert-butyloxycarbonyl) aminomethyl-1-piperidinylcarbonyl-oxy) -3-phenyl-propionyl) -L-histidinyl] - (2S, 3R, 4S) -1 -cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide This compound is prepared on the compound of Example 33a according to the procedure given in Example 1.

MS (FAB): 318 (M + H)

a) N- [N- (2 (S) - (4-tert-butyloxycarbonyl) aminomethyl-1-piperidinylcarbonyl-oxy) -3-phenylpropionyl) -L-histidinyl (DNP)] - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridinyl) -2-hexylamide

The title compound was prepared wild by the procedure given in Example 1 a from the compounds of Examples 1 fund 33b; yellow resin. MS (FAB): 984 (M + H)

b) 2 (S) -l4- (tert-butyloxycarbonyl) aminomethyl-1-piperidinyl-carbonyl-oxy] -3-phenyl-propionic acid

This compound is prepared from the compound of Example 33c by the method of Example 3b. MS (DCI): 407 (M + H)

c) 2 (S) - [4- (tert-Butyloxycarbonyl) aminomethyl-1-piperidinyl-carbonyl-oxy] -3-phenyl-propionic acid ethyl ester This compound is prepared from ethyl 2 (S) -hydroxy-3-phenyl-propionate and the Compound prepared from Example 31 d according to the procedure given in Example 3c.

MS (DCI): 435 (M + H)

Example 34

N- [N- (2 (S) - (<; - aminomethyl-1-piperidinyl-carbonyl-oxy) -3-phenyl-propionyl) -L-histidinyll- (2S, 3R, 4S) -1-cyclohexyl-3 , 4-dihydroxy-6 (2-pyridyl) -2-hexylamide acetate.

The title compound is prepared according to the procedure given in Example 2 from the compound of Example 33; beige, amorphous dye.

MS (FAB): 718 (M + H)

Example 35

N- [N- (2 (R) -benzyl-3- (4- (tert-b ⁱ jtyloxycarbonyl) amino-1-piperidinyl-carbonyl) propionyl) -S-methyl-L-cysteinyl] - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide

90.0 mg of the compound from Example 35a are stirred in 1 ml of CH ₂ Cl ₂ with 600ulTrifluoressigsäureh 4h at room temperature. It is concentrated, codistilled with toluene and CH ₂ Cl ₂ , the residue taken up in EA and washed several times with 1 N NaHCO ₃ solution. After shaking with sat. NaCl solution and drying over Na ₂ SC ^ is concentrated. The resulting residue is dissolved after drying in a high vacuum in 1 liter of acetonitrile, successively 67 mg of the compound from Example 1b, 26 mg of 1-hydroxybenzotriazole, 32 μM of N-ethylmorpholine and 68 mg of O-benzotriazol-1-yl-N, N, N ', N' tetramethyluronium hexafluorophosphate (HBTU) was added and the solution stirred for 4 h at room temperature. The solution was saturated with 5ml. NaCl solution, extracted three times with EA, the combined EE extracts twice with sat. NaHCOV solution and once with ge. NaCl solution washed. After drying over Na ₂ SCU and concentration, chromatography on silica gel (CH ₂ Cl ₂ / MeOH 15: 1). This results in 80 mg of Titelverbinduiig as a slightly beige resin

R, (SiO ₂ , CH ₂ Cl ₂ / MeOH 9: 1): 0.45 MS (FAB): 782 (M HH), 804 (M + Na)

a) S-Methyl-L-cysteine (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide This compound is prepared from the compound of Example 1 g and BOC -S-methyl-L-cystine according to the procedure given in Example 1 f.

MS (FAB): 510 (M + H), 516 (M + Li)

Example 36

N- [N- (3- (4-Amino-1-piperidinyl-carbonyl-2 (R) -benzylpropionyl) -S-methyl-L-cysteinyll- (2S, 3R, 4S) -1-cyclohexyl-3,4 dihydroxy-6 (2-pyridinyl) -2-hexylamide acetate.

The title compound is prepared from the compound of Example 35 following the procedure set forth in Example 2; pale yellow, amorphous solid.

MS (FAB): 682 (M + H), 704 (M + Na)

Example 37

N- [N- (3- (4-tert-butyloxycarbonyl) aminomethyl-1-piperidinyl-carbonyl) -2 (R) - (1-naphthylmethyl) propionyl) -L-histidinyl] - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexyl3mid

The title compound is prepared from the compound of Example 37a by the method of Example 1.

