HK1083511B

HK1083511B - Antibacterial amide macrocycles

Info

Publication number: HK1083511B
Application number: HK06103632.2A
Authority: HK
Inventors: Thomas Lampe; Isabelle Adelt; Dieter Beyer; Nina Brunner; Rainer Endermann; Kerstin Ehlert; Hein-Peter Kroll; Franz Von Nussbaum; Siegfried Raddatz; Joachim Rudolph; Guido Schiffer; Andreas Schumacher; Yolanda Cancho-Grande; Martin Michels; Stefan Weigand
Original assignee: Aicuris Gmbh & Co. Kg
Priority date: 2002-06-17
Filing date: 2003-06-10
Publication date: 2008-03-14

Description

Antibacterial amide macrocycles

Technical Field

The present invention relates to antibacterial amide macrocycles and to processes for their preparation, as well as to their use for the preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular bacterial infections.

Background

The natural products of biphenmycin B with antibacterial activity are described in the topics of US 3,452,136, R.U.Meyer, Stuttgart University, Germany 1991, Synthesis (1992), (10), 1025-30, J.Chem.Soc., Perkin Trans.1(1992), (1), 123-30, J.Chem.Soc., Chem.Commun. (1991), (10), 744, Synthesis (1991), (5), 409-13, J.Chem.Soc., Chem.Commun. (1991), (5), 275-7, J.Antibiot. (1985), 38(11), 1462-8, J.Antibiot. (1985), 38(11), 1453-61. Structure and structure of biphenomycin BAccording to formula (I) wherein R¹、R²、R³、R⁴、R⁷、R⁸And R⁹Is hydrogen, R³Is 3-amino-2-hydroxypropan-1-yl, and C (O) NR⁵R⁶Substituted by Carboxyl (COOH). Some steps in the synthesis of biphenomycin B are described in Synlett (2003), 4, 522-525.

Chirality (1995), 7(4), 181-92, J.Antibiot. (1991), 44(6), 674-7, J.Am.Chem.Soc. (1989), 111(19), 7323-7, J.Am.Chem.Soc. (1989), 111(19), 7328-33, J.Org.Chem. (1987), 52(24), 5435-7, anal.biochem. (1987), 165(1), 108-13, J.Org.Chem. (1985), 50(8), 1341-2, J.Antibiot. (1993), 46(3), C-2, J.Antibiot. (1993), 46(1), 135-40, Synthesis (1992), (12), 8-54, appl.environ.124 (1992), Microbiol. (1992), 9-9, 2-13, 2-A-9, 2-9, 9-9, and the macrocyclic derivatives thereof are described in further references.

The properties of these natural products do not meet the requirements of antibacterial drugs. Although substances with antibacterial activity of different structures are available on the market, resistance may often develop. There is therefore a need for new substances for good and more effective treatment.

Disclosure of Invention

It is therefore an object of the present invention to provide novel and alternative compounds having the same or improved antibacterial effect for the treatment of bacterial diseases in humans and animals.

It has surprisingly been found that derivatives of these natural products in which the carboxyl groups of the natural product are replaced by amide groups have antibacterial activity.

The present invention relates to compounds of formula I and salts thereof, solvates thereof and solvates of the salts,

wherein

R¹Is hydrogen, alkyl, aryl, heteroaryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl or a carbonyl-linked amino acid residue,

wherein R is¹By 0, 1, 2 or 3 substituents R in addition to hydrogen^1-1Substituted, wherein the substituent R^1-1Independently of one another, from the group consisting of halogen, alkyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy and carboxyl,

R²is a hydrogen or an alkyl group,

wherein R is²By 0, 1, 2 or 3 substituents R in addition to hydrogen^2-1Substituted, wherein the substituent R^2-1Independently of one another, from halogen, amino, alkylamino and dialkylamino, or

R¹And R²Together with the nitrogen atom to which they are attached form a substituent R which may be substituted by 0, 1 or 2^1-2Substituted heterocycles in which the substituent R is^1-2Independently of one another, from the group consisting of halogen, trifluoromethyl, amino, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, carboxyl, alkoxycarbonyl and aminocarbonyl,

R³is hydrogen, alkyl or a pendant amino acid group, wherein the alkyl group may be substituted with 0, 1, 2 or 3 substituents R^3-1Substituted, wherein the substituent R^3-1Independently of one another, from trifluoromethyl, nitro, amino, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, carboxyl, alkoxyAlkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, guanidino and amidino,

wherein cycloalkyl, aryl, heteroaryl and heterocyclyl may be substituted by 0, 1 or 2 substituents R^3-2Substituted, wherein the substituent R^3-2Independently of one another, from halogen, alkyl, trifluoromethyl and amino,

and wherein the free amino group of said amino acid side group may be substituted with an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl or heteroarylsulfonyl group,

R³is hydrogen, C₁-C₆-alkyl or C₃-C₈-a cycloalkyl group,

R⁴is hydrogen, C₁-C₆-alkyl or C₃-C₈-a cycloalkyl group,

R⁵is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or an amine-linked amino acid residue,

wherein R is⁵May be substituted by 0, 1, 2 or 3 substituents R^5-1Substituted, wherein the substituent R^5-1Independently of one another, from the group consisting of halogen, alkyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, heteroarylaminosulfonyl, aminocarbonylamino, hydroxycarbonylamino and alkoxycarbonylamino,

wherein the alkyl, alkylamino, dialkylamino, cycloalkyl, or substituted alkyl,The aryl, heteroaryl and heterocyclyl radicals may be substituted by 0, 1, 2 or 3 substituents R^5-2Substituted, wherein the substituents

R^5-2Independently of one another, from hydroxyl, amino, carboxyl and aminocarbonyl,

R⁶is hydrogen, alkyl or cycloalkyl,

or

R⁵And R⁶Together with the nitrogen atom to which they are attached form a substituent R which may be substituted by 0, 1, 2 or 3^5-6Substituted heterocycles in which the substituent R is^5-6Independently of one another, from the group consisting of halogen, alkyl, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, cycloalkyl, aryl, haloaryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, carboxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl,

R⁷is hydrogen, C₁-C₆Alkyl, alkylcarbonyl or C₃-C₈-a cycloalkyl group,

R⁸is hydrogen or C₁-C₆-alkyl, and

R⁹is hydrogen or C₁-C₆-an alkyl group.

The compounds of the invention are compounds of the formula (I) and salts, solvates and solvates of salts thereof, compounds of the formula (I ') and salts, solvates and solvates of salts thereof, which are encompassed by the formula (I) and/or (I ') and which are mentioned below as exemplary embodiments (embodiments), and solvates of salts, solvates and solvates of salts thereof, wherein the compounds encompassed by the formula (I) and/or (I ') and which are mentioned below are not salts, solvates and solvates of salts thereof.

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and to the respective mixtures thereof. The stereoisomerically pure components can be separated in a known manner from mixtures of such enantiomers and/or diastereomers by known methods, for example chromatography using a chiral phase or crystallization using chiral amines or chiral acids.

Depending on the structure of the compound, the invention also relates to tautomers of the compound.

Preferred salts for the purposes of the present invention are the physiologically acceptable salts of the compounds of the invention.

Physiologically acceptable salts of compound (I) include acid addition salts of inorganic acids, carboxylic and sulfonic acids, for example salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic, trifluoroacetic and benzoic acids.

Physiologically acceptable salts of compound (I) include salts of conventional bases such as, for example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16C atoms such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, arginine, lysine, ethylenediamine and methylpiperidine.

For the purposes of the inventionSolvatesThese forms of the compound are referred to as solid or liquid complexes formed by complexation with solvent molecules. Hydrates are a special form of solvates in which coordination takes place with water.

For the purposes of the present invention, unless specified otherwise, the substituents have the following meanings:

alkyl radicalAnd substitutionRadicals such as alkoxy, mono-and dialkylamino, the alkyl part of alkylsulfonyl including straight-chain and branched alkyl, e.g. C₁-C₁₂-, in particular C₁-C₆-and C₁-C₄-an alkyl group.

C₁-C₆ -alkyl radicalIncluding methyl, ethyl, n-and i-propyl, n-, i-, s-and t-butyl, n-pentyl, isopentyl, neopentyl, hexyl,

C₁-C₄alkyl includes methyl, ethyl, n-and i-propyl, n-, i-, s-and t-butyl,

for the purposes of the inventionAlkyl carbonylPreferably a straight or branched chain alkyl group having 1 to 6 or 1 to 4 carbon atoms. These may be mentioned as preferred examples: methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl and t-butylcarbonyl.

Alkenyl radicalIncluding straight and branched C₂-C₁₂-, in particular C₂-C₆-and C₂-C₄Alkenyl radicals, such as, for example, vinyl, allyl, prop-1-en-1-yl, isopropenyl, but-1-enyl, but-2-enyl, but-1, 2-dienyl, but-1, 3-dienyl.

Alkynyl radicalIncluding straight and branched C₂-C₁₂-, in particular C₂-C₆-and C₂-C₄Alkynyl, such as, for example, ethynyl, propargyl (2-propynyl), 1-propynyl, but-1-ynyl, but-2-ynyl.

Cycloalkyl radicalsComprising polycyclic saturated hydrocarbon radicals having up to 14 carbon atoms, i.e. monocyclic C₃-C₁₂-, preferably C₃-C₈Alkyl, especially C₃-C₆Alkyl radicals such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and polycyclic alkyl radicals, i.e. preferably bicyclic and tricyclic, optionally spirocyclic C₇-C₁₄Alkyl radicals, such as, for example, bicyclo [2.2.1]-hept-1-yl, bicyclo [2.2.1]-hept-2-yl, bicyclo [2.2.1]Hept-7-yl, bicyclo [2.2.2]-oct-2-yl, bicyclo [3.2.1]-oct-2-yl, bicyclo [3.2.2]-non-2-yl and Adamantyl (Adamantyl).

For the purposes of the inventionAryl radicalsIs an aromatic group having preferably 6 to 10 carbon atoms. Preferred aryl groups are phenyl and naphthyl.

For the purposes of the inventionAlkoxy radicalPreference is given to linear or branched alkoxy, in particular alkoxy having 1 to 6, 1 to 4 or 1 to 3 carbon atoms. Linear or branched alkoxy groups having 1 to 3 carbon atoms are preferred. Examples of such preferred groups which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

For the purposes of the inventionAlkoxycarbonyl radicalPreferably a linear or branched alkoxy group having 1 to 6 or 1 to 4 carbon atoms attached through a carbonyl group. Straight-chain or branched alkoxycarbonyl groups having 1 to 4 carbon atoms are preferred. Examples of such preferred groups which may be mentioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxy-carbonyl and tert-butoxycarbonyl.

For the purposes of the inventionMonoalkylamino group(alkylamino) is amino with one straight or branched chain alkyl substituent, preferably with 1 to 6, 1 to 4 or 1 or 2 carbon atoms. Preference is given to straight-chain or branched monoalkylamino groups having from 1 to 4 carbon atoms. Examples of such preferred groups which may be mentioned are: methylamino, ethylamino, n-propyl-amino, isopropylamino, tert-butylamino, n-pentylamino and n-hexylamino.

For the purposes of the inventionDialkylamino radicalIs an amino group having two identical or different straight or branched alkyl substituents, said alkyl substituents preferably having 1 to 6, 1 to 4 or 1 or 2 carbon atoms. Preferably in each alkyl substituent independentlyStraight or branched dialkylamino having 1, 2, 3 or 4 carbon atoms. Examples of such preferred groups that may be mentioned include: n, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-isopropyl-N-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-pentylamino and N-hexyl-N-methylamino.

For the purposes of the inventionMonoalkylaminocarbonyl (alkylaminocarbonyl) or dialkylamino Carbonyl radicalIs an amino group which is linked via a carbonyl group and has one straight-chain or branched-chain or two identical or different straight-chain or branched-chain alkyl substituents, each of said alkyl substituents preferably having 1 to 4 or 1 or 2 carbon atoms. Examples of such preferred groups which may be mentioned are: methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, N-dimethylaminocarbonyl, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl and N-tert-butyl-N-methylaminocarbonyl.

For the purposes of the inventionAryl amino carbonylIs an aromatic group having 6 to 10 carbon atoms attached through an aminocarbonyl group. Preferred groups are phenylaminocarbonyl and naphthylaminocarbonyl.

For the purposes of the inventionAlkylcarbonylamino (acylamino)Is an amino group having a straight or branched alkanoyl substituent, preferably having 1 to 6, 1 to 4 or 1 or 2 carbon atoms, attached via a carbonyl group. Monoacylamino having 1 or 2 carbon atoms is preferred. Examples of such preferred groups which may be mentioned are: carboxamido, acetylamino, propionylamino, n-butyrylamino and pivaloylamino.

For the purposes of the inventionAlkoxycarbonyl amino groupIs an amino group having a straight or branched alkoxycarbonyl substituent, said alkoxycarbonyl substituent preferably having 1 to 6 or 1 to 4 carbon atoms in the alkoxy group and being linked via a carbonyl group. Alkoxy preferably having 1 to 4 carbon atomsAn alkylcarbonylamino group. Examples of such preferred groups which may be mentioned are: methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino and tert-butoxycarbonylamino.

For the purposes of the inventionHeterocyclic radical(heterocyclic) is a cyclic compound having 4 to 10 ring atoms and up to 3, preferably up to 1, atoms selected from the group consisting of N, O, S, SO₂A mono-or polycyclic heterocyclic group of a heteroatom or hetero group of (a). Preference is given to 4-to 8-membered, in particular 5-to 6-membered, heterocyclic radicals. Mono-or bicyclic heterocyclic groups are preferred. Monocyclic heterocyclic groups are particularly preferred. N and O are preferred as heteroatoms. The heterocyclic group may be saturated or partially unsaturated. Saturated heterocyclic groups are preferred. The heterocyclic group may be attached through a carbon atom or a heteroatom. Particular preference is given to 5-to 6-membered saturated monocyclic heterocyclic groups having up to two heteroatoms selected from O, N and S. Examples of such preferred groups which may be mentioned are: oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, thiopyranyl, morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, perhydroazepin * -yl, piperazin-1-yl, piperazin-2-yl. Azaheterocyclyl rings are heterocyclic rings in which only the nitrogen atom serves as a heteroatom.

Heteroaryl radicalIs an aromatic monocyclic or bicyclic group having 5 to 10 ring atoms and up to 5 heteroatoms selected from S, O and/or N. Preference is given to 5-to 6-membered heteroaryl having up to 4 heteroatoms. The heteroaryl group may be attached through a carbon atom or a heteroatom. Examples of such preferred groups which may be mentioned are: thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuryl, benzothienyl, quinolinyl, isoquinolinyl.

Carbonyl radicalIs a group-C (O) -. Correspondingly, arylcarbonyl, heterocyclylcarbonyl and heteroarylcarbonyl are substituted on the carbonyl by suitable groups, i.e. aryl, heterocyclyl and the like.

Sulfonyl radicalIs a group-S (O)₂-. Correspondingly, alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl and heteroarylsulfonyl are substituted on the sulfonyl group with suitable groups, i.e., alkyl, aryl and the like.

Aminosulfonyl radicalsIs a group-S (O)₂NH₂-. Correspondingly, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylamino-sulfonyl and heteroarylaminosulfonyl groups are substituted on the amino group with suitable groups, i.e., alkyl, aryl, and the like.

For the purposes of the inventionHalogen elementIncluding fluorine, chlorine, bromine, and iodine. Fluorine and chlorine are preferred.

For the purposes of the inventionPendant groups of amino acidsRefers to the organic group of the alpha-amino acid molecule attached to the alpha-carbon atom of the amino acid. It is preferably a residue of a naturally occurring alpha-amino acid in the L or D configuration, in particular a naturally occurring alpha-amino acid in the natural L configuration.

These include, for example, hydrogen (glycine), methyl (alanine), alanine-2-yl (valine), 2-methyl-alanine-1-yl (leucine), 1-methyl-alanine-1-yl (isoleucine), (3-indolyl) -methyl (tryptophan), benzyl (phenylalanine), methylthioethyl (methionine), hydroxymethyl (serine), p-hydroxybenzyl (tyrosine), 1-hydroxy-eth-1-yl (threonine), mercaptomethyl (cysteine), carbamoylmethyl (asparagine), carbamoylethyl (glutamine), carboxymethyl (aspartic acid), carboxyethyl (glutamic acid), 4-aminobut-1-yl (lysine), 3-guanidinopro-1-yl (arginine), Imidazol-4-ylmethyl (histidine), 3-ureidoprop-1-yl (citrulline), mercaptoethyl (homocysteine), hydroxyethyl (homoserine), 4-amino-3-hydroxybut-1-yl (hydroxylysine), 3-amino-prop-1-yl (ornithine), 2-hydroxy-3-amino-prop-1-yl (hydroxyornithine).

Carbonyl-linked amino acid residuesThrough the acidic functional group of the amino acidThe carbonyl group of (a) to which an amino acid residue is bonded. Preferred are the L or D configuration of alpha-amino acids, especially the naturally occurring alpha-amino acids of the natural L configuration, such as the groups given for glycine, L-alanine and L-proline.

Amine-linked amino acid residuesAre amino acid residues linked through the amino group of an amino acid. Preferably a-amino acid or a beta-amino acid. Particularly preferred are alpha-amino acids in the L or D configuration, especially naturally occurring alpha-amino acids in the natural L configuration, such as glycine (R)⁵Is carboxymethyl), alanine (R)⁵Is a 1-carboxyeth-1-yl group). The acidic functionality of the amino acid can also be in the form of an ester, such as methyl, ethyl, tert-butyl ester, or in the form of an amide, such as aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, benzylaminocarbonyl.

For the purposes of the inventionAmino protecting groupThese are organic groups with which amino groups can be temporarily protected from attack by agents to allow reactions such as oxidation, reduction, substitution and condensation only at the desired (unprotected) sites. During the protection period, it is stable under all the reaction and purification operating conditions carried out and can be selectively eliminated in high yields under mild conditions (R ö mpp Lexikon Chemie-version2.0, Stuttgart/New York: Georg Thieme Verlag 1999; T.W.Greene, P.G.Wuts, protecting groups in organic synthesis, 3 rd edition, John Wiley, New York, 1999).

Preferred thereof are oxycarbonyl derivatives such as carbamates, and especially the following groups: benzyloxycarbonyl, 4-bromo-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl, dichlorobenzyloxycarbonyl, 3, 4-di-methoxybenzyloxycarbonyl, 3, 5-dimethoxybenzyloxycarbonyl, 2, 4-dimethoxy-benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitro-4, 5-dimethoxybenzyloxycarbonyl, 3,4, 5-tri-methoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, n-butyloxycarbonyl, n-butyl, Cyclohexyloxycarbonyl, octyloxycarbonyl, 2-ethylhexyloxycarbonyl, 2-iodohexyloxycarbonyl, 2-bromoethoxy-carbonyl, 2-chloroethoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, 2, 2, 2-trichloro-tert-butoxycarbonyl, benzhydryloxycarbonyl, bis (4-methoxyphenyl) methoxycarbonyl, benzoylmethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2- (di-n-butyl-methyl-silyl) ethoxycarbonyl, 2-tris-phenylsilylethoxycarbonyl, 2- (dimethyl-tert-butylsilyl) ethoxycarbonyl, Methoxy-carbonyl, vinyloxycarbonyl, allyloxycarbonyl, phenoxycarbonyl, tolyloxycarbonyl, 2, 4-dinitrophenoxycarbonyl, 4-nitrophenoxycarbonyl, 2, 4, 5-trichlorophenoxy-carbonyl, naphthyloxycarbonyl (carboyl), fluorenyl-9-methoxycarbonyl, pentanoyl (Valeroyl), isovaleryl, butyryl, ethylthiocarbonyl, methylthiocarbonyl, butylthiocarbonyl, tert-butylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2-iodoacetyl, 2, 2, 2-trifluoroacetyl, 2, 2, 2-trichloroacetyl, 2, 4-dinitrophenoxycarbonyl, 4-nitrophenoxycarbonyl, 2, 4, 5-trichlorophenoxycarbonyl, naphthyloxycarbonyl (carboyl), naphthyloxycarbonyl (carbony), fluorenyl), tert-butyloxycarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, benzylcarbonyl, methylamino, Benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 4-nitrobenzyl, 4-nitrobenzoyl, naphthylcarbonyl, phenoxyacetyl, adamantylcarbonyl, dicyclohexylphosphoryl, diphenylphosphoryl, dibenzylphosphoryl, bis (4-nitrobenzyl) phosphoryl, phenoxyphenylphosphoryl, diethylphosphinyl, diphenylphosphinyl, phthaloyl, phthalimido or benzyloxymethylene.

Particularly preferred are tert-butoxycarbonyl (Boc), 9-Fluorenylmethoxycarbonyl (FMOC), benzyloxycarbonyl (Cbz-/Z-) and allyloxycarbonyl (Aloc).

The symbol on the bond indicates the attachment site in the molecule.

For the purposes of the present invention, preferred compounds of the invention are those corresponding to formula (I') and salts thereof, solvates thereof and solvates of the salts thereof,

wherein R is¹To R⁹Has the same meaning as in formula (I).

