EP2379539A1

EP2379539A1 - Amino acid ester prodrugs and the use thereof

Info

Publication number: EP2379539A1
Application number: EP09760499A
Authority: EP
Inventors: Daniel Meibom; Hans-Georg Lerchen; Alexandros Vakalopoulos; Barbara ALBRECHT-KÜPPER; Peter Nell; Jörg Keldenich; Katja Zimmermann; Ursula Krenz
Original assignee: Bayer Pharma AG
Current assignee: Bayer Pharma AG
Priority date: 2008-12-16
Filing date: 2009-12-03
Publication date: 2011-10-26
Also published as: WO2010072315A1; JP2012512203A; CA2746727A1; DE102008062566A1; US20110237629A1

Abstract

The invention relates to amino acid ester prodrug derivatives of 2-amino-6-({[2-(4-chlorphenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)4-(4-{[2,3-dihydroxypropyl]oxy}phenyl)pyridine- 3,5-dicarbonitriles of formula (I), where R^A is hydrogen or methyl, and R^PD is a group of the formulas (II) or (III), wherein # is the linking site having each O atom, to a method for the production thereof, to the use thereof for treating and/or preventing illnesses, and to the use thereof for producing pharmaceuticals for treating and/or preventing illnesses, particularly of cardiovascular diseases.

Description

Amino acid ester prodrugs and their use

The present application relates to amino acid ester prodrug derivatives of 2-amino-6 - ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -4- (4 - {[2 , 3-dihydroxypropyl] oxy} phenyl) pyridine-3,5-dicarbonitriles, process for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular of cardiovascular diseases.

Prodrugs are derivatives of an active substance which undergo a single or multistage biotransformation of enzymatic and / or chemical nature in vivo before the actual active substance is released. A prodrug residue is usually used to improve the property profile of the underlying drug [P. Ettmayer et al., J. Med. Chem. 47, 2393-2404 (2004)]. In order to achieve an optimal Wirkprofϊl, the design of the prodrug remainder as well as the desired release mechanism must be tailored very closely to the individual drug, the indication, the site of action and the route of administration. A large number of drugs are administered as prodrugs which have improved bioavailability over the underlying drug, for example, by improving physicochemical profile, especially solubility, active or passive absorption properties or tissue-specific distribution. Examples of the extensive literature on prodrugs are: H. Bundgaard (Ed.), Design of Prodrugs: Bioreversible Derivatives for Various Functional Groups and Chemical Entities, Elsevier Science Publishers B.V., 1985.

Adenosine, a purine nucleoside, is present in all cells and is released from a variety of physiological and pathophysiological stimuli. Adenosine is produced intracellularly in the degradation of adenosine 5'-monophosphate (AMP) and S-adenosyl homocysteine as an intermediate, but can be released from the cell and then exerts effects as a hormone-like substance or neurotransmitter by binding to specific receptors. So far, the receptor subtypes Al, A2a, A2b and A3 are known [cf. K.A. Jacobson and Z.-G. Gao, NaL Rev. Drug Discover. 5, 247-264 (2006)].

Activation of Al receptors by specific Al agonists results in a frequency-dependent reduction in heart rate in humans without affecting blood pressure. Selective al agonists could thus be suitable, inter alia, for the treatment of angina pectoris and atrial fibrillation.

The activation of A2b receptors by adenosine or specific A2b agonists leads to a blood pressure reduction via the dilation of vessels. The blood pressure reduction is from one accompanied by reflex heart rate increase. Heart rate increase can be reduced by activation of Al receptors by specific Al agonists.

The combined effect of selective Al / A2b agonists on the vascular system and heart rate thus results in a systemic lowering of blood pressure with no relevant increase in heart rate. With such a pharmacological profile, dual Al / A2b agonists for the treatment of e.g. of hypertension in humans.