MS (FAB): 866 (M + H)

a) N- [N- (3- (4- (tert-Butyloxycarbonyl) aminomethyl-1-piperidinylcarbonyl) -2 (R) - (1-naphthylmethyl) propionyl) -L-histidinyl (DNP)] - ( 2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide

This compound is prepared from the compounds of Examples 1 f and 37 b according to the procedure given in Example 1 a.

MS (FAB): 1032 (M + H), 1038 (M + Li)

b) 3- [4- (tert-Butyloxycarbonyl) aminomethyl-1-piperidinylcarbonyl-2- (R) - (1-naphthylmethyl) -propionic acid This compound was obtained from Example 37c the method of Example 1 b shown. MS (DCI): 455 (M + H)

c) 3- [4- (tert -BiJtylox, ci; rboiiyl) aminomethyl-1-piperidinylcarbonyl) -2 (R) - (1-naphthylmethyl) -propionic acid benzyl ester These Ve. Binding is prepared from 2 (R) - (carboxymethyl) -3- (1-naphthyl) -propionic acid benzyl ester and the compound of Example 1 d according to the procedure given in Example 1 c.

MS (DCI): 545 (M + H)

Example 38

N- [N- (3- (4-aminomethyl-1-piperidinyl-carbonyl) -2 (R) - (1-naphth / lmethyl) propionyl) -L-histidinyl] - (2S, 3R, 4S) -1 cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide acetate

The title compound is prepared from the compound of Example 37 according to the procedure given in Example 2.

MS (FAB): 766 (M + H!

N- | N- (3- (4- (tert-butyloxycarbonyl) amino-1-piperidinyl-carbonyl) -2 (R) - (1-naphthylmethyl) propionyl) -S-methyl-L-cysteinyl] - (2S , 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide The title compound is prepared from the compounds of Examples 25b and 35a according to the procedure given in Example 35.

MS (FAB): 832 (M + H)

Example 40

N- [N- (3- (4-Amino-1-piperidinyl-carbonyl) -2 (R) - (1-naphthylmethyl) propionyl) -Smethyl-L-cysteinyl] - (2S, 3R, 4S) -1 -cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide acetate The title compound is prepared from the compound of Example 39 following the procedure of Example 2.

MS (FAB): 732 (M + H)

Example 41

N- | N- (3- (4- (tert -butyloxycarbonyl) amino-1-piperidinylcarbonyl) -2 (R) - (1-tetrahydronaphthylmethyl) propionyl ⁽ l) -L-histidinyl) - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydro-6 (2-pyridyl) -2-hexylamide The title compound is prepared from the compound of Example 41a by the method of Example 1.

MS (FAB): 856 (M + H)

a) N- [N- (3- (4- (tert-Butyloxycarbonyl) amino-1-piperidinylcarbonyl) -2 (R) - (1-tetrahydronaphthylmethyl) propionyl) -L-histidinyl (DNP)] - ( 2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide

This compound is prepared from the compounds of Examples 1 f and 41 b by the method given in Example 35.

MS (FAB): 1022 (M + H)

b) 3- [4- (tert-Butyloxycarbonyl) amino-1-piperidinylcarbonyl] -2 (R) - (1-tetrahydronaphthylmethyl) propionic acid This compound is formed in addition to that of Example 25b from the compound of Example 25c according to the Example 1 b, if the hydrogenation is extended from 1 h to 24 h. The title compound is isolated by chromatography on KG (CM ₂ Cl ₂ / MeOH 95: 5).

MS (DCI): 455 (M + H)

Example 42

N-LN- (3- (4-Amino-1-piperidinyl-carbonyl) -2 (R) - (1-tetrahydronaphthylmethyl) propionyl) -L-histidinyl] - (2S, 3R, 4S) -cyclohexyl-3,4 -dihydroxy-6 (2-pyridyl) -2-hexylamide acetate The title compound is prepared from the compound of Example 41 following the procedure set forth in Example 2.

MS (FAB): 756 (M + H)

Example 43

N- [N- (2 (R) -benzyl-3- (4- (tert-butyloxycarbonyl) amino-2,6-dimethyl-1-piperidinyl-carbonyl) -propionic / l) -L-histidinyl] - ( 2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide. The title compound is prepared from the compound of Example 43a according to the procedure given in Example 1.