For the purposes of the present invention, preference is given to compounds of the invention in which

R²is a hydrogen or an alkyl group,

R¹And R²Together with the nitrogen atom to which they are attached form a substituent which may be substituted by 0, 1 or 2

R^1-2Substituted heterocycles in which the substituent R is^1-2Independently of one another, from the group consisting of halogen, trifluoromethyl, amino, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, carboxyl, alkoxycarbonyl and aminocarbonyl,

R³is hydrogen, alkyl or a pendant amino acid group, wherein the alkyl group may be substituted with 0, 1, 2 or 3 substituents R^3-1Substituted, wherein the substituent R^3-1Independently of one another, from trifluoromethyl, nitro, amino, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl,

and wherein the free amino group in the amino acid side group may be substituted with an alkyl, alkenyl, cycloalkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl or heteroarylsulfonyl group,

R³is hydrogen or C₁-C₆-an alkyl group,

R⁴is hydrogen, C₁-C₆-alkyl or C₃-C₈-a cycloalkyl group,

wherein R is⁵May be substituted by 0, 1, 2 or 3 substituents R^5-1Substituted, wherein the substituent R^5-1Independently of one another, from the group consisting of halogen, alkyl, trifluoromethyl, trifluoromethoxy, cyano, amino, alkylamino, dialkylamino, cycloalkyl, arylHeteroaryl, heterocyclyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl,

R⁶is hydrogen, alkyl or cycloalkyl,

or

R⁵And R⁶Together with the nitrogen atom to which they are attached form a substituent R which may be substituted by 0, 1, 2 or 3^5-6Substituted heterocycles in which the substituent R is^5-6Independently of one another from the group consisting of halogen, alkyl, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, cycloalkyl, aryl, haloaryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, carboxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and diaminoaminocarbonyl,

R⁷is hydrogen or C₁-C₆-an alkyl group,

R⁸is hydrogen or C₁-C₆-an alkyl group,

and

R⁹is hydrogen or C₁-C₆-an alkyl group.

For the purposes of the present invention, preference is also given to compounds of the invention in which

R¹Is hydrogen, alkyl, alkylcarbonyl, arylcarbonyl, heterocyclyl-carbonyl, heteroarylcarbonyl, alkoxycarbonyl or a carbonyl-linked amino acid residue,

wherein R is¹By 0, 1 or 2 substituents R other than hydrogen^1-1Substituted, wherein the substituent R^1-1Independently of one another, from the group consisting of halogen, trifluoromethyl, amino, alkylamino, dialkylamino, phenyl, 5-to 6-membered heteroaryl, 5-to 6-membered heterocyclyl, hydroxyl and alkoxy,

R²is hydrogen or a methyl group, or a mixture thereof,

R³is aminocarbonylmethyl, 3-aminopropyl, 2-hydroxy-3-aminopropyl, 3-guanidinopropyl, 2-aminocarbonylethyl, 2-hydroxycarbonylethyl, 4-amino-butyl, hydroxymethyl or 2-hydroxyethyl, 4-amino-3-hydroxybutan-1-yl,

and wherein the free amino groups in the amino acid side groups may be substituted by alkyl, alkenyl, C₃-C₆-cycloalkyl, alkylcarbonyl, phenylcarbonyl, 5-to 6-membered heteroarylcarbonyl, 5-to 6-membered heterocyclylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, phenylaminocarbonyl, alkylsulfonyl, arylsulfonyl, 5-to 6-membered heterocyclylsulfonyl or 5-to 6-membered heteroarylsulfonyl is substituted,

R³' is a hydrogen atom, and the compound is,

R⁴is hydrogen or a methyl group, or a mixture thereof,

R⁵is hydrogen, alkyl, C₃-C₆-cycloalkyl, phenyl, 5-to 6-membered heteroaryl, 5-to 6-membered heterocyclyl or amine-linked amino acid residue,

at R⁵Is alkyl, C₃-C₆In the case of a cycloalkyl or 5-to 6-membered heterocyclyl, the latter may be substituted by 0, 1 or 2 substituents R^5-2Substituted, wherein the substituent R^5-2Independently of one another, from alkyl, trifluoromethyl, amino, alkylamino, dialkylamino, C₃-C₆-cycloalkyl, phenyl, 5-to 6-membered heteroaryl, 5-to 6-membered heterocyclyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl,

and

at R⁵In the case of phenyl or 5-to 6-membered heteroaryl, the latter may be substituted by 0, 1 or 2 substituents R^5-3Substituted, wherein the substituent R^5-3Independently of one another, from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkylamino, C₃-C₆Cycloalkyl, 5-to 6-membered heteroaryl, 5-to 6-membered heterocyclyl, hydroxyAlkyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl,

and

at R⁵In the case of amine-linked amino acid residues, the latter may be substituted by 0, 1 or 2 substituents R^5-4Substituted, wherein the substituent R^5-4Independently of one another, from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkylamino, C₃-C₆-cycloalkyl, phenyl, 5-to 6-membered heteroaryl, 5-to 6-membered heterocyclyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl,

R⁶is hydrogen, alkyl or C₃-C₆-a cycloalkyl group,

or

R⁵And R⁶Together with the nitrogen atom to which they are attached form a substituent which may be substituted by 0, 1 or 2

R^5-6Substituted 5-to 6-membered heterocyclic ring, wherein the substituent R^5-6Independently of one another, from amino, alkylamino, di-alkylamino, C₃-C₆Cycloalkyl, phenyl, halogenated phenyl, 5-to 6-membered heteroaryl, hydroxyl, alkoxy, carboxyl and aminocarbonyl,

R⁷is a hydrogen atom, and is,

R⁸is a hydrogen atom, and is,

and

R⁹is hydrogen or methyl.

R¹Is hydrogen, alkyl or alkylcarbonyl,

R²is a hydrogen atom, and is,

R³is an alkyl groupOr side groups of amino acids, in which the alkyl radical may be substituted by 0, 1, 2 or 3 substituents R^3-1Substituted, wherein the substituent R^3-1Independently of one another, from trifluoromethyl, nitro, amino, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, guanidino and amidino,

and wherein the amino group in the amino acid side group may be substituted with an alkyl group,

R³' is hydrogen, C₁-C₆-alkyl or C₃-C₈A cycloalkyl group,

R⁴is hydrogen, C₁-C₆-alkyl or C₃-C₈A cycloalkyl group,

wherein alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted by 0, 1, 2 or 3 substituents R^5-1Substituted, wherein the substituent R^5-1Independently of one another, from the group consisting of halogen, alkyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl,

wherein the alkyl, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl and heterocyclyl radicals may be substituted by 0, 1, 2 or 3 substituents R^5-2Substituted, wherein the substituent R^5-2Independently of one another, from hydroxyl, amino, carboxyl and aminocarbonyl,

R⁶is hydrogen, alkyl or cycloalkyl, or

R⁵And R⁶Together with the nitrogen atom to which they are attached form a substituent R which may be substituted by 0, 1, 2 or 3^5-6Substituted heterocycles in which the substituent R is^5-6Independently of one another, from the group halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl,

R⁷is hydrogen, C₁-C₆Alkyl, alkylcarbonyl or C₃-C₈-a cycloalkyl group,

R⁸is a hydrogen atom, and is,

and

R⁹is hydrogen.

For the purposes of the present invention, it is also preferred that, in the compounds of the invention,

R¹is a hydrogen atom, and is,

R²is a hydrogen atom, and is,

R³is an alkyl group or a pendant amino acid group, wherein the alkyl group may be substituted with 0, 1, 2 or 3 substituents R^3-1Substituted, wherein the substituent R^3-1Independently of one another, from amino, alkylamino, dialkylamino, cycloalkyl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, guanidino and amidino,

wherein the cycloalkyl, heteroaryl and heterocyclyl radicals may be substituted by 0, 1 or 2 substituents R^3-2Substituted, wherein the substituent R^3-2Independently of one another, from alkyl and amino groups,

R³' is a hydrogen atom, and the compound is,

R⁴is hydrogen, C₁-C₆-alkyl or C₃-C₈-a cycloalkyl group,

R⁵is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or an amine-linked amino acid residue,

in the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl radicals may be substituted by 0, 1, 2 or 3 substituents R^5-1In the case of substitution, the substituent R^5-1Independently of one another, from the group consisting of halogen, alkyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl,

wherein alkyl, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl

And the heterocyclic radical may be substituted by 0, 1, 2 or 3 substituents R^5-2Substituted, wherein the substituents

R⁶is hydrogen, alkyl or C₃-C₈-a cycloalkyl group,

or

R⁵And R⁶Together with the nitrogen atom to which they are attached form piperidinyl, morpholinyl, piperazinyl or pyrrolidinyl, wherein piperidinyl, morpholinyl, piperazinyl and pyrrolidinyl may be substituted with 0, 1, 2 or 3 substituents, wherein the substituents are independently from each other selected from alkyl, amino, alkylamino, dialkylamino, hydroxy, alkoxy, carboxy, alkoxycarbonyl and aminocarbonyl,

R⁷is a hydrogen atom, and is,

R⁸is a hydrogen atom, and is,

and

R⁹is hydrogen.

R¹is a hydrogen atom, and is,

R²is a hydrogen atom, and is,

R³is aminocarbonylmethyl, 3-aminopropan-1-yl, 2-hydroxy-3-aminopropan-1-yl, 1-hydroxy-3-aminopropan-1-yl, 3-guanidinoprop-1-yl, 2-aminocarbonylethyl, 2-hydroxycarbonylethyl, 4-aminobutan-1-yl, hydroxymethyl, 2-hydroxyethyl, 2-aminoethyl, 4-amino-3-hydroxybutan-1-yl or (1-piperidin-3-yl) -methyl,

R³' is a hydrogen atom, and the compound is,

R⁴is hydrogen, methyl, ethyl, i-propyl or cyclopropyl,

R⁵is hydrogen, C₁-C₆-alkyl or C₃-C₈-a cycloalkyl group,

wherein the alkyl and cycloalkyl radicals may be substituted by 0, 1, 2 or 3 substituents R^5-1Substituted, wherein the substituent R^5-1Independently of one another, from halogen, C₁-C₆-alkyl, trifluoromethyl, trifluoromethoxy, amino, C₁-C₆-alkylamino radical, C₁-C₆Dialkylamino radical, C₃-C₈-cycloalkyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, 5-to 7-membered heterocyclyl, hydroxy, alkoxy, carboxy, C₁-C₆Alkoxycarbonyl, aminocarbonyl, C₁-C₆-alkylaminocarbonyl and C₁-C₆-a dialkylaminocarbonyl group,

R⁶is hydrogen or a methyl group, or a mixture thereof,

or

R⁵And R⁶Together with the nitrogen atom to which they are attached form a piperidinyl or morpholinyl group,

R⁷is a hydrogen atom, and is,

R⁸is a hydrogen atom, and is,

and

R⁹is hydrogen.

For the purposes of the present invention, particular preference is given to compounds according to the invention in which,

R¹is a hydrogen atom, and is,

R²is a hydrogen atom, and is,

R³is 3-aminopropyl-1-yl or 2-hydroxy-3-aminopropyl-1-yl,

R³' is a hydrogen atom, and the compound is,

R⁴is hydrogen or a methyl group, or a mixture thereof,

R⁵is hydrogen, C₁-C₆-an alkyl group or a cyclopropyl group,

wherein the alkyl radical may be substituted by 0, 1, 2 or 3 substituents R^5-1Substituted, wherein the substituent R^5-1Independently of one another, from trifluoromethyl, amino, hydroxyl, carboxyl, aminocarbonyl and phenyl,

R⁶is hydrogen or a methyl group, or a mixture thereof,

R⁷is a hydrogen atom, and is,

R⁸is a hydrogen atom, and is,

and

R⁹is hydrogen.

For the purposes of the present invention, preference is also given to those in which R¹Is a compound of hydrogen.

For the purposes of the present invention, preference is also given to those in which R²Is a compound of hydrogen.

For the purposes of the present invention, preference is also given to those in which R³Is a compound of 3-aminopropyl-1-yl or 2-hydroxy-3-aminopropyl-1-yl.

For the purposes of the present invention, preference is also given to those in which R³' Compound which is hydrogen.

For the purposes of the present invention, preference is also given to those in which R⁴Is hydrogen or methyl.

For the purposes of the present invention, preference is also given to those in which R⁵Is hydrogen, C₁-C₆-an alkyl group or a cyclopropyl group,

wherein the alkyl radical may be substituted by 0, 1, 2 or 3 substituents R^5-1Substituted, wherein the substituent R^5-1

Independently of one another, from trifluoromethyl, amino, hydroxyl, carboxyl, aminocarbonyl and phenyl.

For the purposes of the present invention, preference is also given to those in which R⁶Is hydrogen or methyl.

For the purposes of the present invention, preference is also given to those in which R⁵And R⁶A compound which forms a piperidinyl group or morpholinyl group together with the nitrogen atom to which it is attached.

For the purposes of the present invention, preference is also given to those in which R⁷Is a compound of hydrogen.

For the purposes of the present invention, preference is also given to those in which R⁸Is a compound of hydrogen.

For the purposes of the present invention, preference is also given to those in which R⁹Is a compound of hydrogen.

The invention also relates to a method for producing compounds of formula (I), wherein a compound of formula (II) is reacted with a compound of formula III),

wherein R is¹To R⁴And R⁷To R⁹Wherein optionally the compound (II) can be in active form (acyl donor),

H-NR⁵R⁶ (III)

wherein R is⁵And R⁶The meaning of (A) is as defined above.

Optionally blocking reactive functional groups (e.g. free amino functional groups) in the compound of formula (II) prior to reacting the compound of formula (II) with the compound of formula (III). This can be done using standard methods of protecting group chemistry. It is preferably R¹(or R)²) As acid-labile protecting groups on, or as groups R³And R³' the form of the substituent is particularly preferably Boc. Radical R of a compound of formula (III)⁵And R⁶The reactive functional group in (a) is introduced into the synthesis in an already protected form, preferably an acid-labile protecting group (e.g. Boc). After the reaction to give the compound of formula (I), the protecting group may be removed by deprotection reaction. This can be done using standard methods in protecting group chemistry. The deprotection reaction is preferably carried out under acidic conditions.

For example, if R in the compound of formula (I)²Is a protecting group which can be selectively removed, then deprotection can be carried out (e.g. at R)²After hydrogenolysis in the case of ═ Z) and then with the desired substituent R²Amino function (R) to be exposed²H) functionalization.

Suitable for converting compound (II) into the active form (acyl donor) are, for example, carbodiimides such as, for example, N ' -diethyl-, N, ' -dipropyl-, N ' -diisopropyl-, N ' -dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N ' -ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-N-propoxymethylpolystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N, N-N ', N' -tetramethyluronium (uronium) Hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridyl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate (TPTU), or O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), or benzotriazol-1-yloxytris (dimethylamino) phosphonium Onium hexafluorophosphates (BOP), or mixtures of these with bases, optionally in the presence of coupling additives such as 1-hydroxybenzotriazole (HOBt).

Examples of bases are alkali metal carbonates, such as, for example, sodium or potassium carbonate or bicarbonate, or organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Suitable solvents in this case are inert organic solvents which do not change under the reaction conditions. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, toluene, tetrahydrofuran, dioxane, acetonitrile or dimethylformamide. Mixtures of these solvents may also be used. Anhydrous dichloromethane and dimethylformamide are particularly preferred.

Preferably O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) is used for activation in dimethylformamide.

The compounds of the formula (III) are known or can be prepared in analogy to known methods.

The compounds of the formula (II) are known and can be prepared by cleavage of the compounds of the formula (IIa) on esters

Wherein

R¹To R⁴And R⁷To R⁹Have the above meanings, and

R¹⁰is benzyl (or is alkyl, such as methyl or ethyl).

When R is¹⁰The cleavage of the ester when it is benzyl is preferably carried out with hydrogen in the presence of palladium on charcoal. Suitable solvents in this case are inert organic solvents which do not change under the reaction conditions. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as tetrahydrofuran, dioxane, dimethylformamide or alcohols (preferably methanol, ethanol and isopropanol), optionally in the presence of an acid having one or more acid equivalents. Mixtures of these solvents may also be used. Formic acid in ethanol, aqueous acetic acid and THF is particularly preferred.

Alternatively, the ester (R) may also be hydrolyzed by basic hydrolysis¹⁰Alkyl) to the corresponding carboxylic acid. The base preferably used is aqueous lithium hydroxide or sodium hydroxide. Suitable solvents in this case are organic solvents which are partially or infinitely miscible with water. These include alcohols (preferably methanol and ethanol), tetrahydrofuran, dioxane and dimethylformamide. Mixtures of these solvents may also be used. Methanol, tetrahydrofuran and dimethylformamide are particularly preferred.

Scheme 1: synthesis of exemplary embodiments

The compound of formula (IIa) may be prepared by cyclising the compound of formula (IV) under peptide coupling conditions

Wherein

R¹To R⁴And R⁷To R¹⁰Has the meaning of the above-mentioned formula,

wherein these compounds are optionally present in activated form. Alternatively, the process may be a multistep process wherein the compound of formula (IVa) is converted (to R) by elimination of the protecting group of the amine protecting group¹²Hydrogen-equivalent species) which is subsequently cyclized under basic conditions to give the compound of the formula (IIa)

Wherein

R¹To R⁴And R⁷To R¹⁰Has the meaning of the above-mentioned formula,

R¹¹after activation is pentafluorophenol, and

R¹²is an amine protecting group (preferably Boc).

Suitable substances for converting the compounds into activated form are, for example, carbodiimide-type substances such as, for example, N '-diethyl-, N,' -dipropyl-, N '-diisopropyl-, N' -dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N '-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-N' -propoxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium 3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, Or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N, N-N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridyl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate (TPTU), or O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexa Fluorophosphate (BOP), or mixtures of these with bases, optionally in the presence of 1-hydroxybenzotriazole (HOBt).

Examples of bases are alkali metal carbonates, such as, for example, sodium or potassium carbonate or bicarbonate, or preferably organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Suitable solvents in this case are inert organic solvents which do not change under the reaction conditions. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, toluene, tetrahydrofuran, dioxane, dimethylformamide or acetonitrile. Mixtures of these solvents may also be used. Particular preference is given to dichloromethane and dimethylformamide.

Pentafluorophenyl ester (R) is particularly preferred¹¹＝C₆F₅) In activated form and subsequently subjected to base-catalyzed ring closure.

The compounds of the formula (IV) are known or can be prepared in analogy to known methods or by elimination of R¹²After the protective group(s) above, the compounds of formula (IVb) are reacted with fluorides, in particular tetrabutylammonium fluoride

Wherein

R¹To R⁴And R⁷To R¹⁰And R¹³Have the above meanings, and

R¹¹is a silyl protecting group, especiallyOther are 2- (trimethylsilyl) ethyl.

Suitable solvents in this case are inert organic solvents which do not change under the reaction conditions. These include halogenated hydrocarbons such as methylene chloride, hydrocarbons such as benzene, toluene, tetrahydrofuran, dioxane and dimethylformamide. Mixtures of these solvents may also be used. Preferred solvents are tetrahydrofuran and dimethylformamide.

The compounds of formula (IVb) are known or can be prepared in analogy to known methods or by reacting a compound of formula (V) with a compound of formula (VI)

Wherein

R¹、R²、R⁴、R⁷、R⁸And R¹⁰Has the meaning of the above-mentioned formula,

R¹¹is a protecting group for the silyl group,

wherein

R³、R³’ 、R⁹And R¹²Has the meaning described above, and

optionally the compound may be present in active form.

Substances suitable for converting these compounds into active form are, for example, substances of the carbodiimide type, such as, for example, N '-diethyl-, N,' -dipropyl-, N '-diisopropyl-, N' -dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N '-ethylcarbodiimide hydrochloride (EDC) (in the presence of pentafluorophenol (PFP)), N-cyclohexyl-carbodiimide-N' -propoxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds, such as carbonyldiimidazole, or 1, 2-oxazolium compounds, such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate Or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N, N-N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridyl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate (TPTU), or O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), or benzotriazol-1-yloxytris (dimethylamino) phosphonium ) Phosphonium hexafluorophosphates (BOP), or mixtures of these with bases, optionally with coupling additives such as 1-hydroxybenzotriazole (HOBt).

Suitable solvents in this case are inert organic solvents which do not change under the reaction conditions. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, toluene, acetonitrile, tetrahydrofuran, dioxane or dimethylformamide. Mixtures of these solvents may also be used. Anhydrous dichloromethane and dimethylformamide are particularly preferred.

The reaction is particularly preferably carried out in the presence of HATU and N, N-diisopropylethylamine.

The compounds of the formula (VI) are known or can be prepared in analogy to known methods.

The compounds of the formula (V) and their salts, for example the hydrochloride, are known and can be used analogously to known methodsOr a compound of formula (Va) may be prepared by reacting a compound of formula (Va) at R¹³By reaction with deprotection

Wherein

R¹¹is a silyl protecting group, and

R¹³is an amine protecting group, especially Boc.

It is carried out by standard methods of protecting group chemistry when R is¹³Particularly preferably it is carried out in dioxane and hydrogen chloride.

Scheme 2: synthesis of Biphenomycin protective derivatives

The compounds of formula (ya) are known, can be prepared in analogy to known methods or can be prepared by reacting a compound of formula VII with a compound of formula VIII

Wherein

R⁴And R⁷Has the meaning of the above-mentioned formula,

R¹⁰is benzyl or alkyl, and

R¹³is an amino protecting group (preferably Boc),

wherein

R¹、R²And R⁸Have the above meanings, and

R¹¹is a silyl protecting group, in particular 2- (trimethylsilyl) -ethyl.

This reaction, known as the Suzuki reaction (Synlett 1992, 207-; chem. Rev.1995, 95, 2457- & 2483), is carried out in the presence of a palladium-catalyst and a base, preferably in the presence of bis (diphenylphosphino) ferrocene-palladium (II) chloride and cesium carbonate.

Suitable solvents in this case are inert organic solvents which do not change under the reaction conditions. Which include hydrocarbons such as benzene, toluene, tetrahydrofuran, dioxane, dimethylformamide and dimethylsulfoxide.

Mixtures of these solvents may also be used. Dimethylformamide and dimethyl sulfoxide are particularly preferred.

The compounds of the formula (VII) are known and can be prepared in analogy to known methods or by reacting the compounds of the formula (VIIa) with bis (pinacolato) diboron

Wherein

R⁴And R⁷Has the meaning of the above-mentioned formula,

R¹⁰is benzyl or alkyl, and

R¹³is an amino protecting group (preferably Boc).

This reaction, which is known to be a particular variant of the Suzuki reaction (J.org.chem.1995, 7508-7510; Tetrahedron Lett., 1997, 3841-3844), is carried out in the presence of a palladium-catalyst and a base, preferably in the presence of bis (diphenylphosphino) ferrocene-palladium (II) chloride and potassium acetate.