2-Amino-6- ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -4- (4- {[2,3-dihydroxypropyl] oxy} phenyl) pyridine-3,5-dicarbonitriles of the formula (A)

in which

R ^{A is} hydrogen or methyl,

represent potent and selective adenosine A1 receptor agonists with a certain dual, A2b agonistic active component (see PCT application WO 2009/015776-A1). The compounds are currently undergoing in-depth investigation as potential new drug agents for the prevention and therapy, in particular, of cardiovascular diseases. Of particular importance here is the compound of the formula (A) in which R ^{A is} hydrogen and the C * carbon atom of the propan-l, 2-diol group has an R-configuration.

However, the compounds of the formula (A) have only a limited solubility in water, physiological media and organic solvents and only a low bioavailability after oral administration of a suspension of crystalline material. On the one hand, this allows intravenous administration of the active ingredient only at very low dosages; Infusion solutions based on physiological saline solutions are difficult to prepare using common solubilizers. On the other hand, formulation in tablet form is difficult. The object of the present invention was therefore to identify derivatives or prodrugs of compounds of the formula (A) which have improved solubility in the abovementioned media and / or improved bioavailability after oral administration and, at the same time, a controlled release of the relevant active substance in the body after administration allow the patient. Improved intravenous applicability could also open up further therapeutic applications for this class of drugs.

A review of prodrug derivatives based on carboxylic acid esters and possible properties of such compounds is described, for example, in K. Beaumont et al., Curr. Drug Metab. 4, 461-485 (2003).

The present invention relates to compounds of the general formula (I)

in which

R ^{A is} hydrogen or methyl

and

R is a group of the formula

stands in which

the point of attachment to the respective O atom means

L ^{1 is} a bond or -CH ₂ -, L ^{2 is} straight-chain (C ₃ -C ₆ ) -alkanediyl which may be monosubstituted, identically or differently, by (C ₁ -C ₄ ) -alkyl, hydroxyl and / or (C 1 -C ₄ ) -alkoxy,

R ¹ and R ² are the same or different and are independently hydrogen or (C _r C ₄₎ alkyl substituted with hydroxy, (Ci-C ₄₎ -alkoxy, amino, mono- (Ci-C ₄₎ alkylamino or di - (Cj -C ₄ ) alkylamino may be substituted mean

or

R ¹ and R ² are linked to one another and together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocycle which contains a further ring heteroatom from the series N and O and one or two times, may be substituted with same or different (Ci-C ₄₎ alkyl, amino, hydroxy and / or (C _r C ₄₎ alkoxy,

R ^{3 is} hydrogen or the side group of a natural α-amino acid or its homologs or isomers

or

R ³ is linked with R ¹ and the two together with the atoms to which they are attached form a 5- or 6-membered saturated heterocycle containing one or two times by identical or different (C _r C ₄₎ -alkyl , Amino, hydroxy and / or (C 1 -C ₄ ) -alkoxy may be substituted,

R ^{4 is} hydrogen or methyl

or

R ³ and R ⁴ are linked together and together with the carbon atom to which they are attached form a 3- to 6-membered saturated carbocycle,

and

R ⁵ and R ^{6 are} identical or different and independently of one another denote hydrogen or (C ₁ -

C ₄₎ alkyl, which (with hydroxy, (Ci-C ₄₎ alkoxy, amino, mono-Ci-C ₄₎ alkylamino or di- may be substituted (C _r C ₄₎ alkylamino, mean

and their salts, solvates and solvates of the salts. Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

Suitable salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention. In addition to mono-salts, the present invention also includes optionally possible multiple salts, such as di- or tri-salts.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, as exemplified and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, choline, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, morpholine, N-methylmorpholine, arginine, lysine, ethylenediamine, piperidine and N-methylpiperidine. In the context of the invention, solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

(CVCV) -alkyl in the context of the invention is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.

In the context of the invention, (C 1 -C 4 -alkanediyl and C 1 -C 4 -alkanediyl represent a straight-chain, α, ω-divalent alkyl radical having 3 to 6 or 3 to 5 carbon atoms by way of example and preferably: propan-1,3-diyl (1,3-propylene Butane-1,4-diyl (1,4-butylene), pentane-l, 5-diyl (1,5-pentylene), hexane-l, 6-diyl (1,6-hexylene).

In the context of the invention, C 1 -C 4 -alkoxy is a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms and may be mentioned by way of example and preferably: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy.