MS (FAB): 830 (M + H)

a) N- [N- (2 (R) -benzyl-3- (4- (tert-butyloxycarbonyl) ^am; no-2,6-dimethyl-1-piperidinyl-carbonyl) propionyl) -L-histidinyl ( DNP)] - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide

The title compound is prepared from the compounds of Examples 1 fund 43 b by the method given in Example 35.

MS (FAB): 996 (M + H)

b) 2 (R) -benzyl-3- [4- (tert-butyloxycarbonyl) amino-2,6-dimethyl-1-piperidinylcarbonyl] -propionic acid

The title compound is prepared from the compound of Example 43c by the procedure given in Example 1b. MS (DCI): 419 (M + H)

c) 2 (R) -Benzyl-3 [4- (tert -butyloxycarbonyl) amino-2,6-dimethyl-1-piperidinylcarbonyl-propionic acid, boryl ester

The title compound is prepared from (2R) -2- (carboxymethyl) -3-phenylpropionic acid benzyl ester and the compound from Example 43d by the method of Example 1c. MS (DCI): 509 (M + H)

d) 4- (tert -butyloxycarbonyl) amino-2,6-dimethyl-piperidine

This compound is prepared from the compound of Example 43c by the method of Example 1d. MS (DCI): 229 (M + H)

e) 1-Benzyl-4 - [(tert-butyloxycarbonyl) aminole-2,6-dimethyl-piperidine

This compound is prepared from the compound of Example 43f according to the procedure given in Example 1 e. MS (DCI): 319 (M + H)

f) 4-amino-1-benzyl-2,6-dimethyl-piperidine

5 g of the compound from Example 43g are dissolved in 10 mmol of methanol, 2 ml of conc. Ammonia solution and Raney nickel added and hydrogenated in an autoclave at a pressure of 100 atm. It is filtered, concentrated and the resulting residue is purified by distillation. MS (DCI): 2 "9 (M + H)

g) 1-Denzyl-2,6-dimethyl-4-piperidine oxime

10 g of 1-.3-benzyl-2,6-dimethyl-4-piperidone (prepared from benzylamine and crotonic acid ethyl ester analogously to Bull. Chem. Soc. Japan 31 (1958) 410 are dissolved in 60 ml of methanol and this solution is dissolved in a solution of 3 ., 8 g of hydroxylamine hydrochloride and 4.5 g of sodium acetate was dropped into 150 ml of water is stirred for 2 h at 6O ⁰ C, cooled to ⁰ ° C and filtered off the precipitated oxime After drying resulting 5.2 g of the title compound MS (DCI)..: 233 (M + H)

Example 44

N-LN- (3- (4-amino-2,6-dimethyl-1-piperidinyl-carbonyl) -2 (R) -benzyl-propionyl) -L-histidinyl] - (2S, 3R, 4S) -1- cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide acetate The title compound is prepared from the compound of Example 43 following the procedure set forth in Example 2.

MS (FAB): 730 (M + H)

Example 45

N- | N- (2 (S) - (4- (tert-ButyloxyccVbonyl) amino-2,6-dimethyl-1-piperidinyl-carbonyl-oxy) -3-phenyl-propionyl) -L-histidinyl] - ( 2S, 3R, 4S) -1-cyclohexyl-3,4-di ../hydroxy-6 (2-pyridyl) -2-hexylamide. The title compound is prepared from the compound of Example 39a, following the procedure given in Example 1.

MS (FAB): 832 (M + H)

a) N- [N- (2 (S) - (4- (tert -butyloxycarbonyl) amino-2,6-dimethyl-1-piperidinylcarbonyl-oxy) -3-phenylpropionyl) -L-histidinyl ( DNP)] - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide

The title compound is prepared from the compounds of Examples 1 fund 45 b according to the procedure given in Example 35.

MS (FAB): 998 (M + H)

b) 2 (S) - [4- (tert-Butyloxycarboryl) amino-2,6-dimethyl-1-piperidinyl-carbonyl-oxy) -3-phenyl-propionic acid. This compound is prepared from the compound of Example 45c by the method of Example 3b. MS (DCI): 421 (M + H)

c) 2 (S) - [4- (tert-Butyloxycarbonyl) amino-2,6-dimethyl-1-piperidinyl-carbonyl-oxy] -3-phenyl-propionic acid ethyl ester This compound is prepared from 2 (S) -hydroxy-3 -phenyl-propionic acid ethyl ester and the compound of Example 43d by the method of Example 3c.