Suitable solvents in this case are inert organic solvents which do not change under the reaction conditions. Which include hydrocarbons such as benzene, toluene, tetrahydrofuran, dioxane, dimethylformamide and dimethylsulfoxide. Mixtures of these solvents may also be used. Particularly preferred are dimethylformamide and dimethylsulfoxide.

The compounds of formula (VIIa) are known, can be prepared in analogy to known methods or by activating the compounds of formula IX with a free carboxylate function¹⁰R-OH (preferably benzyl alcohol, allyl alcohol and lower aliphatic alcohol) in the presence of 4-dimethylaminopyridine

Wherein

R⁴And R⁷Have the above meanings, and

R¹³is an amino protecting group (preferably Boc).

Suitable substances for converting the carboxylic acid into the active form are, for example, substances of the carbodiimide type, such as, for example, N '-diethyl-, N,' -dipropyl-, N '-diisopropyl-, N' -dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N '-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N' -propoxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds, such as carbonyldiimidazole.

Suitable solvents in this case are inert organic solvents which do not change under the reaction conditions. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, toluene, acetonitrile, tetrahydrofuran, dioxane or dimethylformamide. Mixtures of these solvents may also be used. Particularly preferred are anhydrous dichloromethane and acetonitrile.

Preference is given to reactions activated with EDC or DIC in anhydrous acetonitrile or dichloromethane at low temperatures (-10 ℃).

The compounds of the formula (VIII) are known, can be prepared in analogy to known methods or can be prepared by reacting a compound of the formula (IXa) after activation of the free carboxylate function with a compound of the formula (IXa)¹¹R-OH (preferably 2-trimethylsilylethanol) in the presence of 4-dimethylaminopyridine

Wherein

R¹、R²And R⁸Have the above-mentioned meanings.

Suitable substances for converting the carboxylic acid into the active form are, for example, substances of the carbodiimide type, such as, for example, N '-diethyl-, N,' -dipropyl-, N '-diisopropyl-, N' -dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N '-ethylcarbodiimide-hydrochloride (EDC), N-cyclohexylcarbodiimide-N' -propoxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds, such as carbonyldiimidazole.

The carboxylic acids of the formula (IXa) are known, can be prepared in analogy to known methods or can be prepared by a first step in R¹⁵The compound of formula (IXb) is deprotected as described above

Wherein

R¹And R⁸Have the above meanings, and

R¹⁵is a protecting group for the amino group, particularly Boc,

it is carried out by standard methods of protecting group chemistry when R is¹⁵In the case of Boc, preference is given to working with hydrogen chloride in dioxane or with trifluoroacetic acid in dichloromethane in the presence of small amounts of water. The resulting free amine is reacted with R in a second step²-X is reacted in an inert solvent in the presence of a base, preferably in the presence of potassium iodide,

wherein

R¹And R⁸Has the meaning of the above-mentioned formula,

wherein the amine optionally may be present in the form of a salt, preferably the hydrochloride or trifluoroacetate salt, at said R²in-X, R²Having the above meaning and X is a leaving group, the reaction temperature of the reaction is preferably from 0 ℃ over room temperature up to the reflux temperature of the solvent, which is carried out at atmospheric pressure. For X, preference is given to mesylate, tosylate, succinate or halogen,for halogen, chlorine, bromine or iodine is preferred.

Examples of bases are alkali metal carbonates such as, for example, sodium or potassium carbonate, or sodium or potassium bicarbonate, or organic bases such as trialkylamines, for example triethylamine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Suitable solvents in this case are inert organic solvents which do not change under the reaction conditions. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, toluene, acetonitrile, tetrahydrofuran, dioxane, acetone or dimethylformamide. Mixtures of these solvents may also be used. Particularly preferred are dimethylformamide and dichloromethane.

Scheme 3: synthesis of biphenyl-diamino acid derivatives

R²Optionally a protecting group (e.g., Z, benzyloxycarbonyl).

In another alternative process, the compound of formula (Va) may be prepared by reacting a compound of formula (VIIa) with a compound of formula (VIIIa)

Wherein

R⁴And R⁷Has the meaning of the above-mentioned formula,

R¹⁰is benzyl or alkyl, and

R¹³is an amino protecting group (preferably Boc),

wherein

R¹、R²And R⁸Have the above meanings, and

R¹¹is a silyl protecting group, in particular 2- (trimethylsilyl) -ethyl.

This reaction, known as the Suzuki reaction (Synlett 1992, 207-; chem. Rev.1995, 95, 2457-.

The compound of formula (VIIIa) may be prepared from the compound of formula (VIII) by the methods described for compound (VII).

Enantiomerically pure compounds of the formulae (IX) and (IXb) are known or can be obtained from racemic precursors in known ways, such as, for example, crystallization from chiral amine bases or by chromatography using chiral stationary phases.

The compounds of the formulae (IX) and (IXb) are known and can be prepared in analogy to known methods or by decarboxylation of the compounds of the formulae (X) and (Xa),

wherein

R⁴And R⁷And R¹And R⁸Has the meaning of the above-mentioned formula,

R¹³and R¹⁵Is an amino protecting group, and

R¹⁴is an alkyl group (particularly preferably an ethyl group).

The reaction is preferably carried out in a water-ethanol mixture in an alkaline medium.

The compounds of the formulae (X) and (Xa) are known and can be prepared in analogy to known methods or by reacting compounds of the formulae (XII) and (XIIa) with compounds of the formulae (XI) and (XIa)

Wherein

R⁷And R⁸Has the meaning of the above-mentioned formula,

wherein

R⁴And R¹Has the meaning of the above-mentioned formula,

R¹³and R¹⁵Is an amino protecting group, and

R¹⁴is an alkyl group (preferably ethyl).

The reaction is preferably carried out with alkali metal alcoholates in alcohols, in particular with sodium ethylate in ethanol.

The compounds of the formulae (XII) and (XIIa) are known and can be prepared in analogy to known processes or by reacting compounds of the formulae (XIIb) and (XIIc) with phosphorus tribromide

Wherein

R⁷And R⁸Have the above-mentioned meanings.

The reaction is preferably carried out in toluene.

The compounds of the formulae (XIIb) and (XIIc) are known, can be prepared in analogy to known methods or can be prepared by reducing compounds of the formulae (XIId) and (XIIe)

Wherein

R⁷And R⁸Have the above-mentioned meanings.

The reduction is preferably carried out with a solution of diisobutylaluminum hydride in dichloromethane, followed by addition of a saturated solution of sodium potassium tartrate.

The compounds of the formulae (XIId) and (XIIe) are known, can be prepared in analogy to known methods or can be prepared by reacting 2-hydroxy-5-iodobenzaldehyde with compounds of the formulae (XIII) and (XIIIa), respectively, in inert solvents

R⁷-X and R⁸-X

(XIII) (XIIIa)，

Wherein

R⁷And R⁸Have the above meanings, and

x is a leaving group which is a substituent of,

optionally it is carried out in the presence of a base, optionally in the presence of potassium iodide, preferably at atmospheric pressure, at a temperature ranging from room temperature up to the reflux temperature of the solvent. For X, preference is given to mesylate, tosylate or halogen, and for halogen, preference is given to chlorine, bromine or iodine.

Examples of inert solvents are halogenated hydrocarbons such as dichloromethane, trichloromethane or 1, 2-dichloroethane, ethers such as dioxane, tetrahydrofuran or 1, 2-dimethoxyethane, or other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, preferably tetrahydrofuran, dichloromethane, acetone, 2-butanone, acetonitrile, dimethylformamide or 1, 2-dimethoxyethane. Dimethylformamide is preferred.

Examples of bases are alkali metal carbonates such as cesium carbonate, sodium or potassium methoxide, or sodium or potassium ethoxide or sodium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or metal organic compounds such as butyllithium or phenyllithium, tertiary amine bases such as triethylamine or diisopropylethylamine, or other bases such as sodium hydroxide, DBU, preferably sodium tert-butoxide, cesium carbonate, DBU, sodium hydride, potassium carbonate or sodium carbonate. Potassium carbonate is preferred.

The compounds of the formulae (XIII) and (XIIIa) are known or can be prepared in analogy to known methods.

The following synthetic schemes may be used to illustrate the preparation of the compounds of the present invention. Wherein the Roman numerals used in the description are retained for clarity of illustration, but in some particular embodiments the reaction schemes specifically indicate R in (XI) and (XIa)¹⁴Is ethyl and R¹³And R¹⁵Is Boc.

Scheme 4: synthesis of phenylalanine derivatives

In another process, the substituent R can also be substituted by compounds of the formula (VII) or (VIIa)⁵And R⁶Is introduced into the synthesis. For this purpose, the acidic function of the compound of the formula (VII) or (VIIa) is released under conditions known to the person skilled in the art and is reacted with the compound of the formula (III) under conditions known to the person skilled in the art.

The compounds of the invention exhibit unmeasurable pharmacological and pharmacokinetic effects without expected value.

Therefore, it is suitable for use as a medicament for the treatment and/or prevention of human and animal diseases.

Because of their pharmacological properties, the compounds of the invention can be used alone or in combination with other active ingredients for the treatment and/or prevention of infectious diseases, in particular bacterial infectious diseases.

For example, it can treat and/or prevent local and/or systemic diseases caused by the following pathogens or by mixtures of the following pathogens:

gram-positive cocci, such as staphylococci (staphylococcus aureus, staphylococcus epidermidis) and streptococci (streptococcus agalactiae, streptococcus faecalis, streptococcus pneumoniae, streptococcus pyogenes); gram-negative cocci (diplococcus gonorrhoeae) and gram-negative bacilli such as enterobacteriaceae, e.g. escherichia coli, bacillus influenzae, citrobacter freuinii, citrob. divernis, salmonella and shigella; also Klebsiella (pneumonia bacillus, Klebs. oxytoca), Verticillium (aerobacter aerogenes, Enterobacter agglomerans), Hafnia, Linnaeus (Serratia marcescens), Proteus (Proteus mirabilis, Proteus reesei, Proteus vulgaris), providencia, Yersinia, and Acinetobacter. The said antibacterial range also includes the genera Pseudomonas (Pseudomonas aeruginosa, Pseudomonas maltophilia) and strictly anaerobic bacteria such as, for example, Bacteroides fragilis, Peptococcus, representatives of the genus Peptostreptococcus, and Clostridium; also included are mycoplasma (m.pneumoniae, m.hominis, m.urealyticum) and mycobacteria, such as mycobacterium tuberculosis.

The above pathogens are by way of example only and are not meant to be limiting. Examples which may be mentioned of diseases caused by these pathogens or of the mentioned mixed infections which can be prevented, ameliorated or cured by the topically applicable preparations of the invention are:

infectious diseases of humans, such as, for example, septic infections, bone and joint infections, skin infections, post-operative wound infections, abscesses, cellulitis, wound infections, burn wounds, infections in the oral area, infections after dental procedures, septic arthritis, mastitis, tonsillitis, genital infections and eye infections.

Bacterial infections of other species besides humans can be treated. Examples which may be mentioned are:

a pig: coliform diarrhea, enterotoxemia, septicemia, dysentery, salmonellosis, metritis-mastitis-agalactia syndrome, mastitis;

ruminants (cattle, sheep, goats): diarrhea, septicemia, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections;

horse: bronchopneumonia, foal joint disease, postpartum and post partum (postpuloperal) infection, salmonellosis;

dogs and cats: bronchopneumonia, diarrhea, dermatitis, otitis, urinary tract infection, prostatitis;

poultry (chicken, turkey, quail, pigeon, ornamental birds, etc.): mycoplasmosis, escherichia coli infection, chronic tracheal disorder, salmonellosis, pasteurellosis, psittacosis.

Bacterial diseases in the breeding and management of productive and ornamental fish can likewise be treated, with an antibacterial spectrum exceeding the above-mentioned pathogens, further involving e.g. pasteurella, brucella, campylobacter, listeria, erysipelothrix, corynebacterium, borrelia (Borellia), treponema, nocardia, rickettsia, yersinia.

The invention also relates to compounds of formula (I) for use in the control of diseases, in particular bacterial diseases, medicaments comprising compounds of formula (I) and excipients, and the use of compounds of formula (I) for the preparation of a medicament for the treatment of bacterial diseases.

The invention also relates to medicaments comprising at least one compound according to the invention, preferably also comprising one or more pharmaceutically acceptable excipients or carriers, and to the use thereof for the above-mentioned purposes.

The active ingredient may act systemically and/or locally. For this purpose, it can be administered in a suitable manner, such as, for example, by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival or otic route or by implantation.

The active ingredient may also be administered in a suitable form for such administration.

Suitable forms for oral administration are the known administration forms which can rapidly deliver and/or release the active ingredient in a modified manner, such as, for example, tablets (uncoated tablets and coated tablets, for example tablets with a coating resistant to gastric juices or film-coated tablets), capsules, sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, solutions and aerosols.

Parenteral administration can be carried out in a form avoiding the absorption step (intravenous, intraarterial, intracardiac, intraspinal or intralumbar administration) or in a form including the absorption step (intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal administration). Administration forms suitable for parenteral administration are, in particular, solutions, suspensions, emulsions, lyophilisates and preparations in the form of sterile powders for injection and infusion. .

Suitable for other routes of administration are, for example, pharmaceutical forms for inhalation (in particular powder inhalers, nebulizers), nasal drops/solutions, sprays; tablets or capsules for lingual, sublingual or buccal administration, suppositories, preparations for the ear and eye, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, emulsions, pastes, dusting powders or implants.

The active ingredient can be converted into the administration forms described in a known manner. Such conversion may be carried out using inert, non-toxic pharmaceutically acceptable excipients. It includes, inter alia, carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycol), emulsifiers (e.g. sodium lauryl sulfate), dispersants (e.g. polyvinylpyrrolidone), synthetic and natural biopolymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), colorants (e.g. inorganic pigments such as iron oxide) or taste-masking agents and/or fragrances.

It has been demonstrated that effective results can be obtained by parenterally administering about 5 to 250mg/kg body weight to the user, generally every 24 hours. The amount administered orally is generally about 5 to 100mg/kg body weight per 24 hours.

However, it is optionally necessary to deviate from the above-mentioned amounts, which vary in particular according to the body weight, the route of administration, the individual's behaviour towards the active ingredient, the nature of the preparation and the time of administration or the time interval taken for administration. Thus, in some cases a smaller quantity than the minimum quantity may be sufficient to achieve the desired effect, while in other cases the quantity used may exceed the upper limit described above. In the case where a larger number is used, it may divide the number into a number of single doses over the day.

Unless otherwise specified, percentages in the following tests and examples are percentages by weight; parts are parts by weight. The solvent ratio, dilution ratio and concentration data for the liquid/liquid solutions are in each case based on volume.

Detailed Description

A. Examples of the embodiments

Abbreviations used:

aloc allyloxycarbonyl radical

aq. aqueous phase

* quiv. equivalent

Bn benzyl group

Boc-butoxycarbonyl

CDCl₃Chloroform

CH-cyclohexane

D doublet of peaks (¹In H-NMR)

Doublet of Dd doublet

DCM dichloromethane

DCC dicyclohexylcarbodiimide

DIC diisopropylcarbodiimide

DIPEA isopropyl ethylamine

DMSO methyl sulfoxide

DMAP 4-N, N-dimethylaminopyridine

DMF methyl formamide

Of d.Th. theoretical values

EE Ethyl acetate

EDC N' - (3-dimethylaminopropyl) -N-ethylcarbodiimide x HCl

eq equivalent weight

ESI electrospray ionization (MS)

Es. saturated

HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium

Hexafluorophosphates

HBTU O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

Acid salts

HOBt 1-hydroxy-1H-benzotriazole x H₂O

H hour (n)

HPLC high pressure, high performance liquid chromatography

LC-MS coupled liquid chromatography-mass spectrometry

M multiplet (¹H-NMR)

Min clock

MS Mass Spectrometry

MeOH methanol

NMR nuclear magnetic resonance spectroscopy

MTBE methyl tert-butyl ether

Pd/C Palladium/carbon

percent pro z

Q multiplet (¹H-NMR in

R_fRetention index (in TLC)

RT Room temperature

R_tRetention time (HPLC)

(S single peak)¹H-NMR in

T triplet (¹H-NMR in

TBS tert-butyldimethylsilyl group

THF tetrahydrofuran

TMSE 2- (trimethylsilyl) -ethyl

TPTU 2- (2-oxo-1 (2H) -pyridinyl) -1, 1, 3, 3-tetramethyluronium tetrakis

Fluorophosphate salts

Z Benzyloxycarbonyl

General LC-MS and HPLC methods:

preparative RP-HPLC: column: YMC gel; eluent: acetonitrile/water (gradient); flow rate: 50 ml/min; temperature: 25 ℃; the detector UV 210 nm.

Method 1 (HPLC): column: kromasil C18, L-R temperature: 30 ℃; flow rate: 0.75 ml/min; eluent A: 0.01M HClO₄Eluent B: acetonitrile, gradient: → 0.5min 98% A → 4.5min 10% A → 6.5min 10% A.

Method 2 (HPLC): column: kromasil C1860 x 2mm, L-R temperature: 30 ℃; flow rate: 0.75ml/min, eluent a: 0.01M H₃PO₄Eluent B: acetonitrile, gradient: → 0.5min 90% A → 4.5min 10% A → 6.5min 10% A.

Method 3 (HPLC): column: kromasil C1860 x 2mm, L-R temperature: 30 ℃; flow rate: 0.75 ml/min; eluent A: 0.005M HCLO₄Eluent B: acetonitrile, gradient: → 0.5min 98% A → 4.5min 10% A → 6.5min 10% A.

Method 4 (HPLC): column: symmetry C182.1 × 150 mm; column oven: 50 ℃; flow rate: 0.6 ml/min; eluent A: 0.6g of 30% hydrochloric acid/l of water, eluent B: acetonitrile, gradient: 0.0min 90% A → 4.0min 10% A → 9min 10% A.

Method 5 (LC-MS): an instrument Micromass Quattro LCZ; column SymmetryC18, 50mm × 2.1mm, 3.5 μm; temperature: 40 ℃; flow rate: 0.5 ml/min; eluent A: acetonitrile + 0.1% formic acid, eluent B: water + 0.1% formic acid, gradient: 0.0min 10% A → 4min 90% A → 6min 90% A.

Method 6 (LC-MS): an instrument Micromass Platform LCZ; column SymmetryC18, 50mm × 2.1mm, 3.5 μm; temperature: 40 ℃; flow rate: 0.5 ml/min; eluent A: acetonitrile + 0.1% formic acid, eluent B: water + 0.1% formic acid, gradient: 0.0min 10% A → 4min 90% A → 6min 90% A.

Method 7 (LC-MS): an instrument Micromass Quattro LCZ; column SymmetryC18, 50mm × 2.1mm, 3.5 μm; temperature: 40 ℃; flow rate: 0.5 ml/min; eluent A: acetonitrile + 0.1% formic acid, eluent B: water + 0.1% formic acid, gradient: 0.0min 5% A → 1min 5% A → 5min 90% A → 6min 90% A.

Method 8 (HPLC): column: 250 x 4mm, Kromasil 100, C-18, 5 μm; temperature: 40 ℃; flow rate: 1 ml/min; eluent: acetonitrile 15% and 0.2% perchloric acid 85%; UV-detector: 210 nm.

Method 9 (LC-MS): the instrument comprises the following steps: waters Alliance 2790 LC; column: SymmetryC18, 50nun × 2.1mm, 3.5 μm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; gradient: 0.0min 5% B → 5.0min 10% B → 6.0min 10% B; temperature: 50 ℃; flow rate: 1.0 ml/min; UV-detector: 210 nm.

Method 10 (LC-MS): ZMD Waters; column: inertsil ODS 350mm X2.1 mm, 3 μm; temperature: 40 ℃; flow rate: 0.5 ml/min; eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid, gradient: 0.0min 5% B → 12min 100% B → 15min 100% B.

Method 11 (LC-MS): MAT 900, Finnigan MAT, Bremen; column: x-terra50mm X2.1 mm, 2.5 μm; temperature: 25 ℃; flow rate: 0.5 ml/min; eluent A: water + 0.01% formic acid, eluent B: acetonitrile + 0.01% formic acid, gradient: 0.0min 10% B → 15min → 90% B → 30min 90% B.

Method 12 (LC-MS): TSQ 7000, Finnigan MAT, Bremen; column: inertsi1ODS 350 mm. times.2.1 mm, 3 μm; temperature: 25 ℃; flow rate: 0.5 ml/min; eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid, gradient: 0.0min 15% B → 15min → 100% B → 30min 100% B.

Method 13 (LC-MS): 7 Tesla ApexII, Bruker Daltronics with an external electrospray ion source; column: x-terra C1850 mm X2.1 mm, 2.5 μm; temperature: 25 ℃; flow rate: 0.5 ml/min; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid, gradient: 0.0min 5% B → 13min → 100% B → 15min 100% B.

Method 14 (HPLC): column: X-Terra from Waters^TMRP8, 5 μm, 3.9X 150 mm; beginning: 95% of A, 5% of B; 12 min: 5% A, 95% B. Eluent A: water + 0.01% trifluoroacetic acid; eluent B: acetonitrile + 0.01% trifluoroacetic acid; flow rate: 1.2 ml/min.

Method 15 (LC-MS): MS instrument type: micromass ZQ; HPLC instrument type: waters Alliance 2795; column: merck Chromolith speedROD RP-18e 50X 4.6 mm; eluent A: water + 500. mu.l 50% formic acid/l; eluent B: acetonitrile + 500. mu.l 50% formic acid/l; gradient: 0.0min 10% B → 3.0min 95% B → 4.0min 95% B; column oven: 35 ℃; flow rate: 0.0min 1.0ml/min → 3.0min 3.0ml/min → 4.0min 3.0 ml/min; UV detector: 210 nm.