Mono-rCVQValkylamino in the context of the invention represents an amino group having a straight-chain or branched alkyl substituent which has 1 to 4 carbon atoms. By way of example and by way of preference: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, tert.-butylamino.

Di- (CVCA Valkylamino is in the context of the invention an amino group having two identical or different straight-chain or branched alkyl substituents having in each case 1 to 4 carbon atoms Preferred examples which may be mentioned are:. N, N-dimethylamino, N ₁ N-diethylamino , N-ethyl-N-methylamino, N-methyl-N-propylamino, N-isopropyl-NH-propyl-amino, N, N-diisopropylamino, Nn-butyl-N-methylamino, N-tert.-butyl-N methylamino.

A 3- to 6-membered carbocycle in the context of the invention is a monocyclic, saturated cycloalkyl group having 3 to 6 ring carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

A 5- or 6-membered heterocycle in the context of the invention is a monocyclic, saturated heterocycloalkyl group having a total of 5 or 6 ring atoms which form a ring nitrogen atom. atom and may optionally contain a second ring heteroatom from the series N and O. By way of example and by way of preference: pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl.

The side group of an α-amino acid in the meaning of R ³ includes both the side groups of the naturally occurring α-amino acids and the side groups of homologues and isomers of these α-amino acids. The α-amino acid can be present both in the L and in the D configuration or as a mixture of the L and D form. As side groups are exemplified: methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropan-1-yl (isoleucine) , Butan-1-yl (norleucine), tert. Butyl (2- / tert-butylglycine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indol-3-ylmethyl (tryptophan), imidazol-4-ylmethyl ( Histidine), hydroxymethyl (serine), 2-hydroxyethyl (homoserine), 1-hydroxyethyl (threonine), mercaptomethyl (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamoyl methyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutan-1-yl (lysine), 4-amino-3-hydroxybutan-1-yl (hydroxylysine ), 3-aminopropan-1-yl (ornithine), 2-aminoethyl (2,4-diaminobutyric acid), aminomethyl (2,3-diaminopropionic acid), 3-guanidinopropan-1-yl (arginine), 3-ureidopropane. l-yl (citrulline). Preferred α-amino acid side groups in the meaning of R ³ are methyl (alanine), propan-2-yl (valine), 2-methylpropan-1-yl (leucine), benzyl (phenylalanine), imidazol-4-ylmethyl (histidine ), Hydroxymethyl (serine), 1-hydroxyethyl (threonine), 4-aminobutan-1-yl (lysine), 3-aminopropan-1-yl (ornithine), 2-aminoethyl (2,4-diaminobutyric acid), aminomethyl (2 , 3-diaminopropionic acid), 3-guanidinopropan-1-yl (arginine). The L configuration is preferred in each case.

In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. Substitution with one or two identical or different substituents is preferred here; particularly preferred is substitution with a substituent.

Preferred in the context of the present invention are compounds of the formula (I) in which

R ^{A is} hydrogen or methyl

and

R ^{PD is} a group of the formula stands in which

# means the point of attachment to the respective O atom,

L ^{1 is} a bond or -CH ₂ -,

L ² denotes straight-chain (C ₃ -C ₆ ) -alkanediyl,

R ¹ and R ² independently of one another denote hydrogen or methyl,

R ^{3 is} hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, benzyl, imidazol-4-yl-methyl, hydroxymethyl, 1-hydroxyethyl, 4-aminobutan-1-yl, 3-aminopropane-1 yl, 2-aminoethyl, aminomethyl or 3-guanidinopropan-1-yl

or

R ^{3 is} linked to R ¹ and both together with the atoms to which they are attached form a pyrrolidine ring,

R ^{4 is} hydrogen

and

R ⁵ and R ⁶ independently of one another denote hydrogen or methyl,

and their salts, solvates and solvates of the salts.