MS (DCI): 449 (M + H)

Example 46

N- [N- (2 (S) - (4-amino-2,6-dimethyl-1-piperidinyl-carbonyl-oxy) -3-phenylpropionyl) -L-histidinyl) - (2S, 3R, 4S) - 1-Cyclohexyl-3,4-dihydroxy-6 (2-pyridyl) -2-hexylamide acetate The title compound is prepared from the compound of Example 45 following the procedure given in Example 2.

MS (FAB): 732 (M + H)

Claims (5)

² R ³ OH R ⁴ R ^x -XY-CH-CB-NH-CH-CH-CH-R ^ ^v ' in which R ^{1 is} a radical of the formula II, III or IV R ¹⁰ R ¹⁰ R ⁶ ^ R ¹² [CHOl ^ - [CHl ^ JCHoI ^ - [CHU R ¹² N- R ⁸ - N NN- (II) N - Z (IV) means, in which R ⁶ and R ^{7 are} identical or different and represent hydrogen, an optionally substituted aliphatic radical having 1-21 C atoms, an optionally substituted alicyclic radical having 3-20 C atoms, an optionally substituted alicyclic-aliphatic radical having 4-20 C atoms, an optionally substituted aromatic radical having 6-12 C atoms, an optionally substituted araliphatic radical having 7-32 C atoms, an optionally substituted heteroaromatic or heteroaromatic (C ₁ -C ₈ ) -aliphatic radical having in each case 5-12 ring atoms, or, if not already covered by the above definitions, for an optionally substituted alkanoyl radical having 1-18 C atoms, an optionally substituted (Ca-CeJ-cycloalkyl - ^ - CeJ alkanoyl radical, an optionally substituted (Cy-C ^ -Aroyl radical,
an optionally substituted heteroaroyl radical,
an optionally substituted (C ₆ -C ₁₂ ) -aryl (C ₁ -C ₁₈ ) alkanoyl radical, an optionally substituted heteroaryl-C ₁ -J-alkanoyl radical or an optionally substituted (C ₆ -C ₁₂ ) -aryl - (C ₁ -C 4) alkoxycarbonyl radical, or R ⁶ and R ⁷ together with the N atom carrying them form a 4- to 8-membered ring, which may be saturated or unsaturated, and another heteroatom selected from the group N. , O and S may contain;
or R ^{6 is} as defined above and
R ⁷ for amino, optionally substituted (C 1 -C 4) -alkylamino, optionally substituted di - ^ - O-alkylamino, hydroxy, optionally substituted (C ₁ -Ct) -alkoxy, optionally substituted (C ₁ -C ₄ ) -alkylsulfonyl, optionally substituted (C 9 -C 12 arylsulfonyl or carbamoyl; R ^{8 has} the meaning given for R ⁶ or R ⁷ ; R ^{9 is} hydrogen, (C 1 -C ₈ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl, (Ca-CeJ-cycloalkyl-fC-CJ-alkyl, optionally substituted (C ₆ -C ₁₂ ) -aryl I . optionally substituted _(C7-C13) aralkyl group; R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are hydrogen or (C ₁ -Ce) -AlkYl; or R ¹⁰ and R ¹¹ together form a (C 1 -C 6 -alkanediyl bridge and R ^{12 is} as defined above, m is 0,1,2 or 3, η = 1,2,3 or 4 is ο = 0,1,2 or 3 is and ρ = 1,2,3 or 4; X is -CO -, - CS -, - SO ₂ -or-SO-; Y is - (CH ₂ ) _q - (CR ¹³ R ¹⁴ ) _r , -O-or-S-, in which q = 0,1,2 or 3, r = 0,1 or 2, Z is a branched or unbranched aliphatic radical having 1-6 C atoms; R ¹³ and R ^{14 are the} same or different and are hydrogen or (C 1 -C ₆ ) alkyl; R ^{2 is} hydrogen, (C 1 -C ₁₀ ) -alkyl, (C 1 -C 4 -aryl, (C 1 -C 4 -aryrMCr-CJ-alkyl, (C 1 -C ₈ ) -cycloalkyl, (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₄₎ alkyl, heteroaryl or heteroaryl (Ci-C ₄₎ -alkyl, where aryl or heteroaryl substituted by one or two identical or different radicals from the series halogen, hydroxy, (Cr