Method 16 (LC-MS): MS instrument type: micromass ZQ; HPLC instrument type: waters Alliance 2795; column: merck Chromolith speedROD RP-18e 50X 4.6 mm; eluent A: water + 500. mu.l 50% formic acid/l; eluent B: acetonitrile + 500. mu.l 50% formic acid/l; gradient: 0.0min 10% B → 2.0min 95% B → 4.0min 95% B; column oven: 35 ℃; flow rate: 0.0min 1.0ml/min → 2.0min 3.0ml/min → 4.0min 3.0 ml/min; UV detector: 210 nm.

Method 17 (LC-MS): the instrument comprises the following steps: MicromassPlatform LCZ with HPLC Agilent series 1100; column: from-SIL 120 ODS-4HE, 50 mm. times.2.0 mm, 3 μm; eluent A: 11 water +1ml 50% formic acid, eluent B: 11 acetonitrile +1ml 50% formic acid; gradient: 0.0min 100% A → 0.2min 100% A → 2.9min 30% A → 3.1min 10% A → 4.5min 10% A; column oven: 55 ℃; flow rate: 0.8 ml/min; UV-detector: 210 nm.

Method 18 (LC-MS): MS instrument type: micromass ZQ; HPLC instrument type: waters Alliance 2795; column: merck Chromolith speedROD RP-18e 50X 4.6 mm; eluent A: water +500ul 50% formic acid/l; eluent B: acetonitrile + 500. mu.l 50% formic acid/l; gradient: 0.0min 10% B → 3.0min 95% B → 4.0min 95% B; column oven: 35 ℃; flow rate: 0.0min 1.0ml/min → 3.0min 3.0ml/min → 4.0min 3.0 ml/min; UV detector: 210 nm.

Method 19 (LC-MS): MS instrument type: micromass ZQ; HPLC instrument type: waters Alliance 2790; column: from-Sil 120 ODS-4HE 50mm × 2mm, 3.0 μm; eluent B: acetonitrile + 0.05% formic acid, eluent a: water + 0.05% formic acid; gradient: 0.0min 5% B → 2.0min 40% B → 4.5min 90% B → 5.5min 90% B; column oven: 45 ℃; flow rate: 0.0min 0.75ml/min → 4.5min 0.75ml/min → 5.5min 1.25 ml/min; UV detector: 210 nm.

Method 20 (LC-MS): MS instrument type: micromass ZQ; HPLC instrument type: waters Alliance 2790; column: uptisphere C18, 50 mm. times.2.0 mm, 3.0 μm; eluent B: acetonitrile + 0.05% formic acid, eluent a: water + 0.05% formic acid; gradient: 0.0min 5% B → 2.0min 40% B → 4.5min 90% B → 5.5min 90% B; column oven: 45 ℃; flow rate: 0.0min 0.75ml/min → 4.5min 0.75ml/min → 5.5min 1.25 ml/min; UV-detector: 210 nm.

Method 21 (LC-MS): the instrument comprises the following steps: micromass Quattro LCZ with HPLCAgilent series 1100; column: UPTI SPHERE HDO, 50mm × 2.0mm, 3 μm; eluent A: 11 water +1ml 50% formic acid, eluent B: 11 acetonitrile +1ml 50% formic acid; gradient: 0.0min 100% A → 0.2min 100% A → 2.9min 30% A → 3.1min 10% A → 4.5min 10% A; column oven: 55 ℃; flow rate: 0.8 ml/min; UV-detector: 208-400 nm.

Method 22 (LC-MS): MS instrument type: micromass ZQ; HPLC instrument type: HP1100 series; UV DAD; column: from-Sil 120 ODS-4HE 50X 2mm, 3.0 μm; eluent A: water +500 μ l 50% formic acid/l, eluent B: acetonitrile + 500. mu.l 50% formic acid/l; gradient: 0.0min 0% B → 2.9min 70% B → 3.1min 90% B → 4.5min 90% B; column oven: 50 ℃; flow rate: 0.8 ml/min; UV-detector: 210 nm.

Method 23 (LC-MS): MS instrument type: micromass ZQ; HPLC instrument type: waters Alliance 2795; column: phenomenex Synergi 2. mu. Hydro-RPMercury 20X 4 mm; eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A (flow rate: 1ml/min) → 2.5min 30% A (flow rate: 2ml/min) → 3.0min 5% A (flow rate: 2ml/min) → 4.5min 5% A (flow rate: 2 ml/min); column oven: 50 ℃; UV-detector: 210 nm.

Method 24 (LC-MS): MS instrument type: micromass ZQ; HPLC instrument type: HP1100 Series; UV DAD; column: phenomenex Synergi 2. mu. Hydro-RPMercury 20X 4 mm; eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A (flow rate: 1ml/min) → 2.5min 30% A (flow rate: 2ml/min) → 3.0min 5% A (flow rate: 2ml/min) → 4.5min 5% A (flow rate: 2 ml/min); column oven: 50 ℃; U-V-Detector: 210 nm.

Method 25 (LC-MS): MS instrument type: micromass ZQ; HPLC instrument type: HP1100 Series; UV DAD; column: from-Sil 120 ODS-4HE 50X 2mm, 3.0 μm; eluent A: water +500 μ l 50% formic acid/l, eluent B: acetonitrile + 500. mu.l 50% formic acid/l; gradient: 0.0min 70% B → 4.5min 90% B; column oven: 50 ℃, flow rate: 0.8ml/min, UV-detector: 210 nm.

Method 26 (LC-MS): the instrument comprises the following steps: micromass Quattro LCZ with HPLCAgilent series 100; column: from-SIL 120 ODS-4HE, 50 mm. times.2.0 mm, 3 μm; eluent A: 11 water +1ml 50% formic acid, eluent B: 11 acetonitrile +1ml 50% formic acid; gradient: 0.0min 100% A → 0.2min 100% A → 2.9min 30% A → 3.1min 10% A → 4.5min 10% A; column oven: 55 ℃; flow rate: 0.8 ml/min; UV-detector: 208-400 nm.

Chemical Synthesis of the examples

Synthesis of the starting compounds:

synthesis of substituted phenylalanine derivatives exemplified by (-) -3- (2-benzyloxy-5-iodophenyl) -2(S) -tert-butoxycarbonylamino-propionic acid [ (-) -6A ]

Synthesis of protected biphenyl-diamino acid with 2(S) -benzyloxycarbonylamino-3- [4, 4 '-dibenzyloxy-3' - (2(S) -benzyloxycarbonyl-2 (S) -tert-butoxycarbonylaminoethyl) biphenyl-3-yl ] propanoic acid- (2S) -trimethylsilyl-ethyl ester (12A) as an example

Synthesis of protected Hydroxyornithine derivative exemplified by 5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (tert-butyldimethylsilyloxy) pentanoic acid (14A)

With (8S, 11S, 14S) -14- [ (tert-butoxycarbonyl) amino]-11- { (2R) -3- [ (tert-butoxycarbonyl) amino group]-2-hydroxy-propyl } -5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]-henicosa-1(20)，2(21)Synthesis of protected Biphenomycin derivatives, exemplified by 3, 5, 16, 18-hexene-8-carboxylic acid (21A)

Starting compounds

Example 1A

2-hydroxy-5-iodobenzaldehyde

A solution of 250g (1.54mol) of iodine chloride in 600ml of anhydrous dichloromethane was added dropwise over 2 hours under argon to a solution of 188g (1.54mol) of salicylaldehyde in 1l of anhydrous dichloromethane in a thermally dried flask. After stirring it at room temperature for 3 days, a saturated aqueous sodium sulfite solution was added thereto with vigorous stirring. The organic layer was separated, washed once with water and saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The solvent was evaporated and the residue was recrystallized from ethyl acetate. 216g (57% of theory) of product are obtained.

LC-MS (ESI, method 10): m/z is 246(M-H).

¹H-NMR(400MHz，CDCl₃)：δ＝6.7(d，1H)，7.77(dd，1H)，7.85(d，1H)，9.83(s，1H)，10.95(s，1H).

Example 2A

2-benzyloxy-5-iodobenzaldehyde

67.2g (0.48mol) of potassium carbonate are added to a solution of 100g (0.40mol) of 2-hydroxy-5-iodobenzaldehyde (example 1A) in 1.51 dimethylformamide, to which, after a few minutes, 51ml (0.44mol) of benzyl chloride are added. The reaction mixture was stirred at reflux at 120 ℃ for 24 hours. After stirring it at room temperature for a further 24 hours and addition of 1.5l of water, a solid precipitated out. The precipitate is filtered off with suction, washed twice with water and then dried in vacuo. The solid was recrystallized from 230ml of ethanol. 122.9g (90% of theory) of product are obtained.

LC-MS (ESI, method 10): 338(M + H) M/z⁺.

¹H-NMR(400MHz，CDCl₃)：δ＝5.18(s，2H)，6.84(d，1H)，7.33-7.45(m，5H)，7.78(dd，1H)，8.12(d，1H)，10.4(s，1H).

Example 3A

(2-benzyloxy-5-iodophenyl) -methanol

100ml of a 1M solution of diisobutylaluminum hydride in dichloromethane were added to a solution of 33.98g (100.5mmol) of 2-benzyloxy-5-iodobenzaldehyde (example 2A) in 200ml of dichloromethane cooled to 0 ℃. After stirring it at 0 ℃ for 2 hours, a saturated aqueous solution of potassium sodium tartrate was added thereto while cooling (strongly exothermic reaction), and the reaction mixture was stirred for another 2 hours. After phase separation, the organic phase was washed twice with water, once with saturated sodium chloride in water, and then dried over sodium sulfate. The solvent was evaporated in vacuo. 31.8g (93% of theory) of product are obtained.

¹H-NMR(400MHz，CDCl₃)：δ＝2.17(t，1H)，4.68(d，2H)，5.1(s，2H)，6.72(d，1H)，7.32-7.42(m，5H)，7.54(dd，1H)，7.63(d，1H).

Example 4A

1-benzyloxy-2-bromomethyl-4-iodobenzene

3.3ml (35mmol) of phosphorus tribromide are added dropwise to a solution of 35g (103mmol) of (2-benzyloxy-5-iodophenyl) -methanol (example 3A) in 350ml of toluene at 40 ℃. The temperature of the reaction mixture was raised to 100 ℃ over 15 minutes and stirred at this temperature for a further 10 minutes. After cooling, the two phases were separated. The organic phase was washed twice with distilled water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated. The yield was 41g (99% of theory).

¹H-NMR(300MHz，CDCl₃)：δ＝4.45(s，2H)，5.06(s，2H)，7.30(m，8H).

Example 5A

2- (2-benzyloxy-5-iodobenzyl) -2-tert-butoxycarbonylaminomalonic acid diethyl ester

To a solution of 28g (101.7mmol) diethyl 2- [ N- (tert-butoxycarbonyl) amino ] malonate and 7.9ml (101.7mmol) sodium ethoxide in 300ml ethanol was added 41g (101.7mmol) 1-benzyloxy-2-bromomethyl-4-iodobenzene (example 4A). After stirring it for 3 hours at RT, the precipitated product is filtered off with suction. After drying in vacuo, 55g (90% of theory) of product were isolated.

¹H-NMR(400MHz，CDCl₃)：δ＝1.12(t，6H)，1.46(s，9H)，3.68(s，2H)，3.8-3.9(m，2H)，4.15-4.25(m，2H)，5.0(s，2H)，5.7(s，1H)，6.58(d，1H)，7.28-7.4(m，6H)，7.4(dd，1H).

Example 6A

(+/-) -3- (2-benzyloxy-5-iodophenyl) -2-tert-butoxycarbonylamino-propionic acid

To a suspension of 58g (97mmol) of diethyl 2- (2-benzyloxy-5-iodobenzyl) -2-tert-butoxycarbonylaminomalonate (example 5A) in 800ml of a mixture of ethanol and water (7: 3) was added 400ml of 1N sodium hydroxide solution. After refluxing for 3h and cooling to room temperature, the pH of the reaction mixture was adjusted to about 2 with concentrated hydrochloric acid. The reaction mixture was evaporated. The residue was taken up in MTBE and water. The aqueous phase was extracted three times with MTBE. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Drying in vacuo gives 47g (97% of theory) of product.

¹H-NMR(400MHz，DMSO)：δ＝1.32(s，9H)，2.68(dd，1H)，3.18(dd，1H)，4.25(m，1H)，5.15(s，2H) 6.88(d，1H)，7.08(d，.1H)，7.30-7.40(m，3H)，7.45-7.55(m，3H).

Example (-) -6A

3- (2-benzyloxy-5-iodophenyl) -2(S) -tert-butoxycarbonylamino-propionic acid

The racemate from example 6A [ (+/-) -3- (2-benzyloxy-5-iodophenyl) -2(S) -tert-butoxy-carbonylamino-propionic acid]The separation was carried out with a chiral silica stationary phase based on a selector from poly (N-isobutyryl-L-leucine dicyclopropylmethylamide) using an iso-hexane/ethyl acetate mixture as eluent. The first eluting enantiomer (98.9% ee) was dextrorotatory ([ alpha ] in dichloromethane]²¹ ₀: +3.0 °, c ═ 0.54, dichloromethane) and as determined by single crystal x-ray structural analysis, it is consistent with the (R) -enantiomer of example (+) -6A. The levorotatory enantiomer of the second example (-) -6A, the (S) -enantiomer, was > 99% ee pure.

Example 7A

3- (2-benzyloxy-5-iodophenyl) -2(S) -tert-butoxycarbonylaminopropionic acid benzyl ester

10g (20.11mmol) (-) -3- (2-benzyloxy-5-iodophenyl) -2(5) -tert-butoxycarbonylaminopropionic acid [ example (-) -6A ] were dissolved in 200ml acetonitrile under argon. 246mg (2.01mmol) of 4-dimethylaminopyridine and 4.16ml (40.22mmol) of benzyl alcohol are added thereto. The mixture was cooled to-10 ℃ and 4.63g (24.13mmol) EDC was added. The mixture was allowed to slowly rise to RT and stirred overnight. After about 16h, the mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (mobile phase: dichloromethane). Yield: 10.65g (88% of theory).

HPLC (method 3): r_t6.03 min; LC-MS (method 9): r_t＝4.70min

M(DCI)：m/z＝605(M+NH₄)⁺

¹H-NMR(200MHz，CDCl₃)：δ＝1.38(s，9H)，2.97(dd，1H)，3.12(dd，1H)，4.50-4.70(m，1H)，5.00-5.10(m，4H)，5.22(d，1H)，6.64(d，1H)，7.28-7.36(m，7H)，7.37-7.52(m，5H).

Example 8A

Benzyl 3- [ 2-benzyloxy-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan (dioxaborolan) -2-yl) phenyl ] -2(S) -tert-butoxycarbonylaminopropionate

To a solution of 10.30g (17.53mol) of benzyl 3- (2-benzyloxy-5-iodophenyl) -2(S) -tert-butoxycarbonylaminopropionate (example 7A) in 70ml of DMSO was added 5.15g (52.60mmol) of potassium acetate. The mixture was deoxygenated by passing argon through the solution during vigorous stirring for 15 minutes. Then 5.17g (20.16mmol) of bis (pinacolato) diborane and 515mg (0.70mmol) of bis (diphenylphosphino) ferrocenepalladium (II) chloride were added thereto. The mixture was then heated to 80 ℃ under a gentle stream of argon and cooled again after 6 hours. The mixture was purified by column chromatography using silica gel (mobile phase: dichloromethane). The DMSO present in the residue was removed by Kugelrohr distillation. The residue was purified by column chromatography using silica gel (mobile phase: cyclohexane: ethyl acetate 4: 1). Yield: 8.15g (79% of theory).

HPLC (method 3): r_t＝6.26min.

LC-MS (method 6): r_t5.93 and 6.09min.

MS(EI)：m/z＝588(M+H)⁺.

¹H-NMR(200MHz，CDCl₃)：δ＝1.26(s，6H)，1.33(s，9H)，1.36(s，6H)，2.91-3.10(m，1H)，3.12-3.28(m，1H)，4.49-4.68(m，1H)，5.05(dd，2H)，5.11(dd，2H)，5.30(d，1H)，6.90(d，1H)，7.27-7.37(m，7H)，7.38-7.42(m，3H)，7.55-7.62(m，1H)，7.67(dd，1H).

Example 9A

2(S) -amino-3- (2-benzyloxy-5-iodo-phenyl) -propionic acid hydrochloride

12g (24.13mmol) of 3- (2-benzyloxy-5-iodophenyl) -2(S) -tert-butoxycarbonylamino-propionic acid [ example (-) -6A ] are placed in 60ml of a 4M solution of hydrochloric acid in dioxane under argon and stirred at RT for 2 h. The reaction solution is concentrated and dried under high vacuum.

Yield: 10.47g (100% of theory).

HPLC (method 3): r_t＝4.10min

MS(EI)：m/z＝398(M+H-HCl)⁺.

¹H-NMR(200MHz，CDCl₃)：δ＝3.17-3.31(m，1H)，3.33-3.47(m，1H)，4.22(t，1H)，5.13(s，2H)，6.69(d，1H)，7.24-7.40(m，2H)，7.41-7.45(m，2H)，7.4g(d，1H)，7.52(d，1H)，7.60(d，1H)，8.66(br.s，2H).

Example 10A

2(S) -benzyloxycarbonylamino-3- (2-benzyloxy-5-iodophenyl) -propionic acid

To a solution of 10.46g (24.13mmol)2(S) -amino-3- (2-benzyloxy-5-iodophenyl) propionic acid hydrochloride (example 9A) in DMF was added 9.25ml (53.09mol) N, N-diisopropylethylamine. 6.615g (26.54mmol) of N- (benzyloxycarbonyl) succinimide (Z-OSuc) was added thereto. The resulting solution was stirred overnight and then dried in vacuo. The residue is taken up in dichloromethane and extracted once in water with 0.1N hydrochloric acid solution and saturated sodium chloride solution each. The organic phase was dried, filtered and concentrated. The mixture was purified by column chromatography using silica gel (mobile phase: cyclohexane/diethyl ether 9: 1 to 8: 2).

Yield: 8.30g (65% of theory).

HPLC (method 3): r_t＝5.01min.

MS(EI)：m/z＝532(M+H)⁺

¹H-NMR(200MHz，DMSO)：δ＝3.14-3.3(m，2H)，4.25-4.45(m，1H)，4.97(s，2H)，5.14(s，2H)，6.88(d，1H)，7.20-7.56(m，12H)，7.62(d，1H)，12.73(br.s，1H).

Example 11A

2- (S) -Benzyloxycarbonylamino-3- (2-benzyloxy-5-iodophenyl) propionic acid (2-trimethylsilyl) ethyl ester

8.35g (15.7mmol) of 2(S) -benzyloxycarbonylamino-3- (2-benzyloxy-5-iodophenyl) propionic acid (example 10A) was added to 150ml of THF, and then 2.14g (18.07mmol) of 2-trimethylsilylethanol and 250mg (2.04mmol) of 4-dimethylaminopyridine were added thereto. The mixture was cooled to 0 ℃ and 2.38g (2.95ml, 18.86mmol) of N, N' -diisopropylcarbodiimide dissolved in 40ml of THF were added thereto. The mixture was stirred at RT overnight and evaporated under vacuum for work-up. The residue was taken up in dichloromethane and extracted once with 0.1N aqueous hydrochloric acid and saturated aqueous sodium chloride, respectively. The organic phase was dried, filtered and concentrated. The mixture is purified by column chromatography (silica gel, mobile phase: cyclohexane/diethyl ether 9: 1 to 8: 2).

Yield: 8.2g (83% of theory).

CHPLC (method 3): r_t＝6.42min

MS(EI)：m/z＝532(M+H)⁺.

¹H-NMR(300MHz，CDCl₃)：δ＝0.01(s，9H)，0.88(t，2H)，2.96(dd，1H)，3.13(dd，1H)，4.04-4.17(m，2H)，4.51-4.62(m，1H)，4.95-5.05(m，4H)，5.44(d，1H)，6.64(d，1H)，7.25-7.33(m，7H)，7.37(dd，4H)，7.45(dd，1H).

Example 12A

2- (trimethylsilyl) ethyl 2(S) -benzyloxycarbonylamino-3- [4, 4 '-dibenzyloxy-3' - (2(S) -benzyloxycarbonyl-2-tert-butoxycarbonylaminoethyl) biphenyl-3-yl ] propionate

The method A comprises the following steps:

to a solution of 0.316g (0.5mmol) of 2(S) -benzyloxycarbonylamino-3- (2-benzyloxy-5-iodophenyl) propionic acid (2-trimethylsilyl) ethyl ester (example 11A) in 2.5ml of degassed DMF at RT under argon was added 45.8mg (0.05mmol) of bis (diphenylphosphino) ferrocene-palladium (II) chloride (PdCl)₂(dppt) and 0.325g (1.0mmol) of cesium carbonate). The reaction mixture was heated to 40 ℃. To this was added dropwise 0.294g (0.5mmol) of 3- [ 2-benzyloxy-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] over 30 minutes]Dioxaborolan-2-yl) phenyl]A solution of benzyl (S) -tert-butoxycarbonylaminopropionate (example 8A) in 2.5ml of degassed DMF. The mixture was stirred at 40 ℃ for 4h and at 50 ℃ for a further 2 h. The solvent was evaporated and the residue was taken up in ethyl acetate. The organic phase was extracted twice with water, dried over sodium sulfate and concentrated. The crude product was purified by chromatography on silica gel, eluting with dichloromethane/ethyl acetate (30/1). 0.320g (66% of theory) of product are obtained.

The method B comprises the following steps:

6.99g (11.06mmol) of 2(S) -benzyloxycarbonylamino-3- (2-benzyloxy-5-iodophenyl) propionic acid (2-trimethylsilyl) ethyl ester (example 11A) and 6.50g (11.06mmol) of 3- [ 2-benzyloxy-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2-tetramethyl- [1]DioxaboronesHeterocyclopentane-2-yl) -phenyl]A solution of benzyl-2 (S) -tert-butoxycarbonylaminopropionate (example 8A) in 40ml of DMF was degassed by argon (ca. 30 min). 812mg (1.11mmol) of bis (diphenylphosphino) ferrocenepalladium (II) chloride (PdCl) were then added thereto₂(dppf)) and 7.21g (22.13mmol) of cesium carbonate. A gentle stream of argon was passed through the reaction mixture and heated at 80 ℃ for 2.5 h. The mixture was cooled and purified using column chromatography using silica gel (mobile phase: cyclohexane/ethyl acetate 7: 3). To this mixture was added diisopropyl ether before complete evaporation to dryness. The crystals obtained are filtered off with suction and dried under high vacuum.