Particularly preferred in the context of the present invention are compounds of the formula (I) in which

R ^{A is} hydrogen

and

R ^{PD is} a group of the formula stands in which

the point of attachment to the respective O atom means

L means a bond

straight-chain (C ₃ -C ₅ ) -alkanediyl,

R ¹ and R ^{2 are} each hydrogen,

R ^{3 is} hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, hydroxymethyl, 1-hydroxyethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 2-aminoethyl, amino-methyl or 3-guanidinopropan-1-yl,

R ^{4 is} hydrogen

and

R ⁵ and R ^{6 are} each hydrogen,

and their salts, solvates and solvates of the salts.

The two prodrug groups R ^PD in the compounds of the formula (I) may be identical or different within the scope of meaning given above. Preference is given to compounds of the formula (I) with identical prodrug groups R ^{PD in} each case.

Of particular importance are the compounds of the formulas (I-A) and (I-B)

(IA)

in which R ^A and R ^{PD have} the meanings given above,

with an S- or /? - configuration at the C * carbon atom of the propan-l, 2,3-triyl group and their salts, solvates and solvates of the salts.

Preferred in the context of the present invention are the compounds of the formula (I-A) having an S configuration on the C * carbon atom of the propane-l, 2,3-triyl group and their salts, solvates and solvates of the salts.

Particularly preferred in the context of the present invention are compounds of the formula (IA) in which R ^{A is} hydrogen and the two prodrug groups R ^{PD are} each identical, and their salts, solvates and solvates of the salts.

Another object of the invention is a process for the preparation of compounds of the formula (I) according to the invention, in which the two prodrug groups R ^{PD are} each identical, characterized in that

[A] the compound of the formula (A)

in which

R ^{A is} hydrogen or methyl,

in an inert solvent with two or more equivalents of a compound of formula (H)

in which L ¹ , R ³ and R ^{4 have} the meanings given above

and

R ^1a and R ^{2a are} identical or different and have the abovementioned meanings of R ¹ or R ² or represent a temporary amino-protecting group,

activating the carboxyl group in (H) to give a compound of formula (HI)

in which L ¹ , R ^A , R ^1a , R ^2a , R ³ and R ^{4 have} the meanings given above,

coupled and then optionally present protecting groups to give a compound of formula (I-C)

in which L, R, R, R, R and R have the meanings given above,

away

respectively [B] the compound of the formula (A) in an inert solvent with two or more equivalents of a compound of the formula (IV)

in which L ^{2 has} the meaning given above

and

R ^5a and R ^{6a are} identical or different and have the abovementioned meanings of R ⁵ or R ⁶ or represent a temporary amino-protecting group,

activating the carboxyl group in (FV) to give a compound of the formula (V)

in which L ² , R ^A , R ^5a and R ^{6a have} the meanings given above,

coupled and then optionally present protecting groups to give a compound of formula (ID)

in which L 2, r R> A, R 5 and R have the meanings given above,

away

and the resulting compounds of the formula (I-C) or (I-D), if appropriate, with the corresponding (i) solvents and / or (ii) acids or bases in their solvates, salts and / or solvates of the salts.

The compounds of the formulas (IC) and (ID) can also be produced directly in the form of salts during the preparation according to the processes described above. If desired, these salts can be converted into the respective free bases or acids by treatment with a base or acid in an inert solvent, by chromatographic methods or by means of ion exchange resins. Other salts of the compounds of the invention can be prepared if necessary by exchanging counter ions using the ion-exchange chromatography, for example with Amberlite ^® resins.

In the compounds of formulas (II) and (IV) or in the radicals R ¹ , R ² , R ³ , R ⁵ , R ⁶ and / or L ² optionally present functional groups - such as in particular amino, guanidino, hydroxy -, mercapto and carboxyl groups - may be in the previously described reaction sequences, if appropriate or necessary, also in temporarily protected form. The introduction and removal of such protective groups is carried out by customary methods known from peptide chemistry [see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999; M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, Berlin, 1984]. As the amino and guanidino protective group is preferably / erΛ-butoxycarbonyl (Boc) or benzyl oxycarbonyl (Z) is used. As a protective group for a hydroxy or carboxyl function, tert-butyl or benzyl is preferably used. The cleavage of these protective groups is carried out by customary methods, preferably by reaction with a strong acid such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid in an inert solvent such as dioxane, dichloromethane or acetic acid; optionally, the cleavage can also be carried out without an additional inert solvent. In the case of benzyl and benzyloxycarbonyl as a protective group, these can also be removed by hydrogenolysis in the presence of a palladium catalyst. The cleavage of the protective groups mentioned can optionally be carried out simultaneously in a one-pot reaction or in separate reaction steps.