C ₄ ) alkoxy, amino, (C 1 -C ₆ ) alkylamino, di-C 1 -C ₄ -alkylamino, CF ₃ and (C 1 -C ₄ ) -alkyl may be substituted; R ^{3 is} hydrogen, (C 1 -C ₁₀ ) -alkyl, (C ³ -C ₈ ) -cycloalkyl, (C ₁ -C 8 -cycloalkyl-F C ₁ -C ₆ -alkyl, (C ₆ -C ₁₂ ) -aryl or (C ₆ -C 4) -cycloalkyl) ₁₂ ) aryl- (C ₁ -C ₄ ) -alkyl; R ^{4 is} hydrogen, (C ₁ -C ₁ Q) -alkyl, (Ce-C ₁₂ ) -aryl, (C ₆ -C ₁₂ ) -aryl (C ₁ -C ₄ ) -alkyl, hydroxy or amino; R ^{B is} a radical of the formula II (CH ₂ ) _S -CHR ¹⁵ -Het (II) R ^{15 is} hydrogen, (C ₁ -C ₇ ) -alkyl, (C ₁ -C) -alkoxy, (C ₁ -C ₄ -alkylthio, (C ₁ -C ₄ ) -alkylamino, hydroxy, azido or halogen, and Het is a 5- to 7-membered heterocyclic ring which may be benzannellated, aromatic, partially hydrogenated or fully hydrogenated, which may contain as hetero atoms one or two identical or different radicals from the group N, O, S, NO, SO, SO ₂ and by one or two identical or different radicals from the series (C ₁ -Q) -AlkyI, allyl, (C ₁ -C ₄ J -oxyalkoxy, hydroxy, halogen, amino, mono- or di - ^ - CO-alkylamino and CF ₃ may be substituted, and s is 0,1, 2,3 or 4; B is the residue of an amino acid H-B-OH, preferably from the series phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, β-2-thienylalanine, β-3-thienylalanine, β-2-furylalanine, β-3-furylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2- Pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O-benzyl tyrosine, O-tert-butyl tyrosine, phenylglycine, 1-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, β-2-benzo [b] thienylalanine, β-3-benzene [b] thienylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-pyridylalanine, 4-fluorophenylalanine, norleucine, cysteine, S-methyl-cysteine, I ^^ ATetrahydroisoquinoline-S-carboxylic acid, Homophenylalanine, DOPA, O-dimethyl-DOPA, N-methyl-histidine, 2-amino-4- (2-thienyl-butyric acid, 2-amino-4- (3-thienyl) -butyric acid, 3- (2-thienyl) -serin, 2- or 4-thiazolyl-alanine, (Z) -dehydrophenylalanine, (E) -dehydrophenylalanine, 1,3-dioxolan-2-yl-alanine, N-pyrrolylalanine and 1-, 3- or 4-pyrazolylalanine or their physiologically tolerated salts, characterized in that coupling 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.
2. The method according to claim 1, characterized in that a compound of formula I is prepared in which R ⁶ and R ^{7 are the} same or different and hydrogen, (Ci-C ₁₈ ) - alkyl, an aliphatic acyl radical of the formula C _a H ( _2a -b + i) r in which double bonds, if their number exceeds 1, are not cumulated, a is an integer 2 to 18 and b is an even number 2 to a, a mono-, di- or xricyclic, non-aromatic, optionally branched hydrocarbon radical of the formula C _c H ( _2c -1-n, in which c is an integer from 3 to 20, and d is an even number from 0 to (c-2), (C6-C ₁₂ ) -Aryl, which is optionally substituted by one or two identical or different radicals from the series (C ₁ -C ₄ alkyl group, (C ₁ -C ₄ ) -alkoxy, hydroxy, halogen, amino, (C C ₁ -C ₄ ) -alkylamino, di (C ₁ -C ₄ ) -alkylamino and CF _{3 is} substituted, (Cff-C ^ -AryMCv-CeJ-alkyl or (C7-C ₁ 3 () aroyl C ₁ -C ₈₎ -alkyl which can be substituted in the aryl moiety described above, mono- or bicyclic, optionally partially hydrogenated heteroaryl, heteroaryMC-CaJ-alkyl or