Yield: 6.54g (61% of theory).

HPLC (method 3): r_t＝7.65min

MS(EI)：m/z＝987(M+Na)，965(M+H)⁺.

¹H-NMR(200MHz，CDCl₃)：δ＝0.00(s，9H)，0.90(t，2H)，1.37(s，9H)，3.02-3.35(m，4H)4.06-4.25(m，2H)，4.55-4.73(m，2H)，4.98-5.18(m，8H)，5.40(d，1H)，5.63(d，1H)，6.88-7.00(m，2H)，7.19-7.39(m，20H)，7.42-7.53(m，4H).

Example 13A

N^a- (tert-butoxycarbonyl) -N^ε(benzyloxycarbonyl) - (2S, 4R) -hydroxyornithine lactone

A solution of 7.60g (17.3mmol) of 5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) -tert-butyl hydroxypentanoate (prepared as described by org. Lett., 2001, 3, 20, 3153-propan 3155) in 516ml of dichloromethane and 516ml of trifluoroacetic acid was stirred at RT for 2 h. The solvent was evaporated. The remaining crude product was dissolved in 2.61 parts of anhydrous methanol, and 6.3g (28.8mmol) of di-tert-butyl dicarbonate and 7.3ml (52.43mmol) of triethylamine were added thereto while stirring it at 0 ℃. After 15h, the reaction solution was evaporated, and the residue was taken up in 11 ethyl acetate. After phase separation, the organic phase is extracted twice with a 5% strength citric acid solution, twice with water and twice with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography using silica gel eluting with toluene/acetone (5/1). 4.92g (78% of theory) of product are obtained.

LC-HR-FT-ICR-MS (method 13): calculated value C₁₈H₂₈N₃O₆(M+NH₄)⁺382.19726

Found 382.19703.

¹H-NMR(400MHz，CDCl₃)：δ＝1.45(s，9H)，2.3-2.4(m，1H)，2.45-2.55(m，1H)，3.3-3.4(m，1H)，3.5-3.6(m，1H)，4.17-4.28(m，1H)，4.7-4.8(m，1H)，5.0-5.15(m，4H)，7.3-7.4(m，5H).

Example 14A

5-Benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (tert-butyldimethylsilyloxy) pentanoic acid

The method A comprises the following steps:

at 0 ℃ to 0.73g (2mmol) N^a- (tert-butoxycarbonyl) -N^εTo a solution of (benzyloxycarbonyl) - (2S, 4R) -hydroxyornithine lactone (13A) in 50ml 1, 4-dioxane was added 2ml 1M sodium hydroxide solution. The reaction solution was stirred for 2h and then evaporated. The residue is taken up in 50ml of dichloromethane. To this solution was added 1.12ml (8mmol) of triethylamine, and later, 1.38ml (6mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate were added dropwise thereto. In willAfter stirring at RT for 3 hours, the reaction mixture was diluted with dichloromethane. The organic phase is washed with a 1N sodium bicarbonate solution, dried over sodium sulfate and evaporated. The crude product was dissolved in 7.4ml of 1, 4-dioxane, to which 36.2ml of 0.1N sodium hydroxide solution was added. After stirring it for 3 hours at RT, the reaction solution was evaporated and the residue was taken up with water and ethyl acetate. The organic phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. 0.90g (90% of theory) of product are obtained.

The method B comprises the following steps:

a solution of 14.0g (38mmol) of benzyl 2(S) -tert-butoxycarbonylamino-4 (R) -hydroxy-5-nitropentanoate in 840ml of ethanol/water 9/1 was mixed together with 1.96 palladium on charcoal (10% strength) and hydrogenated at RT for 24h at atmospheric pressure. The mixture was filtered through celite and the filtrate was combined with 14.7g (114mmol) of diisopropylethylamine. Then, 11.4g (45.6mmol) of N- (benzyloxycarbonyloxy) succinimide was added thereto, and the mixture was stirred at RT for 4 h. The solution is concentrated, the residue is taken up in dichloromethane and extracted twice with 0.1N hydrochloric acid. The organic layer was separated off and basified with 14.7g (114mmol) of diisopropylamine. The solution was cooled to 0 ℃ and 30.1g (114mmol) of dimethyl-tert-butylsilyl trifluoromethanesulfonate were added and the mixture was stirred at RT for 2.5 h. The organic phase is washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue is dissolved in 50ml of dioxane, mixed with 200ml of 0.1N sodium hydroxide solution and stirred at RT for 3 h. After several extractions with ethyl acetate, the collected organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed using silica gel (mobile phase: dichloromethane/ethanol 20/1, 9/1). 8.11g (43% of theory) of product are obtained.

MS(ESI)：m/z＝497(M+H)⁺.

¹H-NMR(300MHz，d₆-DMSO)：δ＝0.00(s，6H)，0.99(s，9H)，1.33(s，9H)，1.59(m，1H)，1.80(m，1H)，2.75-3.15(m，2H)，3.81(m，1H)，3.98(m，1H)，4.96(m，2H)，7.04(d，1H)，7.19(m，1H)，7.30(m，5H)，12.37(br.s，1H).

Example 15A

3- [3 '- (2(S) -amino-2-benzyloxycarbonylethyl) -4, 4' -dibenzyloxybiphenyl-3-yl ] -2(S) -benzyloxycarbonylaminopropionic acid 2- (trimethylsilyl) ethyl ester hydrochloride

To a solution of 2.65g (2.75mmol)2(S) -benzyloxycarbonylamino-3- [4, 4 '-dibenzyloxy-3' - (2(S) -benzyloxycarbonyl-2-tert-butoxycarbonylaminoethyl) biphenyl-3-yl ] propionic acid 2- (trimethylsilyl) ethyl ester (example 12A) cooled to 0 ℃ in 50ml dry dioxane was added 50ml of a 4M hydrochloric acid/dioxane solution over about 20 minutes.

After stirring for 3h, the reaction solution was evaporated and dried under high vacuum.

Yield: 100% of theory.

HPLC (method 3): r_t＝5.96min.

MS(EI)：m/z＝865(M+H)⁺.

Example 16A

Benzyl 2(S) - [ 5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (tert-butyldimethylsilyloxy) pentanoylamino ] -3- {4, 4 '-dibenzyloxy-3' - [2(S) -benzyloxycarbonylamino-2- (2-trimethylsilylethoxycarbonyl) ethyl ] biphenyl-3-yl } propanoate

To a solution of 0.520g (0.58mmol) of ethyl 3- [3 '- (2(S) -amino-2-benzyloxycarbonylethyl) -4, 4' -dibenzyloxybiphenyl-3-yl ] -2(S) -benzyloxycarbonylaminopropionate (2-trimethylsilyl) hydrochloride (example 15A) and 0.287g (0.58mmol) of 5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (tert-butyldimethylsilyloxy) pentanoic acid (example 14A) in 7.3ml of anhydrous DMF cooled to 0 ℃ were added 0.219g (0.58mmol) of HATU and 0.082g (0.63mmol) of N, N-diisopropylethylamine. After stirring it at 0 ℃ for 30 minutes, 0.164g (1.26mmol) of N, N-diisopropylethylamine was further added thereto. The reaction mixture was stirred at RT for 15 h. Then, the solvent was evaporated, and the residue was taken up in ethyl acetate. The organic phase was washed three times with water, once with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by chromatography on silica gel eluting with methylene chloride/ethyl acetate (gradient 30/1 → 20/1 → 10/1). 533mg (66% of theory) of product are obtained.

LC-MS (ESI, method 12): m/z 1342(M + H)⁺，1365(M+Na)⁺.

Example 17A

2(S) -benzyloxycarbonylamino-3- {4, 4 '-dibenzyloxy-3' - [2(S) -benzyloxycarbonyl-2- (5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) -hydroxypentanoylamino) ethyl ] biphenyl-3-yl } propanoic acid

The method A comprises the following steps:

to a solution of 0.360g (0.27mmol) of benzyl 2(S) - [ 5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (tert-butyldimethylsilyloxy) pentanoylamino ] -3- {4, 4 '-dibenzyloxy-3' - [2(S) -benzyloxycarbonylamino-2- (2-trimethylsilylethoxycarbonyl) ethyl ] biphenyl-3-yl } propanoate (example 16A) in 22.5ml of anhydrous DMF was added 0.80ml of a 1.0M solution of tetrabutylammonium fluoride in THF. After stirring it for 1h at RT, the reaction mixture was cooled to 0 ℃ and water was added thereto. After addition of ethyl acetate, the phases were separated. The organic phase is washed with 1.0M potassium hydrogen sulfate solution, dried over sodium sulfate and evaporated. 0.331g of crude product is obtained. The crude product was reacted without further purification.

LC-MS (ESI, method 10): m/z 1129(M + H)⁺.

LC-HR-FT-ICR-MS: calculated value C₆₅H₆₉N₄O₁₄(M+H)⁺1129.48048

Found 1129.48123.

The method B comprises the following steps:

to a solution of 800mg (0.6mmol) of benzyl 2(S) - [ 5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (tert-butyldimethylsilyloxy) pentanoylamino ] -3- {4, 4 '-dibenzyloxy-3' - [2(S) -benzyloxycarbonylamino-2- (2-trimethylsilylethoxycarbonyl) ethyl ] biphenyl-3-yl } propanoate (example 16A) in 26ml of anhydrous DMF at RT was added dropwise 1.8ml of 1N tetrabutylammonium fluoride in THF. After 25min at RT, the reaction mixture was cooled to 0 ℃ and a large amount of ice water was added thereto. Ethyl acetate and a 1N hydrochloric acid solution were immediately added thereto. The organic phase was dried over magnesium sulfate, concentrated and dried under high vacuum for 1 h. The crude product was reacted without further purification.

Example 18A

Benzyl 2(S) - (5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) -hydroxypentanoylamino) -3- [4, 4 '-dibenzyloxy-3' - (2(S) -benzyloxycarbonylamino-2-pentafluorophenoxycarbonylethyl) biphenyl-3-yl ] propionate

The method A comprises the following steps:

to a solution of 104mg (92. mu. mol) of 2(S) -benzyloxycarbonylamino-3- {4, 4 '-dibenzyloxy-3' - [2(S) -benzyloxycarbonyl-2- (5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) -hydroxypentanoylamino) ethyl ] biphenyl-3-yl } propanoic acid (example 17A) in 3ml of dichloromethane cooled to-25 ℃ were added under argon 90mg of pentafluorophenol (0.49mmol) dissolved in a small amount of dichloromethane, 1.1mg of 4-dimethylaminopyridine (10. mu.M) and 19.4mg (0.10mmol) of EDC. After stirring for 15h, the reaction mixture was concentrated. The crude product was reacted without further purification.

LC-MS (ESI, method 11): m/z 1317(M + Na)⁺，1295(M+H)⁺.

LC-HR-FT-ICR-MS: calculated value C₇₁H₆₈F₅N₄O₁₄(M+H)⁺1295.46467

Found 1295.46430.

The method B comprises the following steps:

691mg (crude mixture, ca. 0.6mmol) of 2(S) -benzyloxycarbonylamino-3- {4, 4 '-dibenzyloxy-3' - [2(S) -benzyloxycarbonyl-2- (5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) -hydroxypentanoylamino) ethyl ] biphenyl-3-yl } propanoic acid (example 17A) were added to 25ml of dichloromethane and 547.6mg (2.98mmol) of pentafluorophenol dissolved in 6ml of dichloromethane were added thereto. 7.3mg (0.06mmol) DMAP was added thereto and the reaction mixture was cooled to-25 deg.C (ethanol/carbon dioxide bath). 148mg (0.774mmol) EDC were added at-25 ℃. The mixture was slowly heated to RT overnight. The reaction mixture was concentrated in vacuo and briefly dried under high vacuum. The crude product was reacted without further purification.

Example 19A

5, 17-bis-benzyloxy-14 (S) -benzyloxycarbonylamino-11 (S) - (3-benzyloxycarbonylamino-2 (R) -hydroxypropyl) -10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]-henicosa-1(19), 2, 4, 6(21), 16(20), 17-hexene-8 (S) -carboxylic acid benzyl ester

The method A comprises the following steps:

to 119.3mg of 2(S) - (5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) -hydroxypentanoylamino) -3- [4, 4 '-dibenzyloxy-3' - (2(S) -benzyloxycarbonylamino-2-pentafluorophenoxycarbonylethyl) biphenyl-3-yl group]To a solution of benzyl propionate (example 18A) in 2.7ml of 1, 4-dioxane was added a solution of 4ml of 4M hydrochloric acid in1, 4-dioxane. At the end of the reaction, 1.5ml of a 4M solution of hydrochloric acid in1, 4-dioxane are added thereto. The reaction solution was evaporated and co-distilled with chloroform twice. The crude product (LC-HR-FT-ICR-MS, method 13: C)₆₆H₆₀F₅N₄O₁₂(M+H)⁺Calculated 1195.41224, found 1195.41419) was dissolved in100 ml chloroform and added dropwise over the course of 3h to a mixture of 200ml chloroform and 100ml saturated aqueous sodium bicarbonate solution which was stirred very efficiently. The reaction mixture was stirred vigorously for 2 h. After separation of the two phases, the aqueous phase was extracted with chloroform. The combined organic phases were washed with 5% strength aqueous citric acid, dried over magnesium sulfate and evaporated to dryness. The crude product was washed with acetonitrile and dried under high vacuum.

Yield: 60.5mg (65% of theory).

LC-MSL, method 11): m/z 1011(M + H)⁺.

The method B comprises the following steps:

0.595mmol of benzyl 2(S) - (5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) -hydroxypentanoylamino) -3- [4, 4 '-dibenzyloxy-3' - (2(S) -benzyloxycarbonylamino-2-pentafluorophenoxycarbonylethyl) biphenyl-3-yl ] propionate (example 18A) are dissolved in 8ml of dioxane and then 16ml of a 4N solution of hydrochloric acid in dioxane are added dropwise thereto at 0 ℃. After 45min, a further 6ml of 4N dioxane solution of hydrochloric acid were added thereto, and after 15min, a further 8ml of this solution were added thereto. The mixture was stirred at 0 ℃ for 30min, then the reaction solution was concentrated under mild conditions, co-distilled (twice) with chloroform and briefly dried under high vacuum. The crude product (732mg, 0.59mmol) was dissolved in 1000ml of chloroform and 6ml of triethylamine in 50ml of chloroform was added dropwise thereto. The mixture was stirred at RT overnight. The mixture was worked up by evaporation under vacuum under mild conditions and stirring the residue in acetonitrile. The crystals obtained are filtered off with suction, washed with acetonitrile and dried under high vacuum.

Yield: 360mg (60% of theory).

MS(EI)：m/z＝1011(M+H)⁺.

HPLC (method 3): r_t＝5.59min.

¹H-NMR(400MHz，d₆-DMSO)：δ＝1.52-1.65(m，1H)，1.73-1.84(m，1H)，2.82-3.01(m，3H)，3.02-3.11(m，1H)，3.46(s，1H)，3.57-3.68(m，1H)，4.47-4.56(m，1H)，4.64-4.71(m，1H)，4.73-4.85(m，2H)，4.88-5.00(m，4H)，5.09(s，2H)，5.14-5.20(m，4H)，6.29(d，1H)，7.00-7.11(m，4H)，7.21-7.40(m，20H)，7.41-7.48(m，9H)，8.77(d，1H)，8.87(d，1H).

Example 20A

14(S) -amino-11 (S) - (3-amino-2 (R) -hydroxy-propyl) -5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]Henicosa-1(19), 2, 4, 6(21), 16(20), 17-hexene-8 (S) -carboxylic acid dihydrochloride

The method A comprises the following steps:

10mg (9.9. mu.M) of 5, 17-bis-benzyloxy-14 (S) -benzyloxycarbonylamino-11 (S) - (3-benzyloxycarbonylamino-2 (R) -hydroxy-propyl) -10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]A solution of henicosa-1(19), 2, 4, 6(21), 16(20), 17-hexene-8 (S) -carboxylic acid benzyl ester (example 19A) and 50. mu.l formic acid in10 ml ethanol was stirred vigorously under hydrogen at atmospheric pressure in the presence of 10mg Pd/C for 16 h. The reaction solution was evaporated, and the residue was taken up in 1N hydrochloric acid solution and filtered. The crude product was purified using an RP18 cartridge eluting with acetonitrile/water. 2mg (42.8% of theory) of product are obtained.

The method B comprises the following steps:

200mg (0.20mmol) of 5, 17-bis-benzyloxy-14 (S) -benzyloxycarbonylamino-11 (S) - (3-benzyloxycarbonylamino-2 (R) -hydroxypropyl) -10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]Henicosa-1(19), 2, 4, 6(21), 16(20), 17-hexene-8 (S) -carboxylic acid benzyl ester (example 19A) was placed in 220ml acetic acid/water/ethanol 4: 1 mixture (THF could be used instead of ethanol). 73mg of 10% strength palladium on charcoal (10% Pd/C) were added and then hydrogenated at atmospheric pressure for 15 h. The reaction mixture was filtered through pre-washed celite, and the filtrate was concentrated in vacuo. The residue was mixed with 4.95ml of 0.1N aqueous hydrochloric acid and concentrated. The residue is stirred with 10ml of diethyl ether and is washed off. The remaining solid was dried under high vacuum.

Yield: 103mg (95% of theory).

HPLC (method 3): r_t＝3.04min；

LC-MS (method 6): r_t＝0.38min

MS(EI)：m/z＝473(M+H)⁺.

¹H-NMR(400MHz，D₂O)：δ＝2.06-2.20 (m，1H)，2.74-2.89(m，1H)，2.94-3.05(m，1H)，3.12-3.25(m，2H)，3.53(d，1H)，3.61-3.72(m，1H)，3.97-4.07(m，1H)，4.53(s，1H)，4.61(d，1H)，4.76-4.91(m，12H)，7.01-7.05(m，2H)，7.07(s，1H)，7.40-7.45(m，2H)，7.51(d，1H).

Example 21A

(8S, 11S, 14S) -14- [ (tert-butoxycarbonyl) amino group]-11- { (2R) -3- [ (tert-butoxycarbonyl) amino group]-2-hydroxypropyl } -5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]henicosa-1(20), 2(21), 3, 5, 16, 18-hexene-8-carboxylic acid

The method A comprises the following steps:

5.2mg (9.5. mu. mol) of 14(S) -amino-11 (S) - (3-amino-2 (R) -hydroxy-propyl) -5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]henicosa-1(19), 2, 4, 6(21), 16(20), 17-hexene-8 (S) -carboxylic acid dihydrochloride (example 20A) was dissolved in dry methanol (analytical grade, 0.5ml) under argon. While this was being vigorously stirred at room temperature, an aqueous sodium hydrogencarbonate solution (1M, 100l) was added dropwise thereto, followed by dropwise addition of a methanol solution of di-tert-butyl carbonate (0.1M, 570. mu.l, 57. mu. mol). Complete conversion is achieved after about 1-2 days. The reaction mixture was evaporated in vacuo and dried under high vacuum. The resulting crude product was purified by gel chromatography [ SephadexLH-20; methanol/1M sodium bicarbonate solution (1: 0.0001)]. 5.3mg (83% of theory) of product are obtained.

HPLC/UV-Vis (method 14) R_t＝7.4min.

λ_max(qualitative) 193nm(s), 206(sh), 269(m), 284(sh) (H)₂O/acetonitrile + 0.01% TFA [ 4: 6 ]]).

LC-HR-FT-ICR-MS: calculated value C₃₃H₄₄N₄O₁₁[M+H]⁺673.3079

Found 673.3082.

The method B comprises the following steps:

50mg (0.09mmol) of 14(S) -amino-11 (S) - (3-amino-2 (R) -hydroxy-propyl) -5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]Henicosa-1(19), 2, 4, 6(21), 16(20), 17-hexene-8 (S) -carboxylic acid dihydrochloride (example 20A) was introduced into 8ml of a methanol/water (9: 1) mixture. 1ml of a 1N sodium hydrogencarbonate solution was added thereto, followed by addition of 80mg (0.37mmol) of di-tert-butyl dicarbonate in 2ml of methanol/water (9: 1). The mixture was stirred at RT overnight. The solution was treated by mixing it with 60ml of ethyl acetate and 30ml of water. The organic phase is washed once with 0.1 standard hydrochloric acid, dried and then concentrated in vacuo.

Yield: 49mg (79% of theory).

LC-MS (method 9): r_t＝2.56min.

MS(EI)：m/z＝673(M+H)⁺.

Example 22A

(2R) -3- [ (8S, 11S, 14S) -8- (aminocarbonyl) -14- [ (tert-butoxycarbonyl) -amino]-5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1^2，6]henicosa-1(20), 2(21), 3, 5, 16, 18-hexen-11-yl]-2-Hydroxypropylcarbamic acid tert-butyl ester

The method A comprises the following steps:

4.1mg (6.1. mu. mol) of (8S, 11S, 14S) -14- [ (tert-butoxycarbonyl) amino group]-11- { (2R) -3- [ (tert-butoxycarbonyl) amino group]-2-hydroxypropyl } -5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]henicosa-1(20), 2(21), 3, 5, 16, 18-hexene-8-carboxylic acid (example 21A) was dissolved in anhydrous N, N-dimethylformamide (analytical grade, 0.5ml) under a protective atmosphere of argon. Solid sodium bisulfite (6.1. mu. mol) was added, followed by dropwise addition at RT of a freshly prepared solution of diisopropylethylamine (7.9mg, 61. mu. mol), ammonium chloride (1.6mg, 30. mu. mol) and HATU (4.6mg, 12.2. mu. mol) in dimethylformamide (0.5ml, solution A). Two more solutions A (after a reaction time of 1.5h and after a reaction time of 2h) have to be added until the conversion of the precursor is complete. The mixture was stirred for a further 20 minutes and then the reaction was stopped by the addition of water (0.5 ml). The reaction mixture was frozen and then freeze-dried. The crude product obtained was purified by gel chromatography [ Sephadex LH-20; methanol/acetic acid (1: 0.0001) incorporating sodium bisulfite]。

Yield: 2.2mg (52% of theory).