Inert solvents for the coupling reaction (ester formation) in process step (A) + (IT) -> (IH) or (A) + (IV) -> (V) are, for example, ethers, such as diethyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as acetone , Ethyl acetate, pyridine, dimethyl sulfoxide, dimethylformamide, N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝMP) or acetonitrile. It is also possible to use mixtures of the solvents mentioned. Preference is given to dichloromethane, dimethylformamide or mixtures of these two solvents.

Carbodiimides such as NN'-diethyl, NN'-dipropyl, NN'-diisopropyl, N, N'-dicyclohexylcarbodiimide are suitable for activating the carboxyl group in compound (H) or (IV) in these coupling reactions (DCC) or N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as NN'-carbonyldiimidazole (CDI), 1,2-oxazolium compounds such as 2-ethyl-5- phenyl-1, 2-oxazolium-3-sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or isobutylchloroformate, propanephosphonic anhydride, cyanophosphonic acid diethyl ester, Bis- (2-oxo-3-oxazolidinyl) -phosphoryl chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, benzotriazole-1-ynyloxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), O - (benzotriazol-1-yl) -NN, N ', N'-tetramethyluronium tetrafluoroborate (TBTU), O- (benzotriazol-1-yl) -NNN', N'-tetramethyluronium hexafluorophosphate (HBTU), 2- ( 2-O xo-l- (2H) -pyridyl) -1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (ΗATU) or O- (1H-6-chlorobenzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate (TCTU), optionally in combination with further auxiliaries, such as 1-hydroxybenzotriazole (ΗOBt) or N- Roydroxysuccinimide (ΗOSu), as well as alkali metal carbonates, for example sodium or potassium carbonate, or organic amine bases such as Triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine or 4-N, N-dimethylaminopyridine. Preference is given to using N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) in combination with 4-N, N-dimethylaminopyridine.

The reactions (A) + (II) -> (HI) and (A) + (IV) -> (V) are generally used in a tem- perarurbereich of 0 ⁰ C to +50 ⁰ C, preferably +10 ⁰ C to +30 ⁰ C performed. The reactions can be carried out at normal, at elevated or at reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.

The compounds of formulas (II) and (IV) are commercially available, known from the literature or can be prepared by literature methods. Thus, for example, compounds of the formula (II) in which L ^{1 is} -CH ₂ - can be prepared by known methods for chain extension of carboxylic acids, such as, for example, the Arndt-Eistert reaction [Eistert et al., Ber. Dtsch. Chem. Ges. 60, 1364-1370 (1927); Ye et al., Chem. Rev. 94, 1091-1160 (1994); Cesar et al., Tetrahedron Leu. 42, 7099-7102 (2001)], starting from compounds of formula (II) in which L ^{1 represents} a bond.

Compounds according to the invention of the formula (I) in which the two prodrug groups R ^{PD are} not identical can be prepared analogously to the method described above by reacting the compound of the formula (A) successively with one equivalent each of correspondingly different Compounds of formula (II) and / or (IV) couples and thereby resulting product mixtures then - optionally before or after the removal of temporary protective groups - separated into the individual components. For such a separation, preference is given to using chromatographic methods, such as chromatography on silica gel or aluminum oxide or HPLC on reverse phases, or recrystallization from aqueous or nonaqueous solvent mixtures.