heteroaryl (C ₁ -C ₈ ) -alkanoyl having in each case 5-7 or 8-10 ring atoms, of which up to 9 ring atoms are carbon and 1 to 2 ring atoms Represent sulfur or oxygen and / or 1 to 4 ring atoms nitrogen, which may be substituted in the heteroaryl moiety as described above for aryl, (C ₁ -C ₁₈ ) alkanoyl, (C ₆ -C ₁₂ aryl- (C ₁ -C ₈ ) -alkanoyl, which may be substituted in the aryl part as described above, (C ₁ -C ₆ ) -Aroyl - C ₁ -C -alkanoyl which may be substituted in the aryl moiety as described above, (C ₁ -C ₆ ) -alkoxycarbonyl- (C ₁ -C ₈ ) -alkanoyl, (Ce-C ^ J-aryloxycarbonyMC ^ CeJ-alkanoyl which may be substituted in the aryl part as described above, (C ₆ -C ₁₂ ) -aryl (C ₁ -C ₈ ) -alkoxycarbonyl, (C ₁ -C ₆ ) -alkoxy (C ₁ -C ₆ ) -alkoxy C ₁ -C ₆₎ alkanoyl, (C _ff -C ₁₂₎ aryloxy (C ₁ -C ₆₎ alkanoyl which may be substituted as described for aryl in Aryltest above, (C ₁ -C ₆₎ acyl - (C ₁ -C ₈ ) -alkanoyl, carboxy-C ₁ -C -alkanoyl, carbamoyl-C ₁ -C ₄ -alkanoyl, amino- (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) Alkanoylamino (C ₁ -C ₄ ) alkyl, (C ₇ -C ₁₃ ) arylamino (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ alkoxycarbonylamino) -O-alkyl, (C ₆ - C ₁₂ ) -aryl (C ₁ -C ₄ ) -alkoxycarbonylamino (C ₁ -C ₄ ) -alkyl, (C ₆ -C ₁₂ ) -aryl (C ₁ -C ₄ ) -alkoxycarbonylamino- (C ₁ -) C ₄₎ alkyl, (C ₆ -C ₁₂ J-aryl- (C ₁ -C ₄₎ alkylamino _(Cr-C4) - <ilkyl, (Cr-aO-alkylamino-I ^ alkyl, di- (C ₁ -C ₄ ) -alkylamino (C ₁ -C ₄ ) -alkyl, guanidino (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkylth io- (C ₁ -C ₄ ) -alkyl, (C ₆ -C ₁₂ ) -arylthio (C ₁ -C ₄ ) -alkyl which may be substituted in the aryl moiety as described above, carboxy - ^ - O-alkyl, Carbamoyl- (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxycarbonyl- (C ₁ -C ₄ ) -alkyl, (C ₆ -C ₁₂ ) -aryloxy- (C ₁ -C ₄ ) - alkyl, which may be substituted in the aryl moiety as described above for aryl, or R ⁶ and R ⁷ together with the N atom carrying them form a 5- or 6-membered ring which may be saturated or unsaturated and one further heteroatom selected from may contain the group N, O and S; or R ^{6 is} as defined above, and R ⁷ is amino, (C ₁ -C ₄₎ alkylamino, di- _(Cr-C4) alkylamino, hydroxy, (C ₁ -C) alkoxy, (C ₁ -C ₄₎ alkylsulfonyl, (CSS-C ^ -Arylsulfonyl or carbamidoyl; R ^{8 has} the meaning given for R ⁶ or R ⁷ ; R ^{9 is} hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₄ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -cycloalkyl- (C ₁ -C ₄ ) -alkyl, (C <rC ₁₂ ) - Aryl or (C ₆ -C ₁₂ ) aryl- (C ₁ -C ₂ ) alkyl; R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are hydrogen or (C ₁ -C ₄ alkyls; m = 0, _{1, 2} or 3; η = 1,2 or 3; ο = 0,1,2 or 3; ρ = 0,1,2 or 3; X is -CO -, - CS -, - SO ₂ -or-SO-; Y is - (CH ₂ ) _q - (CR ¹³ R ¹⁴ ) -, -O- or -S-, in which q = 0,1,2 or 3, r = 0,1 or 2, Z is a branched or unbranched aliphatic radical having 1-4 C atoms; R ¹³ and R ^{14 are the} same or different and are hydrogen or (C ₁ -C ₄ alkyls; R ^{2 is} hydrogen, (C 1 -C ₆ ) -alkyl, (C ₆ -C ₁₂ ) -aryl, (C ₁ -C ₄ -aryl-iC-CJ-alkyl, (C ₄ -C ₆ ) -cycloalkyl, (C ₄ -C ₆₎ -Cyc! oalkyl- (C, -C ₂₎ alkyl, (C ₄ -C ₇₎ -heteroaryl or (C ₄ -C ₇₎ -heteroaryl- (C ₁ -C ₂₎ -alkyl wherein aryl or heteroaryl may be substituted as defined in claim 1 and wherein heteroaryl is as defined above for R ⁶ or R ⁷ ;