HPLC-UV-Vis (method 14): r_t＝7.06min.

λ_maxQualitative (202 nm (s)), 268(m), 285(sh) (-H)₂O/acetonitrile + 0.01% TFA [ 4: 6 ]]).

LC-HR-FT-ICR-MS (method 13): calculated value C₃₃H₄₆N₅O₁₀[M+H]⁺672.3239

Found 672.3239.

The method B comprises the following steps:

49mg (0.07mmol) of (8S, 11S, 14S) -14- [ (tert-butoxycarbonyl) amino group were added under argon]-11- { (2R) -3- [ (tert-butoxycarbonyl) amino group]-2-hydroxypropyl } -5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]Henicosa-1(20), 2(21), 3, 5, 16, 18-hexene-8-carboxylic acid (example 21A) was dissolved in 1ml of DMF and cooled to 0 ℃. Then 42mg (0.11mmol) HATU was added thereto and the mixture was stirred at 0 ℃ for 10 min. 1.46ml (0.73mmol) of a 0.5 molar solution of ammonia in dioxane are added dropwise thereto and the mixture is stirred at RT overnight. After about 18h, the same amount of reagent was added again. After 3 days, the mixture was concentrated in vacuo and purified by preparative RP-HPLC.

Yield: 16mg (33% of theory).

HPLC (method 3): r_t＝3.83min.

Example 23A

(2R) -3- [ (8S, 11S, 14S) -8- [ (benzylamino) carbonyl]-14- [ (tert-butoxycarbonyl) amino group]-5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1^2，6]henicosa-1(20), 2(21), 3, 5, 16, 18-hexen-11-yl]-2-Hydroxypropylcarbamic acid tert-butyl ester

To 7mg (0.01mmol) of ((8S, 11S, 14S) -14- [ (tert-butoxycarbonyl) amino) cooled to 0 ℃ under argon]-11- { (2R) -3- [ (tert-butoxycarbonyl) amino group]-2-hydroxypropyl } -5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]To a solution of henicosa-1(20), 2(21), 3, 5, 16, 18-hexene-8-carboxylic acid (example 21A) in 0.5ml anhydrous DMF was added 7.9mg (0.021mmol) of HATU. After 10min at 0 ℃ 2.3mg (0.021mmol) benzylamine are added and the mixture is stirred at RT overnight. The reaction mixture was concentrated in vacuo and the residue was isolated by preparative RP-HPLC.

Yield: 1.5mg (18.9% of theory).

LC-MS (method 6): r_t＝4.4min.

MS(ESI-pos)：m/z＝785(M+Na)⁺，762(M+H)⁺.

Example 24A

(2R) -3- [ (8S, 11S, 14S) -14- [ (tert-butoxycarbonyl) amino group]-5, 17-bis-hydroxy-8- (1 (2-hydroxyethyl) (methyl) amino } carbonyl } -10, 13-dioxo-9, 12-bis-aza-tricyclo [14.3.1.1^2，6]henicosa-1(20), 2(21), 3, 5, 16, 18-hexen-11-yl]-2-Hydroxypropylcarbamic acid tert-butyl ester

Under argon, 15mg (0.022mmol) of (8S, 11S, 14S) -14- [ (tert-butoxy-carbonyl) amino]-11- { (2R) -3- [ (tert-butoxycarbonyl) amino group]-2-hydroxypropyl } -5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1.^2，6]Henicosa-1(20), 2(21), 3, 5, 16, 18-hexene-8-carboxylic acid (example 21A) was dissolved in 0.5ml DMF and cooled to 0 ℃. To this were added 10.2mg (0.027mmol) of HATU and 8.64mg (0.067mmol) of N, N-diisopropylethylamine, and the mixture was stirred at 0 ℃ for 10 min. 3.34mg (0.045mmol) 2-methylaminoethanol are added thereto and the mixture is stirred at RT overnight. The reaction mixture was concentrated and purified by Gilson HPLC.

Yield: 3.8mg (23% of theory).

LC-MS (method 21): r_t＝3.90min.

Examples 25A to 32A listed in the following table can be prepared similarly to example 24A.

Examples 33A and 34A listed in the following table can be prepared similarly to example 24A with 2 equivalents of HATU and 3 equivalents of amine.

Examples 35A and 36A listed in the table below can be prepared similarly to example 24A with 2 equivalents HATU, 2 equivalents amine without the addition of DIPEA.

Example 37A

2- (benzyloxy) -N- (tert-butoxycarbonyl) -5-iodo-L-phenylalanyl-L-phenylalanine benzyl ester

0.4g (0.8mmol)2- (benzyloxy) -N- (tert-butoxycarbonyl) -5-iodo-L-phenylalanine (example 6A) and 0.282g (0.970mmol, 1.2 equivalents) benzyl L-phenylalanine hydrochloride were added to 6ml DMF under argon, and then 0.382g (1.01mmol, 1.25 equivalents) HATU and 0.49ml (0.36mg, 2.8mmol, 3.5 equivalents) diisopropylethylamine were added successively thereto at RT. The mixture was stirred at RT for 12 hours. After addition of 150ml of water, the product is isolated in the form of white crystals. The crystals are filtered off with suction, washed with water and dried in vacuo.

Yield: 0.669g (quantitative)

LC-MS (method 15): r_t＝3.11min.

MS(EI)：m/z＝235(M+H)⁺

Examples 38A to 41A listed in the following table were prepared similarly to example 37A.

Example 42A

2- (trimethylsilyl) ethyl-2- (S) -benzyloxycarbonylamino-3- [3 ' [ -2- [ tert-butoxycarbonylamino (3-amino- [1- (S) -benzyloxy-1-oxo-2-phenyl-ethyl ] -3-oxopropyl) ] -4, 4 ' -bis (benzyloxy) -1, 1 ' -biphenyl-3-yl ] ] propionate

0.593g (0.939mmol)2- (benzyloxy) -N- [ (benzyloxy) -carbonyl ] -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -L-phenylalanine 2- (trimethylsilyl) ethyl ester (example 84A) and 0.734g (0.939mmol)2- (benzyloxy) -N- (tert-butoxy-carbonyl) -5-iodo-L-phenylalanyl-L-phenylalanine benzyl ester (example 37A) were dissolved in 6ml DMSO under argon. The resulting solution was flushed with argon for 30 min. To this was then added 0.069g (0.094mmol, 0.1 equiv.) of bis (di-phenylphosphino) ferrocene-palladium (II) chloride and 0.612g (1.88mmol, 2.0 equiv.) of cesium carbonate. After flooding with argon for 10 minutes, the mixture was heated at 80 ℃ for 3 days, and flooding with gas was continued. After cooling to RT, the crude solution is purified by chromatography on silica gel (cyclohexane/ethyl acetate 2: 1). The concentrated product-containing fractions were then purified by preparative RP-HPLC.

Yield: 0.367g (29% of theory)

LC-MS (method 15): r_t＝3.50min.

Examples 43A to 46A listed in the table below can be prepared analogously to example 42A.

Example 47A

2- (trimethylsilyl) ethyl 2- (S) -benzyloxycarbonylamino-3- [3 ' [ -2- [ amino (3-amino- [1- (S) -benzyloxy-1-oxo-2-phenylethyl ] -3-oxopropyl) ] -4, 4 ' -bis (benzyloxy) -1, 1 ' -biphenyl-3-yl ] ] propionate

2- (trimethylsilyl) ethyl 2- (S) -benzyloxycarbonylamino-3- [3 ' [ -2- [ tert-butoxycarbonylamino (3-amino- [1- (S) -benzyloxy-1-oxo-2-phenyl-ethyl ] -3-oxopropyl) ] -4, 4 ' -bis (benzyloxy) -1, 1 ' -biphenyl-3-yl ] ] propionate (example 42A) was dissolved in10 ml of a 4M solution of hydrogen chloride in dioxane under argon and stirred at RT for 3 h. The solution was concentrated on a rotary evaporator and dried in vacuo. The crude product was reacted without further purification.

Examples 48A to 51A listed in the following table can be prepared similarly to example 47A.

Example 52A

2- (trimethylsilyl) ethyl 2- (S) -benzyloxycarbonylamino-3- [3 ' [ -2- [ 5-benzyloxy-carbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (tert-butyldimethyl-silanyloxy) pentanoylamino (3-amino- (1- (S) -benzyloxy-1-oxo-2-phenyl-ethyl ] -3-oxopropyl) ] -4, 4 ' -bis (benzyloxy) -1, 1 ' -biphenyl-3-yl ] ] propionate

0.27g (0.27mmol)2- (S) -benzyloxycarbonylamino-3- [3 ' [ -2- [ amino (3-amino- [1- (S) -benzyloxy-1-oxo-2-phenyl-ethyl ] -3-oxopropyl) ] -4, 4 ' -bis (benzyloxy) -1, 1 ' -biphenyl-3-yl ] ] propionic acid 2- (trimethylsilyl) ethyl ester (example 47A) and 0.16g (0.32mmol, 1.2 equivalents) 5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (tert-butyl-dimethylsilyloxy) pentanoic acid were dissolved in 5ml anhydrous DMF under argon. To this were added 0.13g (0.34mmol, 1.25 equiv.) of HATU and 0.16ml (0.12g, 0.95mmol, 3.5 equiv.) of N, N-diisopropylethylamine at RT. The reaction mixture was stirred at RT for 12 h. The reaction mixture was directly purified by preparative RP-HPLC and reacted without further purification. Yield: 0.288g (71% of theory).

Examples 53A to 56A listed in the following table can be prepared similarly to example 52A.

Example 57A

2- (S) -benzyloxycarbonylamino-3- [3 ' [ -2- [ 5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (hydroxy-oxy) pentanoylamino (3-amino- [1- (S) -benzyloxy-1-oxo-2-phenyl-ethyl ] -3-oxopropyl) ] -4, 4 ' -bis (benzyloxy) -1, 1 ' -biphenyl-3-yl ] ] propionic acid

To a solution of 0.29g (0.19mmol) of 2- (S) -benzyloxycarbonylamino-3- [3 ' [ -2- [ 5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (tert-butyldimethylsilyloxy) pentanoylamino (3-amino- [1- (S) -benzyloxy-1-oxo-2-phenyl-ethyl ] -3-oxopropyl)) -4, 4 ' -bis (benzyloxy) -1, 1 ' -biphenyl-3-yl ] ] propionic acid 2- (trimethylsilyl) ethyl ester (example 52A) in 3ml DMF was added 1.2ml of a 1.0M solution of tetrabutylammonium fluoride in THF (1.2mmol, 6.3 equivalents). After stirring it for 4h at RT, the reaction mixture was cooled to 0 ℃ and 50ml of water were added thereto. After addition of 50ml of ethyl acetate and 1ml of 1N aqueous hydrochloric acid, the phases are separated. The aqueous phase was extracted several times with ethyl acetate. After the organic phase has been dried over magnesium sulfate, it is concentrated in vacuo and dried under high vacuum. The crude product was reacted without further purification.

Examples 58A to 61A listed in the table below can be prepared analogously to example 57A.

Example 62A

2- (S) -benzyloxycarbonylamino-3-3 ' [ -2- [ 5-benzyloxy-carbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (hydroxy-oxy) pentanoyl-amino (3-amino- [1- (S) -benzyloxy-1-oxo-2-phenyl-ethyl ] -3-oxopropyl) ] -4, 4 ' -bis (benzyloxy) -1, 1 ' -biphenyl-3-yl ] ] penta-fluorophenyl propionate

0.25g (crude mixture, ca. 0.19mmol) of 2- (S) -benzyloxycarbonylamino-3- [3 ' [ -2- [ 5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (hydroxy-oxy) pentanoylamino (3-amino- [1- (S) -benzyloxy-1-oxo-2-phenyl-ethyl ] -3-oxopropyl) ] -4, 4 ' -bis (benzyloxy) -1, 1 ' -biphenyl-3-yl ] ] propionic acid (example 57A) was added to 4ml of DCM and to it were added 0.18g (0.97mmol, 5.0 equivalents) of pentafluorophenol and 0.02g (0.02mmol, 0.1 equivalents) of DMAP. The mixture was cooled to-25 ℃ and 0.048g (0.25mmol, 1.3 equiv.) of EDC was added. The mixture was slowly warmed to RT over night. The reaction mixture was concentrated in vacuo and briefly dried under high vacuum. The crude product was reacted without further purification.

Examples 63A to 66A listed in the table below can be prepared analogously to example 62A.

Example 67A

2- (S) -benzyloxycarbonylamino-3- [3 ' [ -2- [ 5-benzyloxycarbonyl-amino-2 (S) -amino-4 (R) - (hydroxy-oxy) pentanoylamino (3-amino- [1- (S) -benzyloxy-1-oxo-2-phenyl-ethyl ] -3-oxopropyl) ] -4, 4 ' -bis (benzyloxy) -1, 1 ' -biphenyl-3-yl ] ] penta-fluorophenyl propionate

0.28g (0.19mmol) of pentafluorophenyl 2- (S) -benzyloxycarbonylamino-3- [3 ' [ -2- [ 5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (hydroxy-oxy) pentanoylamino (3-amino- [1- (S) -benzyloxy-1-oxo-2-phenyl-ethyl ] -3-oxopropyl) ] -4, 4 ' -bis (benzyloxy) -1, 1 ' -biphenyl-3-yl ] ] propionate (example 62A) are dissolved at RT in 4ml of a 4M solution of hydrogen chloride in dioxane. After 3h at RT, the reaction solution is concentrated in vacuo at 30 ℃ and dried under high vacuum. The crude product was reacted without further purification

Examples 68A to 71A listed in the table below can be prepared analogously to example 67A.

Example 72A

N- { [ (8S, 11S, 14S) -5, 17-bis (benzyloxy) -14- { [ (benzyloxy) carbonyl]Amino } -11- ((2R) -3- { [ (benzyloxy) carbonyl]Amino } -2-hydroxypropyl) -10, 13-dioxo-9, 12-diazacyclo [14.3.1.1^2，6]henicosa-1(20), 2(21), 3, 5, 16, 18-hexen-8-yl]Carbonyl } -L-phenylalanine benzyl ester

0.26g (0.19mmol) of pentafluorophenyl 2- (S) -benzyloxycarbonylamino-3- [3 ' [ -2- [ 5-benzyloxycarbonylamino-2 (S) -amino-4 (R) - (hydroxyoxy) pentanoylamino- (3-amino- [1- (S) -benzyloxy-1-oxo-2-phenyl-ethyl ] -3-oxopropyl) ] -4, 4 ' -bis (benzyloxy) -1, 1 ' -biphenyl-3-yl ] ] propionate (example 67A) are dissolved in 200ml of chloroform and added dropwise at RT over the course of 4h to a solution of 2000ml of chloroform and saturated aqueous sodium bicarbonate solution. After complete addition it was stirred for 1 h. The phases are then separated. The aqueous phase was washed twice with 500ml of DCM. The combined organic phases are washed with 2000ml of 0.1M aqueous hydrochloric acid, dried over sodium sulfate and concentrated in vacuo. The residue was suspended in 15ml acetonitrile: methanol (2: 1) and stirred at RT for 1 h. Undissolved solid was filtered off and dried in vacuo. The solid was boiled in methanol for 15min for further purification. The product was obtained by re-filtration and drying in vacuo.

Yield: 0.022g (10% of theory).

LC-MS (method 15): r_t＝3.13min.

MS(EI)：m/z＝1158(M+H)⁺

Examples 73A to 76A listed in the table below can be prepared analogously to example 72A.

Example 77A

Benzyl 2(S) - [ S-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-pentanoyl-amino ] -3- {4, 4 '-dibenzyloxy-3' - [2(S) -benzyloxycarbonylamino-2- (2-trimethyl-silyl-ethoxy-carbonyl) ethyl ] biphenyl-3-yl } propanoate

Analogously to example 16A from 0.47g (0.51mmol) of the compound from example 15A and 0.19g (0.51mmol) of N_α-Boc-N_δ-Z-L-ornithine was prepared from 0.19g (0.51mmol) of HATU and 0.35ml (1.65mmol) of N, N-diisopropylethylamine in 5.55ml of anhydrous DMF.

Yield: 0.58g (92% of theory).

LC-MS (method 18): r_t＝3.46min

MS：m/z＝1212(M+H)⁺

Example 78A

2(S) -benzyloxycarbonylamino-3- {4, 4 '-dibenzyloxy-3' - [2(S) -benzyloxycarbonyl-2- (5-benzyloxycarbonylamino) -2(S) -tert-butoxycarbonylamino pentanoylamino ] ethyl } biphenyl-3-yl } propanoic acid

Prepared analogously to example 17A from 0.82g (0.68mmol) of the compound from example 77A with 2 equivalents (1.3ml) tetrabutylammonium fluoride (1M in THF) in 30ml anhydrous DMF.

Yield: 772mg (94% of theory).

LC-MS (method 20): r_t＝1.62min.

MS：m/z＝1112(M+H)⁺

Example 79A

Benzyl 2(S) - (5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylaminopentanoylamino) -3- [4, 4 '-dibenzyloxy-3' - (2(S) -benzyloxycarbonylamino-2-pentafluorophenoxycarbonylethyl) biphenyl-3-yl ] propionate

Prepared in analogy to example 18A (method A) from 422mg (0.38mmol) of the compound from example 78A and 349mg (1.9mmol) of pentafluorophenol with 80mg (0.42mmol) EDCI and 4.63mg (0.04mmol) DMAP in 4ml dichloromethane.

Yield: 502mg (95% of theory).

LC-MS (method 20): r_t＝3.13min.

MS：m/z＝1278(M+H)⁺

Example 80A

2(S) - (5-benzyloxycarbonylamino-2 (S) -amino-pentanoylamino) -3- [4, 4 '-dibenzyloxy-3' - (2- (S) -benzyloxycarbonylamino-2-pentafluorophenoxycarbonylethyl) biphenyl-3-yl ] -propionic acid benzyl ester-hydrochloride

To 215mg (0.17mmol) of the compound from example 79A, 5ml of a 4M dioxane/hydrogen chloride solution are added with stirring in an ice bath. The mixture was stirred for one hour and the whole was evaporated under vacuum to constant weight.

Yield: 200mg (92% of theory).

LC-MS (method 20): r_t＝4.25min.

MS：m/z＝1178(M+H)⁺

Example 81A

5, 17-dibenzyloxy-14 (S) -benzyloxycarbonyl-amino-11 (S) - (3-benzyloxycarbonylaminopropyl) -10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]-henicosa-1(19), 2, 4, 6(21), 16(20), 17-hexene-8 (S) -carboxylic acid benzyl ester

1.35g (0.91mmol) of the compound from example 80A are added to 31 ml of chloroform with vigorous stirring, to which 2.54ml (18.2mmol) of triethylamine in 50ml of chloroform are added at RT in the course of 20 min. The mixture was stirred overnight and evaporated to dryness under vacuum. The residue was stirred with 5ml acetonitrile, filtered and dried until the residue was constant weight.

Yield: 890mg (93% of theory).

LC-MS (method 20): r_t＝5.10min.

MS：m/z＝994 (M+H)⁺

Example 82A

(8S, 11S, 14S) -14-amino-11- (3-aminopropyl) -5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]-henicosa-1(20), 2(21), 3, 5, 6, 18-hexene-8-carboxylic acid dihydrochloride

50mg (0.05mmol) of the compound from example 81A are suspended in 50ml of glacial acetic acid/water/ethanol (4/1/1), mixed with 30mg of Pd/C (10% strength) catalyst and hydrogenated at RT for 20 hours. After removing the catalyst by filtration over celite, the filtrate was evaporated to dryness under vacuum, to which 2.5ml of 0.1N hydrochloric acid was added while stirring. The mixture was evaporated to dryness under vacuum and dried to constant weight.

Yield: 17mg (63% of theory).

TLC (methanol/dichloromethane/25% concentrated ammonia water 5/3/2): r_r＝0.6

LC-MS (method 9) R_t＝0.28min.

MS：m/z＝457(M+H)⁺

Example 83A

(8S, 11S, 14S) -14- [ (tert-butoxycarbonyl) amino-11- [3- [ (tert-butoxycarbonyl) amino group]Propyl } -5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]-henicosa-1(20), 2(21), 3, 5, 16, 18-hexene-8-carboxylic acid

225mg (0.42mmol) of the compound from example 82A are dissolved in 2.25ml of water and 2.25ml of 1N sodium hydroxide solution cooled on an ice bath and 278mg (1.27mmol) of di-tert-butyl dicarbonate are added thereto while stirring. After the addition, it is briefly heated to 30 ℃ and the reaction is then allowed to proceed overnight at RT the mixture is acidified to pH 5 with 0.1N hydrochloric acid and evaporated to dryness at RT under vacuum with caution. The residue was stirred with ether, filtered and dried to constant weight.

Yield: 259mg (93% of theory).

LC-MS (method 18): r_t＝1.96min.

MS：m/z＝656(M+H)⁺

Example 84A

2- (benzyloxy) -N- [ (benzyloxy) carbonyl ] -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -L-phenylalanine 2- (trimethylsilyl) ethyl ester

0.924g (3.64mmol, 1.15 equivalents) of 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -di-1, 3, 2-dioxaborolane, 0.932g (9.50mmol, 3 equivalents) of potassium acetate and 0.116g (0.160mmol, 0.05 equivalents) of bis (diphenylphosphino) ferrocenepalladium (II) chloride are added at RT to a degassed solution of 2.00g (3.17mmol) of 2(S) -benzyloxycarbonylamino-3- (2-benzyloxy-5-iodo-phenyl) -propionic acid- (2-trimethylsilyl) ethyl ester (example 11A) in 20ml of DMF. The mixture was stirred at 80 ℃ for 6 hours. This was taken up in water and ethyl acetate, the phases were separated and the aqueous phase was washed several times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel (cyclohexane/ethyl acetate 10: 1).

Yield: 1.12g (56% of theory).

LC-MS (method 22): r_t＝4.50min

MS(EI)：m/z＝632(M+H)⁺

¹H-NMR(200MHz，CDCl₃)：δ＝0.92(dd，2H)，1.31(s，12H)，2.95-3.95(m，2H)，4.11(mc，2H)，4.55(11(mc，1H)，4.99(s，2H)，5.08(s，2H)，5.53(d，1H)，6.90(d，1H)，7.15-7.47(m，10H)，7.58(d，1H)，7.67(dd，1H).

The example examples 85A to 87A listed in the table below can be prepared analogously to example 37A.

Examples 88A to 90A listed in the table below were prepared similarly to example 42A.

Examples 91A to 93A listed in the table below can be prepared analogously to example 47A.

Examples 94A to 96A listed in the table below can be prepared analogously to example 52A.

Examples 97A to 99A listed in the table below can be prepared analogously to example 57A.

The examples 100A to 102A listed in the table below were prepared similarly to example 62A.

Examples 103A to 105A listed in the table below can be prepared similarly to example 67A.

Examples 106A to 108A listed in the table below can be prepared similarly to example 72A.

Example 109A, detailed in the table below, can be prepared similarly to example 24A.

Example 110A

2- (benzyloxy) -N- (tert-butoxycarbonyl) -iodo-N-methyl-L-phenylalanine

500mg (1mmol) of the compound from example 6A are dissolved in 20ml of THF under an argon atmosphere, 90.5mg (3.02mmol) of sodium hydride and 0.51ml (1141.6 mg; 8.04mmol) of iodomethane (80% pure) are added to it, and the mixture is stirred at room temperature overnight. It is diluted with 25ml of ethyl acetate and 25ml of water and brought to pH 9 with 0.1N hydrochloric acid. The mixture was evaporated under vacuum to a small volume. 10ml of ethyl acetate and 10ml of water are added thereto, the mixture is shaken vigorously and the organic phase is separated off. Drying over sodium sulphate and concentration thereof in vacuo gives 140mg of product (19% of theory). The aqueous phase was acidified (pH ═ 3) and extracted three times with 20ml ethyl acetate. Concentration in vacuo and drying in vacuo gave 351mg of product (68% of theory).

LC-MS (method 17): r_t＝3.9min.

MS(EI)：m/z＝511(M+H)⁺

Example 111A

2- (benzyloxy) -N- (tert-butoxycarbonyl) -5-iodo-N-methyl-L-phenylalanine benzyl ester

Prepared analogously to example 7A from 350mg (0.68mmol) of the compound from example 110A, 8.29mg (0.07mmol) of DMAP, 148mg (1.37mmol) of benzyl alcohol and 157.46mg (0.82mmol) of EDC in 3ml of acetonitrile.

Yield: 382mg (93% of theory).

LC-MS (method 17): r_t＝4.8min.

MS(EI)：m/z＝601(M+H)⁺

Example 112A

2- (benzyloxy) -N- (tert-butoxycarbonyl) -N-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -L-phenylalanine benzyl ester

Similar to example 8A, 380mg (0.63mmol) of the compound from example 111A were placed in 4ml of DMF in a hot dry flask and 184.5mg (0.73mmol) of 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -di-1, 3, 2-dioxaborolane, 186mg (1.9mmol) of potassium acetate and 23.15mg (0.03mmol) of bis (diphenylphosphino) ferrocene-palladium (II) chloride were added thereto while stirring it at room temperature. The reaction was allowed to proceed at 80 ℃ for 4 h. The product is obtained after work-up and chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate 4/1).

Yield: 196mg

LC-MS (method 17): r_t＝4.9min.

MS(EI)：m/z＝601(M+H)⁺

Example 113A

2- (trimethylsilyl) ethyl 2(S) -benzyloxycarbonylamino-3- [4, 4 '-dibenzyloxy-3' - (2(S) -benzyloxy-carbonyl- (2-tert-butoxycarbonyl-2-methyl) aminoethyl) biphenyl-3-yl ] propionate

Prepared analogously to example 12A (method B) from 190mg (0.32mmol) of the compound from example 112A, 199.5mg (0.32mmol) of the compound from example 11A, 195.5mg (0.63mmol) of cesium carbonate and 23.15mg (0.03mmol) of bis (diphenylphosphino) ferrocenepalladium (II) chloride in 1.5ml of DMF under an argon atmosphere.

Yield: 212mg (66% of theory).

LC-MS (method 25): r_t＝4.86min.

MS(EI)：m/z＝978(M+H)⁺

Example 114A

2- (trimethylsilyl) ethyl 2(S) -benzyloxycarbonylamino-3- [4, 4 '-dibenzyloxy-3' - (2(S) -benzyloxy-carbonyl-2-methylaminoethyl-biphenyl-3-yl ] propionate hydrochloride

Prepared analogously to example 15A from 930mg (0.95mmol) of the compound from example 113A and 22.14ml of 4M dioxane/hydrogen chloride solution in 15ml dioxane.

Yield: 915mg (78% of theory).

LC-MS (method 25): r_t＝2.53min.

MS(EI)：m/z＝878(M+H)⁺

Example 115A

Benzyl 2(S) - { methyl- [ 5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) - (tert-butyldimethylsilyloxy) pentanoyl ] amino } -3- {4, 4 '-dibenzyloxy-3' - [2(S) -benzyloxycarbonylamino-2- (2-trimethylsilylethoxycarbonyl) ethyl ] -biphenyl-3-yl } propanoate

Prepared analogously to example 16A from 922mg (1.01mmol) of the compound from example 114A, 0.5g (1.01mmol) of the compound from example 14A, 421mg (1.11mmol) of HATU and 0.7ml (518 mg; 3.27mmol) of DIPEA in 4.2ml of DMF.

Yield: 703mg (51% of theory).

LC-MS (method 16): r_t＝3.17min.

MS(EI)：m/z＝1356(M+H)⁺

Example 116A

2(S) -benzyloxycarbonylamino-3- {4, 4 '-dibenzyloxy-3' - [2(S) -benzyloxy-carbonyl-2- { methyl- (5-benzyloxycarbonylamino-2 (S) -tert-butoxycarbonylamino-4 (R) -hydroxypentanoyl) amino } ethyl ] biphenyl-3-yl } propanoic acid

Preparation was carried out analogously to example 17A from 360mg (0.27mmol) of the compound from example 115A and 0.8ml (3 eq) of a 1M solution of tetrabutylammonium fluoride (THF) in 20ml of DMF.

Yield: 159mg (53% of theory).

LC-MS (method 23): r_t＝3.19min.

MS(EI)：m/z＝1142(M+H)⁺

Example 117A

Benzyl 2(S) - [ methyl- (5-benzyloxycarbonylamino) -2(S) -tert-butoxycarbonylamino-4 (R) -hydroxy-pentanoyl ] amino-3- [4, 4 '-dibenzyloxy-3' - (2(S) -benzyloxycarbonylamino-2-pentafluorophenoxycarbonylethyl) biphenyl-3-yl ] propionate

Prepared in analogy to example 18A (method A) from 330mg (0.29mmol) of the compound from example 116A, 265.6mg (1.44mmol) of pentafluorophenol, 3.53mg (0.03mmol) of DMAP and 60.87mg (0.32mmol) of EDC in10 ml of dichloromethane.

Yield: 271mg (69% of theory).

LC-MS (method 23): r_t＝338min.

MS(EI)：m/z＝1308(M+H)⁺

Example 118A

Benzyl 2(S) - [ methyl- (5-benzyloxycarbonylamino) -2(S) -amino-4 (R) -hydroxypentanoyl ] amino-3- [4, 4 '-dibenzyloxy-3' - (2(S) -benzyloxycarbonylamino-2-pentafluorophenoxycarbonylalkyl) biphenyl-3-yl ] propionate hydrochloride

130mg (0.1mmol) of the compound from example 117A are dissolved in 0.5ml of dioxane, to which 5ml of a 4M dioxane/hydrogen chloride solution (ice bath) are added cautiously. After 30 minutes, the reaction was allowed to continue at room temperature for an additional 2 h. The mixture was evaporated to dryness under vacuum and dried to constant weight under high vacuum.

Yield: 130mg (70% of theory).

LC-MS (method 15): r_t＝2.68min.

MS(EI)：m/z＝1208(M+H)⁺

Example 119A

(8S, 11S, 14S) -5, 17-bis (benzyloxy) -14- { [ (benzyloxy) carbonyl]Amino } -11- ((2R) -3- { { (benzyloxy) carbonyl]Amino } -2-hydroxypropyl-9-methyl-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]Henicosa-1(20), 2(21), 3, 5, 16, 18-hexene-8-carboxylic acid benzyl ester

130mg (0.1mmol) of the compound from example 118A are added to 220ml of anhydrous chloroform. While stirring it at room temperature, 23ml (20 equivalents) of triethylamine in 5ml of dichloromethane were added thereto over the course of 20 minutes. The mixture was stirred at room temperature overnight, and then the whole was evaporated to dryness in vacuo. The residue was extracted with acetonitrile. The residue was dried to yield 44mg of product. Further product (30mg) was obtained by purification of the mother liquor by RP-HPLC.

Yield: 74mg (69% of theory).

LC-MS (method 15): r_t＝3.13min.

MS(EI)：m/z＝1024(M+H)⁺

Example 120A

(8S, 11S, 14S) -14-amino-11- [ (2R) -3-amino-2-hydroxypropyl]-5, 17-dihydroxy-9-methyl-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1^2.6]hexanicosa-1 (20), 2(21), 3, 5, 16, 18-hexenecarboxylic acid ditrifluoroacetate

33mg (0.032mmol) of the compound from example 119A are treated judiciously with dilute trifluoroacetic acid. The resulting clear solution was then freeze dried.

Yield: 23mg (quantitative)

LC-MS (method 15): r_t＝0.92min.

MS(EI)：m/z＝486(M+H)⁺

Example 121A

(8S, 11S, 14S) -5, 17-bis (benzyloxy) -14- { { benzyloxycarbonyl]Amino } -11- (2R) -3- { [ benzyloxycarbonyl]Amino } -2-hydroxypropyl-9-methyl-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2.6]henicosa-1(20), 2(21), 3, 5, 16, 18-hexene-8-carboxylic acid

37mg (0.04mmol) of the compound from example 119A are dissolved in 2ml of THF, 0.14ml of 1N lithium hydroxide solution are added thereto, and the mixture is stirred at room temperature for 3 h. It is then acidified with 1N hydrochloric acid and evaporated to dryness under high vacuum.

Yield: 33mg (71% of theory).

LC-MS (method 23): r_t＝2.90min.

MS(EI)：m/z＝934(M+H)⁺

Example 122A

(8S, 11S, 14S) -5, 17-bis (benzyloxy) -14- { [ benzyloxycarbonyl]Amino } -11- (2R) -3- { [ benzyloxycarbonyl]Amino } -2-hydroxypropyl-9-methyl-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]henicosa-1(20), 2(21), 3, 5, 16, 18-hexene-8-carboxamide

30mg (0.03mmol) of the compound from example 121A are dissolved in 1ml of DMF, to which 0.01ml (3 equivalents) of triethylamine are then added. After the reaction solution was cooled on an ice bath, 8.76mg (2 equivalents) of isobutyl chloroformate was added thereto, and then, the reaction was allowed to proceed for 30 minutes. After stirring it for a further hour at room temperature, 0.64ml (10 equivalents) of a 0.5N dioxane/ammonia solution was added and the mixture was stirred overnight. After concentration in vacuo, the residue was purified by RP-HPLC.

Yield: 11mg (37% of theory).

LC-MS (method 23): r_t＝2.91min.

MS(EI)：m/z＝934(M+H)⁺

Examples 123A to 129A listed in the table below were prepared from the appropriate precursors in a similar manner to that described for examples 115A to 122A:

example 130A

2(S) -tert-Butoxycarbonylamino-5-nitro-4-oxopentanoic acid benzyl ester

A solution A of 10g (30.9mmol) 1-benzyl 2(S) -tert-butoxycarbonylaminosuccinate and 5.27g (32.5mmol)1, 1' -carbonyldiimidazole in100 ml tetrahydrofuran was stirred at RT for 5 h. 18.8g (30.9mmol) of nitromethane are added dropwise at 0 ℃ to a solution B of 3.2g (34.2mmol) of potassium tert-butoxide in100 ml of tetrahydrofuran. The solution B was allowed to warm to room temperature while being stirred, and then the solution a was added dropwise thereto at RT. The resulting mixture is stirred at RT for 16h and its pH is adjusted to 2 with 20% strength hydrochloric acid. The solvent was evaporated. The remaining crude product was taken up in ethyl acetate/water. After phase separation, the organic phase was extracted twice with water, dried over sodium sulfate and concentrated. 13g (99% of theory) of product are obtained.

MS(ESI)：m/z＝334(M+H)⁺

¹H-NMR(300MHz，d₆-DMSO)：δ＝1.37(s，9H)，2.91(m，1H)，3.13(m，1H)，4.44(m，1H)，5.12(s，2H)，5.81(m，2H)，7.2-7.5(m，5H).

Example 131A

2(S) -tert-Butoxycarbonylamino-4 (R) -hydroxy-5-nitropentanoic acid benzyl ester

A solution of 11.3g (30.8mmol) of benzyl 2(S) -tert-butoxycarbonylamino-5-nitro-4-oxopentanoate in 300ml of tetrahydrofuran was cooled to-78 deg.C, 30.8ml of a solution of 1M L-selectrd ® in tetrahydrofuran were added dropwise and the mixture was stirred at-78 deg.C for 1 h. After warming to RT, saturated ammonium chloride solution was added cautiously to the solution. The reaction solution was concentrated, and then the residue was diluted with water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. The crude product was re-purified with silica gel 60 (mobile phase: cyclohexane/ethyl acetate 10/1) and the collected fractions were concentrated and then stirred with cyclohexane/ethyl acetate 5/1. The remaining crystals are filtered off with suction and dried. 2.34g (21% of theory) of the desired diastereomer are obtained. Chromatography of the mother liquor with Lichrosper Diol 10. mu.M (mobile phase: ethanol/iso-hexane 5/95) gave in turn 0.8g (6.7%) of the product.

MS(ESI)：m/z＝369(M+H)⁺.

¹H-NMR(300MHz，d₆-DMSO)：δ＝1.38(s，9H)，1.77(m，1H)，1.97(m，1H)，4.10-4.44(m，3H)，4.67(m，1H)，5.12(m，2H)，5.49(d，1H)，7.25-7.45(m，5H).

Exemplary embodiments

The synthesis of exemplary embodiments may begin with a partially protected Biphenomycin derivative (such as, for example, 21A).

Example 1

(8S, 11S, 14S) -14-amino-11- [ (2R) -3-amino-2-hydroxypropyl]-5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1^2，6]Henicosa-1(20), 2(21), 3, 5, 16, 18-hexene-8-carboxamide dihydrochloride

The method A comprises the following steps:

to a solution of 2.15mg (3.2. mu. mol) of (2R) -3- [ (8S, 11S, 14S) -8- (aminocarbonyl) -14- [ (tert-butoxycarbonyl) amino group under argon gas]-5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1^2，6]henicosa-1(20), 2(21), 3, 5, 16, 18-hexen-11-yl]To a solution of tert-butyl-2-hydroxypropylcarbamate (example 22A) in anhydrous dioxane (analytical grade, 1.0ml) was added dropwise a solution of 4M hydrochloric acid gas in dioxane (1.0 ml). After about 30min, the conversion was completely complete. The reaction mixture was frozen and freeze-dried to remove the solvent. Purification by gel chromatography [ Sephadex LH-20; methanol/concentrated hydrochloric acid (1: 0.0001) incorporating sodium bisulfite]1.4mg (80% of theory) of product are obtained.

HPLC-UV-Vis (method 14): r_t＝3.09min.

λ_max(qualitative) 204nm(s), 269(m), 285(sh) (H)₂O/acetonitrile + 0.01% TFA [ 7: 3 ]]).

¹H-NMR(500MHz，CD₃OD)：δ＝1.79(ddd，1H，J ＝ 13.6，9.2，5.9Hz)，1.99(ddd，1H，J＝13.6，9.6，4.0Hz)，2.82(dd，1H，J＝12.8，9.6Hz)，2.87(dd 1H，J＝17.1，12.1Hz)，3.04(dd，1H，J＝12.8，2.9Hz)，3.11(dd，1H，J＝14.8，3.0Hz)，3.38(dd，1H，J＝16.9，1.9Hz)，3.57(dd，1H，J＝11.7，5.4Hz)，3.92(tt，1H，J＝9.4，3.5Hz)，4.23(dd，1H，J＝4.9，3.0Hz)，4.90(m，1H)，4.91(m，1H)，6.79(d，1H，J＝8.3Hz)，6.85(d，1H，J＝8.4Hz)，7.10(d，1H，J＝2.3Hz)，7.25(dd，1H，J＝8.3，2.3Hz)，7.36(dd，1H，J＝8.5，2.4Hz)，7.44(d，1H，J＝2.1Hz).

¹³C NMR(125.5MHz，CD₃OD)：δ＝30.3，30.8，39.5，45.4，50.6，53.8，55.3，65.3，115.6，116.3，120.8，125.3，126.2，126.8，127.0，130.9，132.7，133.5，155.0，155.7，168.4，172.8，177.0.

LC-HR-FT-ICR-MS (method 13): calculated value C₂₃H₃₀N₅O₆[M+H]⁺472.2191

Found 472.2191.

The method B comprises the following steps:

14.8mg (0.02mmol) of (2R) -3- [ (8S, 11S, 14S) -8- (aminocarbonyl) -14- [ (tert-butoxycarbonyl) amino group were added under argon gas]-5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1^2，6]henicosa-1(20), 2(21), 3, 5, 16, 18-hexen-11-yl]Tert-butyl-2-hydroxypropylcarbamate (example 22A) is added to 0.5ml of dioxane. The mixture is cooled to 0 ℃ and 0.8ml of a 4M dioxane solution of hydrochloric acid is added dropwise thereto. After 45min, the mixture was concentrated in vacuo, and the residue was then reabsorbed in dioxane and concentrated twice in vacuo.The product was dried under high vacuum.

Yield: 12mg (100% of theory).

HPLC (method 8): r_t＝4.87min.

MS(EI)：m/z＝472(M+H-2HCI)⁺.

¹H-NMR(400MHz，D₂O)：δ＝0.58-0.67(m，2H)，1.65-1.86(m，3H)，1.88-1.98(m，1H)，2.03-2.13(m，1H)，2.87-3.02(m，4H)，3.09-3.19(m，2H)，3.38(d，1H)，3.59-3.69(m，2H)，3.88-3.96(m，1H)，4.46-4.51(m，1H)，4.85-5.01(m，5H)，6.98(dd，2H)，7.05(dd，1H)，7.36(s，1H)，7.43(dd，1H)，7.50(dd，1H).

Example 2

(8S, 11S, 14S) -14-amino-11- [ (2R) -3-amino-2-hydroxypropyl]-N-benzyl-5, 17-di-hydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]Henicosa-1(20), 2(21), 3, 5, 16, 18-hexene-8-carboxamide dihydrochloride

To the (2R) -3- [ (8S, 11S, 14S) -8- [ (benzylamino) carbonyl group while cooling on an ice bath]-14- [ (tert-butoxycarbonyl) amino group]-5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo- [14.3.1.1^2，6]henicosa-1(20), 2(21), 3, 5, 16, 18-hexen-11-yl]To a solution of tert-butyl-2-hydroxypropylcarbamate (example 23A) in 0.5ml of 1, 4-dioxane was added dropwise a solution of 0.5ml of 4N hydrochloric acid in dioxane. The ice chill was removed and the mixture was stirred at RT for 2h, then concentrated in vacuo and dried under high vacuum. The residue was taken up in a mixture of dichloromethane and methanol and the solvent was evaporated off overnight.

LC-MS (method 7): r_t＝2.02min.

MS(ESI-pos)：m/z＝562(M+H-2HCl)⁺.

¹H-NMR(400MHz，D₂O)：δ＝1.70-1.81(m，1H)，1.82-1.91(m，1H)，2.71-2.84(m，2H)，2.89-2.97(m，2H)，3.18(d，1H)，3.42-3.53(m，1H)，3.67-3.73(m，1H)，4.21-4.26(m，1H)，4.29(d，1H)，4.27-4.33(m，1H)，4.34(d，1H)，6.80-6.83(m，2H)，6.89(s，1H)，7.19-7.24(m，4H)，7.26-7.31(m，3H)，7.35(d，1H).

Examples 3 to 14 listed in the table below can be prepared similarly to example 1.

Example 15

N- { [ (8S, 11S, 14S) -14-amino-11- [ (2R) -3-amino-2-hydroxypropyl]-5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1^2，6]henicosa-1(20), 2(21), 3, 5, 16, 18-hexen-8-yl]Carbonyl } -L-phenylalanine dihydrochloride

0.02g (0.02mmol) of N- { [ (8S, 11S, 14S) -5, 17-bis (benzyloxy) -14- { [ (benzyloxy) -carbonyl]Amino } -11- ((2R) -3- { [ (benzyloxy) carbonyl]Amino } -2-hydroxypropyl) -10, 13-dioxo-9, 12-diazacyclo [14.3.1.1^2，6]henicosa-1(20), 2(21), 3, 5, 16, 18-hexen-8-yl]Carbonyl } -L-phenylalanine benzyl ester was suspended in 6ml of acetic acid, water, ethanol (4: 1), and 0.01g of Pd/C was then added thereto. It was hydrogenated under vigorous stirring at atmospheric pressure for 48 h. The reaction solution was filtered. The residue was mixed together with 0.25ml of 0.1N hydrochloric acid. Concentrated on a rotary evaporator and then dried in vacuo. Further purification was carried out by stirring it in isopropanol to diethyl ether (1: 1).