R ^{3 is} isobutyl, benzyl or cyclohexylmethyl; R J--alkyl, (C ₆ -C ₁₀ J-aryl, (C ⁴ is hydrogen, (C ₁ -C _{5 6} -C ₀₎ aryl (C ₁ -C ₄₎ alkyl or hydroxy; R ^{5 is} a Rest of formula II means where R ^{15 is} hydrogen, (C ₁ -C ₄ -alkyl), (C ₁ -C ₄ -alkoxy, (C ₁ -C ₄ ) -alkylthio, (C ₁ -C ₄ ) -alkylamino, hydroxy, azido or halogen Het is as defined in claim 1 and s is 0.1 or 2, and B is a residue of an amino acid HB-OH from the series phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, β- 2-thienylalanine, β-3-thienylalanine, β-2-furylalanine, β-3-furylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 4-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine-O-methyltyrosine, O-benzyl-tyrosine, O-tert-butyl-tyrosine, phenylglycine, 1-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, norleucine, cysteine , S-methyl-cysteine, N-methyl-histidine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- or 4-thiazolylalanine, homophenylalanine, 2-amino-4- (2-thienyl-butyric acid, 2-amino-4- (3 -thienyl) -butyric acid, 3- (2-thienyl) -serine, (Z) -dehydrophenylalanine, (E) -dehydrophenylalanine, 1,3-dioxolan-2-yl-alanine, N-pyrrolylalanine and 1-, 3- or 4-pyrazolylalanine, or their physiologically acceptable salts. 3. The method according to claim 1 or 2, characterized in that a compound of formula I is prepared, in which R ⁶ and R ^{7 are} hydrogen, (C 1 -C ₆ ) -alkyl, (C ₄ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -cycloalkyl- (C ₁ -C ₄ ) -alkyl, (C ₆ -C ₁₂ ) -aryl, which is optionally substituted by one or two identical or different radicals from the series methyl, ethyl, methoxy, ethoxy, halogen and amino, partially hydrogenated (C ₆ -C ₁₂ J-ArYl, (C ₆ -C ₁₂ ) -Aryl- (C ₁ -C ₄ ) -alkyl, which is optionally substituted in the aryl part as described above for aryl, (C ₁ -C ₆ ) alkanoyl, (Ce-C ^ -aryl-C ₁ -C ₄ -alkanoyl which is optionally substituted in the aryl part as described above for aryl, (C ₄ -C ₁₀ ) -heteroaryl- (C ₁ -C ₄ ) -alkanoyl, (C ₁ -C ₄ -alkoxy- (C, -C ₄ ) -alkanoyl, (C ₁ -C ₄ -alkoxyCaTbOnVl- (C ₁ -C ₆ ) -, Jkanoyl, (C ₆ -C ₁₂ ) -Aryloxycarbonyl- (C _l -C ₆ ) alkanoyl, which in the aryl moiety optionally as above when aryl is substituted or (C ₆ -C ₁₂ J-ArYl- (C ₁ -C ₄ ) alkoxycarbonyl which is optionally substituted in the aryl moiety as above for aryl, or R ⁶ and R ⁷ together with the carrying them N- Atom form a piperidino, pyrrolidino, morpholino, piperazino or thiomorpholino radical; or
R ^{6 is} as defined above and R ^{7 is} amino, methylamino, ethylamino, di (C ₁ -C ₂ ) alkylamino, hydroxy, methoxy, ethoxy, methylsulfonyl, ethylsulfonyl, phenylsulfonyl or carbamidoyl; R ^{8 has} the meaning given for R ⁶ and R ⁷ ; R ^{9 is} hydrogen, (C ₁ -C ₃₎ -alkyl, (C ₄ -C ₆ ) -cycloalkyl, (C ₁ -C ₆ -cycloalkyl-fd-CzJ-alkyl, (C ₆ -C ₁₂ ) -aryl or (C ₆ -) C ₁₂ ) aryl- (C ₁ -C ₂ ) alkyl; R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are hydrogen or (C ₁ -C ₃₎ -alkyl, m is 0,1 or 2;
η = 1,2 or 3;
ο = 0,1 or 2;
ρ = 1, 2 or 3;
X is -CO-or -SOr-;
Y is - (CH ₂ Jq- (CR ¹³ R ¹ Voder-O-, wherein
q = 0,1 or 2,
r = 0,1 or 2,