Yield: 0.0037g (28% of theory).

LC-MS (method 15): r_t＝1.27min.

MS(EI)：m/z＝620(M+H)⁺

Examples 16 and 17 listed in the table below can be prepared similarly to example 15.

The amides containing L-ornithine, listed in the following table (examples 18 to 24), can be prepared from (8S, 11S, 14S) -14- [ (tert-butoxycarbonyl) amino-11- [3- [ (tert-butoxycarbonyl) amino [)]Propyl) -5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1^2，6]-henicosa-1(20), 2(21), 3, 5, 16, 18-hexene-8-carboxylic acid (example 83A).

Examples 25 and 26 listed in the table below can be prepared similarly to example 15.

From (8S, 11S, 14S) -14- [ (tert-butoxycarbonyl) -amino-11- [3- [ (tert-butoxy-carbonyl) amino]Propyl } -5, 17-dihydroxy-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1 ]^2，6]-henicosa-1(20), 2(21), 3, 5, 16, 18-hexene-8-carboxylic acid (example 83A) to prepare the amides comprising L-ornithine (examples 27 to 33) listed in the table below.

Example 34

(8S, 11S, 14S) -14-amino-11- [ (2R) -3-amino-2-hydroxypropyl]-5, 17-dihydroxy-9-methyl-10, 13-dioxo-9, 12-diazacyclo [14.3.1.1^2，6]Henicosa-1(20), 2(21), 3, 15, 16, 18-hexenecarboxamide dihydrochloride

11mg (0.01mmol) of the compound from example 122A are dissolved in10 ml of glacial acetic acid/ethanol/water (4/1/1), 6mg of Pd-C (10% strength) catalyst are added and the mixture is hydrogenated at room temperature overnight. After removal of the catalyst by filtration, the residue was evaporated to dryness under vacuum, 0.1N hydrochloric acid was added thereto, and then the mixture was evaporated to dryness again.

Yield: 7mg (96% of theory).

MS(EI)：m/z＝485(M+H)⁺

In a manner analogous to that of example 34, example 35, listed in the table below, can be prepared:

examples 36 and 37 listed in the table below can be prepared similarly to example 1.

Examples 38 to 40 listed in the table below can be prepared similarly to example 15.

A. Evaluation of physiological Activity

The in vitro effect of the compounds of the invention is shown in the following tests:

in vitro transcription-translation with E.coli extracts

S30 extracts were prepared by collecting E.coli MRE600 (M.M muller; university Freiburg), washing and using them as described in the in vitro transcription-translation assay (Muller, M.and Blbel, G.Proc Natl Acad Sci USA (1984)81, p. 7421-7425).

An additional 1. mu.l cAMP (11.25mg/ml) was added per 50. mu.l reaction mixture to obtain a reaction mixture for in vitro transcription-translation assay. The amount of the test mixture was 105. mu.l, which had 5. mu.l of the substance to be tested introduced into DMSO at a concentration of 5%. Using 1. mu.g/100. mu.l of plasmid pBESTLuc (Promega, Germany) as transcription template. After incubating it at 30 ℃ for 60 minutes, 50. mu.l of a fluorescein solution (20mM tricine, 2.67mM MgSO 2. sup. MgSO) was added thereto₄0, 1mM EDTA, 33.3mM DTT pH7.8, 270. mu.M CoA, 470. mu.M fluorescein, 530. mu.M ATP), and then the resultant bioluminescence was measured photometrically for 1 minute. IC (integrated circuit)₅₀Shown is the concentration of inhibitor that results in 50% inhibition of firefly luciferase translation.

In vitro transcription-translation with Staphylococcus aureus extracts

Structure of staphylococcus aureus luciferase reporter plasmid

A reporter plasmid that can be used in the in vitro transcription-translation assay for Staphylococcus aureus can be constructed using the plasmid pBESTluc (Promega Corporation, USA). The e.coli tac promoter was present in this plasmid before the firefly luciferase was replaced by the capA1 promoter with the appropriate Shine-Dalgarno sequence from staphylococcus aureus. With initiators

CAPFor5′-CGGCC-

AAGCTTACTCGGATCCAGAGTTTGCAAAATATACAGGGGATTATATATAA

TGGAAAACAAGAAAGGAAAATAGGAGGTTTATATGGAAGACGCCA-3′und

CAPRev 5′-GTCATCGTCGGGAAGACCTG-3′

For this purpose. The initiator CAPFor comprises the capA1 promoter, a ribosome binding site, and the 5' region of the luciferase gene. After PCR using pBESTluc as a template, it was possible to isolate a PCR product comprising the firefly luciferase gene with the fused capA1 promoter. That is, after restriction with ClaI and HindIII, it was ligated to the vector pBESTluc which had also been digested with ClaI and HindIII. The resulting plasmid pla can be replicated in E.coli and can be used as a template in an in vitro transcription-translation assay for Staphylococcus aureus.

Preparation of S30 extract from Staphylococcus aureus

Six liters of BHI medium were added to 250ml of overnight cultured Staphylococcus aureus strains and allowed to grow at 37 ℃ until OD600nm was 2-4. Cells were harvested by centrifugation and washed with 500ml ice-cold buffer A (10mM Tris-acetate, pH8.0, 14mM Mg acetate, 1mM DTT, 1M KCl). After re-centrifugation, the cells were washed with 250ml ice-cold buffer A with 50mM KCl and the resulting pellet was frozen at-20 ℃ for 60 min. The pellet was dissolved on ice for 30 to 60min and taken up with buffer B (10mM Tris-acetate, pH8.0, 20mM Mg acetate, 1mM DTT, 50mM KCl) to a total volume of 99 ml. 1.5ml portions of lysostaphin (0.8mg/ml) in buffer B were added to 3 pre-cooled centrifuge cups and each mixed with 33ml of cell suspension. The sample was incubated at 37 ℃ for 45 to 60min with occasional shaking, and then 150. mu.l of 0.5M DTT solution was added thereto. The lysed cells were centrifuged at 30000 Xg and 4 ℃ for 30 min. The cell pellet was taken up with buffer B and re-centrifuged under the same conditions, and the collected supernatants were combined. The supernatant was centrifuged again under the same conditions, 0.25 volume of buffer C (670mM Tris acetate, pH8.0, 20mM Mg acetate, 7mM Na3 phosphoenolpyruvate, 7mM DTT, 5.5mM ATP, 70. mu.M amino acid (fully available from Promega), 75. mu.g pyruvate kinase (Sigma, Germany)/ml) was added to the upper 2/3 of the supernatant, the sample was incubated at 37 ℃ for 30min, the supernatant was dialyzed overnight at 4 ℃ with 21 dialysis buffer (10mM Tris acetate, pH8.0, 14mM Mg acetate, 1mM DTT, 60mM K acetate) in a dialysis tube with a buffer change, the dialysate was concentrated to a protein concentration of about 10Mg/ml by covering the dialysis tube with cold PEG 8000 powder (Sigma, Germany) at 4 ℃, the S30 extract was stored as aliquots at-70 ℃.

IC in Staphylococcus aureus in vitro transcription-translation assay₅₀Measurement of (2)

Inhibition of protein biosynthesis by the compounds can be demonstrated using in vitro transcription-translation assays. The assay is based on cell-free transcription and translation of firefly luciferase using reporter plasmid pla as a template and cell-free S30 extract from staphylococcus aureus. The activity of the resulting luciferase can be detected by fluorescence measurement.

The amount of S30 extract or plasmid pla used for each preparation had to be re-determined to ensure the optimal concentration in the assay. Mu.l of the test substance dissolved in 5% DMSO was added to the MTP. Then 10. mu.l of a suitable concentrated plasmid solution pla are added thereto. Then, 23. mu.l of the premix (500mM K acetate, 87.5mM Tris-acetate, pH8.0, 67.5mM ammonium acetate, 5mM DTT, 50. mu.g folic acid/ml, 87.5mg PEG 8000/ml, 5mM ATP, 1.25mM each NTP, 20. mu.M each amino acid, 50mM PEEP (Na) was mixed into 46. mu.l of the mixture₃Salt), 2.5mM cAMP, 250. mu.g of each E.coli tRNA/ml) and 23. mu.l of an appropriate amount of the S30 extract of Staphylococcus aureus, and mixing them. After incubating it at 30 ℃ for 60min, 50. mu.l of fluorescein solution (20mM tricine, 2.67mM MgSO 2. sup. MgSO) was added thereto₄0.1mM EDTA, 33.3mM DTT pH7.8, 270. mu.M CoA, 470. mu.M fluorescein, 530. mu.M ATP) and measuring the resulting bioluminescence in a luminometer for 1 min. IC50 represents the concentration of inhibitor that results in 50% inhibition of firefly luciferase translation.

Determination of Minimum Inhibitory Concentration (MIC):

the Minimum Inhibitory Concentration (MIC) is the minimum concentration of antibiotic that can inhibit the growth of the test microorganism within 18-24 h. Inhibitor concentrations in these cases can be measured by standard microbiological methods (see, for example, The national Committee for Clinical Laboratory Standards, methods for testing The sensitivity of dilute antimicrobial agents for bacteria that grow aerobically; approved Standards, fifth edition, NCCLS document M7-A5[ ISBN 1-56238-]. NCCLS, 940 West Valley Road, Suite1400, Wayne, Pa.19087-. Book (I)The MIC of the inventive compounds was measured in a liquid dilution assay on a 96-well microtiter plate scale. The bacterial microorganisms were grown in minimal medium (18.5mM Na) supplemented with 0.4% BH broth (test medium)₂HPO₄，5.7mM KH₂PO₄，9.3mM NH₄Cl，2.8 mM MgSO₄17.1mM NaCl, 0.033. mu.g/ml thiamine hydrochloride, 1.2. mu.g/ml nicotinic acid, 0.003. mu.g/ml biotin, 1% glucose, 25. mu.g/ml amino acids of each protein gene (excluding phenylalanine); kroll, p.h; not yet published]) Culturing in medium. In the case of enterococcus faecalis ICB27159, heat-inactivated fetal calf serum (FCS; GibcoBRL, Germany) is added to the test medium at a final concentration of 10%. The overnight culture of the test microorganism was diluted to an OD of 0.001 (to 0.01 in the case of enterococcus) with fresh test medium₅₇₈And incubated 1: 1 with a dilution of the test substance (1: 2 dilution gradient) in the test medium (150. mu.l final volume). Culturing the culture at 37 deg.C for 18-24 hr; enterococcus in 5% CO₂The culture was performed under the condition of (1).

The lowest substance concentration at which bacterial growth was no longer visible in each case was defined as the MIC. The MIC values (in μ M) for a series of test microorganisms for some compounds of the invention are listed in the following table by way of example. These compounds exhibit a stepped antibacterial effect on most of the tested microorganisms.

TABLE A

Example number	MIC Staphylococcus aureus 133	MIC Staphylococcus aureus RN4220	MIC Staphylococcus aureus 25701	MIC enterococcus faecalis ICB27159	MIC Branhamella catarrhalis M3	IC₅₀E.coli MRE600 translation	IC₅₀Staphylococcus aureus 133 translation	IC₅₀Staphylococcus aureus RN4220 translation
Example number	MIC Staphylococcus aureus 133	MIC Staphylococcus aureus RN4220	MIC Staphylococcus aureus 25701	MIC enterococcus faecalis ICB27159	MIC Branhamella catarrhalis M3	IC₅₀E.coli MRE600 translation	IC₅₀Staphylococcus aureus 133 translation	IC₅₀Staphylococcus aureus RN4220 translation	1	0.2	0.1	6.25	6.25	1.56	0.15	0.9	0.5
2	25	12.5	50	25	25	0.55	1.3-4.5	3.4	1	0.2	0.1	6.25	6.25	1.56	0.15	0.9	0.5
2	25	12.5	50	25	25	0.55	1.3-4.5	3.4	37	0.8	----	----	----	----	----	0.5	----

All concentration data are in μ M.

Systemic infection with staphylococcus aureus 133

Various animal models can be used to demonstrate the suitability of the compounds of the invention for the treatment of bacterial infections. For this purpose, the animals are generally infected with the appropriate virulent microorganism and then treated with the test compounds of the invention, which are used in the form of preparations suitable for the particular treatment model. The properties of the compounds of the invention which can be demonstrated in particular for the treatment of bacterial infections in a murine sepsis model following infection with Staphylococcus aureus.

For this purpose, Staphylococcus aureus 133 was cultured overnight in BH broth (Oxoid, Germany). The overnight culture was diluted 1: 100 with fresh BH broth and allowed to expand for 3 hours. The bacteria in the logarithmic growth phase were centrifuged and washed twice with a physiological saline buffer solution. The cell suspension with 50 units extinction coefficient in physiological saline solution was then conditioned in a luminometer (dr. lange LP 2W). After the dilution step (1: 15), this suspension was mixed with a 10% strength suspension of mucine in a ratio of 1: 1. The infection solution was i.p. administered to mice in an amount of 0.2ml per 20 g. This corresponds to a cell count of approximately 1-2X 10E 6 microorganisms/mouse. This i.v. treatment was performed 30 minutes after infection. The infection test was performed with female CFW1 mice. The survival of the animals was recorded over a period of 6 days. The animal model is adjusted so that animals that are not treated die within 24h after infection. This model can be used to demonstrate the therapeutic effect of the compound of example 2 (ED100 ═ 1.25 mg/kg).

B. Exemplary embodiments of pharmaceutical compositions

The compounds of the invention can be converted into pharmaceutical preparations by the following method:

and (3) tablet preparation:

consists of the following components:

100mg of the compound according to example 1, 50mg of lactose (monohydrate), 50mg of maize starch (native), 10mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2mg of magnesium stearate.

The tablet weight was 212mg, diameter 8mm, and maze 12 mm.

Preparation:

the mixture of active ingredient, lactose and starch was granulated with a 5% strength solution of PVP in water (m/m). The granules were dried and then mixed with magnesium stearate for 5 min. The mixture is compressed using a conventional tablet press (see above for tablet size). Compression was guided with a pressure of 15 kN.

Suspension that can be administered orally:

consists of the following components:

1000mg of the compound of example 1, 1000mg of ethanol (96%), 400mg of Rhodigel (xanthan gum from Fa. MC, Pa., USA) and 99g of water.

10ml of oral suspension corresponds to a single dose of 100mg of the compound of the invention.

Preparation:

the Rhodigel is suspended in ethanol and the active ingredient is then added to the suspension. Water was added thereto with stirring. The mixture was stirred for about 6h until the Rhodigel had fully swelled.

Claims

1. A compound of formula I or a salt thereof, a solvate thereof or a solvate of a salt thereof,

wherein

R¹Is hydrogen, alkyl, aryl, heteroaryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,An alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl or carbonyl-linked amino acid residue,

R²is a hydrogen or an alkyl group,

R³is hydrogen, alkyl or a pendant amino acid group, wherein the alkyl group may be substituted with 0, 1, 2 or 3 substituents R^3-1Substituted, wherein the substituent R^3-1Independently of one another, from trifluoromethyl, nitro, amino, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, guanidino and amidino,

R³' is hydrogen, C₁-C₆-alkyl or C₃-C₈-a cycloalkyl group,

R⁴is hydrogen, C₁-C₆-alkyl or C₃-C₈-a cycloalkyl group,

R⁶is hydrogen, alkyl or cycloalkyl,

or

R⁵And R⁶Together with the nitrogen atom to which they are attached form a substituent R which may be substituted by 0, 1, 2 or 3^5-6Substituted heterocycles in which the substituent R is^5-6Independently of one another, from the group consisting of halogen, alkyl, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, cycloalkyl, aryl, halogenated aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, carboxy, alkylcarbonyl, alkoxycarbonyl, optionally substituted alkoxycarbonyl,Alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl,

R⁷is hydrogen, C₁-C₆Alkyl, alkylcarbonyl or C₃-C₈-a cycloalkyl group,

R⁸is hydrogen or C₁-C₆-alkyl, and

R⁹is hydrogen or C₁-C₆-an alkyl group.

2. The compound according to claim 1, characterized in that it corresponds to a compound of formula (I'),

wherein R is¹To R⁹Has the same meaning as in formula (I).

3. The compound of claim 1 or 2,

R¹is hydrogen, alkyl or alkylcarbonyl,

R²is a hydrogen atom, and is,

R³is an alkyl group or a pendant amino acid group, wherein the alkyl group may be substituted with 0, 1, 2 or 3 substituents R^3-1Substituted, wherein the substituent R^3-1Independently of one another, from trifluoromethyl, nitro, amino, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, guanidino and amidino,

and wherein the free amino groups in the amino acid side groups may be substituted with alkyl groups,

R³' is hydrogen, C₁-C₆-alkyl or C₃-C₈-a cycloalkyl group,

R⁴is hydrogen, C₁-C₆-alkyl or C₃-C₈-a cycloalkyl group,

wherein the alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclyl radicals may be substituted by 0, 1, 2 or 3 substituents R^5-1Substituted, wherein the substituent R^5-1Independently of one another, from the group consisting of halogen, alkyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, alkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl,

R⁶is hydrogen, alkyl or cycloalkyl,

or

R⁷is hydrogen, C₁-C₆Alkyl, alkylcarbonyl or C₃-C₈-a cycloalkyl group,

R⁸is a hydrogen atom, and is,

and

R⁹is hydrogen.

4. The compound of claim 1 or 2,

R¹is a hydrogen atom, and is,

R²is a hydrogen atom, and is,

R³is aminocarbonylmethyl, 3-aminopropan-1-yl, 2-hydroxy-3-aminopropan-1-yl, 1-hydroxy-3-aminopropan-1-yl, 3-guanidinopropane-1-yl, 2-aminocarbonylethyl, 2-hydroxycarbonylethyl, 4-aminobutan-1-yl, hydroxymethyl, 2-hydroxyethyl, 2-aminoethyl, 4-amino-3-hydroxy-butan-1-yl or (1-piperidin-3-yl) -methyl,

R³' is a hydrogen atom, and the compound is,

R⁴is hydrogen, methyl, ethyl, i-propyl or cyclopropyl,

R⁵is hydrogen, C₁-C₆-alkyl or C₃-C₈-a cycloalkyl group,

wherein the alkyl and cycloalkyl radicals may be substituted by 0, 1, 2 or 3 substituents R^5-1Substituted, wherein the substituent R^5-1Independently of one another, from halogen, C₁-C₆-alkyl, trifluoromethyl, trifluoromethoxy, amino, C₁-C₆-alkylamino radical, C₁-C₆-dialkylamino radical, C₃-C₈-cycloalkyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, 5-to 7-membered heterocyclyl, hydroxy, alkoxy, carboxy, C₁-C₆Alkoxycarbonyl, aminocarbonyl, C₁-C₆-alkylaminocarbonyl and C₁-C₆-a dialkylaminocarbonyl group,

R⁶is hydrogen or a methyl group, or a mixture thereof,

or

R⁷is a hydrogen atom, and is,

R⁸is a hydrogen atom, and is,

and

R⁹is hydrogen.

5. The compound of claim 1 or 2,

R¹is a hydrogen atom, and is,

R²is a hydrogen atom, and is,

R³is 3-aminopropyl-1-yl or 2-hydroxy-3-aminopropyl-1-yl,

R³' is a hydrogen atom, and the compound is,

R⁴is hydrogen or a methyl group, or a mixture thereof,

R⁵is hydrogen, C₁-C₆-an alkyl group or a cyclopropyl group,

R⁶is hydrogen or a methyl group, or a mixture thereof,

R⁷is a hydrogen atom, and is,

R⁸is a hydrogen atom, and is,

and

R⁹is hydrogen.

6. A compound according to claim 1 or 2, wherein R is¹Is hydrogen.

7. A compound according to claim 1 or 2, wherein R is²Is hydrogen.

8. A compound according to claim 1 or 2, wherein R is³Is 3-aminopropyl-1-yl or 2-hydroxy-3-amino-propan-1-yl.

9. A compound according to claim 1 or 2, wherein R is³' is hydrogen.

10. A compound according to claim 1 or 2, wherein R is⁴Is hydrogen or methyl.

11. The compound of claim 1 or 2,

R⁵is hydrogen, C₁-C₆-an alkyl group or a cyclopropyl group,

wherein the alkyl group may be substituted by 0, 1, 2 or 3 substituents^5-1Substituted, wherein the substituent R^5-1Independently of one another, from trifluoromethyl, amino, hydroxyl, carboxyl, aminocarbonyl and phenyl.

12. A compound according to claim 1 or 2, wherein R is⁶Is hydrogen or methyl.

13. A compound according to claim 1 or 2, wherein R is⁵And R⁶Together with the nitrogen atom to which they are attached form a piperidinyl or morpholinyl group.

14. A compound according to claim 1 or 2, wherein R is⁷Is hydrogen.

15. A compound according to claim 1 or 2, wherein R is⁸Is hydrogen.

16. A compound according to claim 1 or 2, wherein R is⁹Is hydrogen.

17. A process for the preparation of a compound of formula (I) as claimed in claim 1, characterized in that a compound of formula (II) is reacted with a compound of formula (III)

Wherein R is¹To R⁴And R⁷To R⁹Has the meaning as set forth in claim 1,

H-NR⁵R⁶ (III)

wherein R is⁵And R⁶Have the meaning as claimed in claim 1.

18. A compound according to any one of claims 1 to 16 for use in the treatment and/or prevention of a disease.

19. A medicament comprising at least one compound according to any one of claims 1 to 16 in combination with at least one pharmaceutically acceptable carrier or other excipient suitable for pharmaceutical use.

20. The use of a compound according to any one of claims 1 to 16 for the preparation of a medicament for the treatment and/or prophylaxis of bacterial diseases.

21. A medicament as claimed in claim 19 for the treatment and/or prevention of bacterial infections.