Z -CH ₂ means and R ¹³ and R ^{14 are the} same or different and are each hydrogen or (C ₁ -C ₃₎ -alkyl; R ^{2 is} (C ₁ -C ₄ ) -alkyl, (C ₄ -C ₆ ) -cycloalkyl (C-CeJ) -Cycloalkyl-i ^ -CzJ-alkyl, (Cg-CJ-AryH ^ -CzJ-alkyl or (C ₄ -C _G ) -Heteroaryl- (C ₁ -C ₂ ) -alkyl, wherein aryl or heteroaryl is optionally substituted by a ortwo identical or different radicals from the series chlorine, fluorine, methoxy, hydroxy and methyl substituted ^: st; R ^{3 is} isobutyl, benzyl or cyclohexylmethyl;
R ^{4 is} hydrogen or hydroxy;
R ^{5 is} a radical of the formula II where R ^{15 is} hydrogen or fluorine, Het is a 2-, 3- or 4-pyridyl radical, a 2-, 4- or 5-imidazolyl radical or a 2-oxazolinyl radical, where the heterocycles mentioned are each represented by one or two identical or different radicals from the series methyl, ethyl, propyl, allyl, fluorine, chlorine, Bromine, CF ₃ and methoxy, and s is 0.1 or 2; and B is a residue of an amino acid HB-OH from the series phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, β-2-thienylalanine, β-3-thienylalanine, β-2-furylalanine, lysine, ornithine , Valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, 4-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, 0-benzyltyrosine, O -tert-butyityrosine, phenylglycine, 1-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, norleucine, I ^^ ATetrahydroisochiMolin-S-carboxylic acid, 2- or 4-thiazolylalanine, homophenylalanine, 2-amino-4- ( 2-thienyl) butyric acid and 1-, 3- and 4-pyrazolylalanine, or their physiologically acceptable salts. 4. Process according to Claims 1 to 3, characterized in that a compound of the formula I is prepared in which R ^6, R ⁷ and R ⁸ are identical or different and are hydrogen, (C ₁ -C ₄ I-AIlOnOyI, _(C6-Ci2) aryl (Ci-C ₄₎ alkyl, (C ₇ -CN) - ArOyI, (C ₄ -C ₁₀ ) -heteroaroyl, (CH 2) 3 -alkoxycarbonyl or benzyloxycarbonyl; R ^{9 is} as defined in claim 3; R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are hydrogen, methyl or ethyl; m = 0.1 or 2; η = 1,2 or 3; ο = 0,1 or 2 is; ρ = 1, 2 or 3; X is -CO-or-SO ^; Y is - (CH ₂ ) C ₁ - (CR ¹³ R ¹⁴ ) -or-O-, in which q = 1, r = O, 2 -CH ₂ means and R ¹³ and R ^{14 are the} same or different and are hydrogen, methyl or ethyl; R ^{2 is} cyclohexylmethyl, benzyl, 1- or 2-naphthylmethyl, 2-, 3- or 4-thienylmethyl, p-methoxybenzyl or p-fluorobenzyl; and R ³ , R ⁴ , R ⁵ and B are as defined in claim 3, or their physiologically acceptable salts. 5. The method according to claim 4, characterized in that a compound of formula I is prepared, in which R ⁶ , R ⁷ and R ^{8 are the} same or different and are hydrogen, acetyl, benzyl, benzoyl, nicotinoyl, tert-butoxycarbonyl or benzyloxycarbonyl and / or R ^{9 is} hydrogen or benzyl or their physiologically acceptable salts. 6. The method according to any one of claims 1 to 5, characterized in that a compound of formula I is prepared in which the radical B is His or Nva, or their physiologically acceptable salts. 7. A process for preparing a preparation containing at least one compound according to any one of claims 1-6, characterized in that one brings these or their physiologically acceptable salt with the appropriate additives in a suitable dosage form. 8. Use of a compound according to any one of claims 1-6 as a remedy.