The 2-amino-6- ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -4- (4- {[2,3-dihydroxypropyl] oxy} phenyl) pyridine-3,5-dicarbonitriles of the formula (A) are prepared by first reacting the benzaldehyde of the formula (VI)

(VI) with two equivalents of 2-cyanothioacetamide in the presence of a base such as N-methylmorpholine to the pyridine derivative (VII)

condensed, this then in the presence of a base such as sodium bicarbonate with an A- (chloromethyl) -2- (4-chlorophenyl) -1, 3-oxazole of the formula (Vm)

in which R ^{A has} the meaning indicated above,

to a compound of the formula (IX)

alkylated and finally the acetonide protecting group with the aid of an aqueous acid such as hydrochloric acid or acetic acid, cleaves [see also the following reaction scheme 2 and the description of the intermediates 1 A-9A and 25A-28A in the Experimental Part]. The compound of the formula (VI) in turn is obtained by reacting 4-hydroxybenzaldehyde with the 3-chloro-1,2-propanediol acetonide of the formula (X)

in the presence of a base such as potassium carbonate. If the enantiomerically pure, R- or ^ -configured 3-chloro-l, 2-propanediol acetonides are used, the corresponding enantiomers of the active compound compounds (A) and, derived therefrom, according to the reaction sequence described above, can be used corresponding prodrug compounds of the formulas (IA) and (IB).

The 2-phenyl-l, 3-oxazole derivatives of the formula (VHI) can be prepared by condensation reactions known from the literature [see the following Reaction Scheme 3].

The preparation of the compounds (I) according to the invention and of the active compounds (A) can be illustrated by way of example by the following synthesis schemes:

Scheme 1

Scheme 2

Scheme 3 [see. eg Y. Goto et al., Chem. Pharm. Bull. 1971, 19, 2050-2057].

The compounds according to the invention and their salts are useful prodrugs of the active compound compounds of the formula (A). On the one hand, they have good stability at different pH values and, on the other hand, show efficient conversion to the active substance (A) at a physiological pH especially in vivo. In addition, the compounds according to the invention have improved solubilities in aqueous or other physiologically tolerated media, which makes them suitable for therapeutic use, in particular in the case of intravenous administration. In addition, the bioavailability from suspension after oral administration is improved over the parent substance (A).

The compounds of the formula (I) are suitable, alone or in combination with one or more other active compounds, for the prophylaxis and / or treatment of various diseases, for example in particular diseases of the cardiovascular system (cardiovascular diseases), cardioprotection for damage to the heart and of Metabolic diseases.

For the purposes of the present invention, diseases of the cardiovascular system or cardiovascular diseases are to be understood as meaning, for example, the following diseases: hypertension (hypertension), peripheral and cardiac vascular diseases, coronary heart disease, coronary restenosis, such as e.g. Restenosis after balloon dilatation of peripheral blood vessels, myocardial infarction, acute coronary syndrome, acute coronary syndrome with ST elevation, acute coronary syndrome without ST elevation, stable and unstable angina pectoris, cardiac muscle weakness, Prinzmetal's angina, persistent ischemic dysfunction ("hibernating myocardium") ), transient postischemic dysfunction ("stunned myocardium"), heart failure, tachycardia, atrial tachycardia, arrhythmias, atrial and ventricular fibrillation, persistent atrial fibrillation, permanent atrial fibrillation, atrial fibrillation with normal left ventricular function, atrial fibrillation with impaired left ventricular function, Wolff-Parkinson-White Syndrome, peripheral circulatory disorders, increased levels of fibrinogen and low density LDL, and elevated levels of plasminogen activator inhibitor 1 (PAI-I), especially hypertension, coronary heart disease, acute coronary syndrome, angina pectoris, heart failure, myocardium farct and atrial fibrillation.

For the purposes of the present invention, the term cardiac failure encompasses both acute and chronic manifestations of heart failure, as well as more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy. cardiac insufficiency, valvular heart failure, cardiac insufficiency in valvular heart failure, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspidal stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic toxicity Cardiomyopathy, cardiac storage disorders as well as diastolic and systolic heart failure.

Furthermore, the compounds according to the invention are also particularly suitable for the reduction of the myocardium affected by an infarct and for the prophylaxis of secondary infarcts.

Furthermore, the compounds according to the invention are in particular for the prophylaxis and / or treatment of thromboembolic disorders, reperfusion injury after ischemia, micro- and macrovascular damage (vasculitis), arterial and venous thromboses, edema,

Ischemia such as myocardial infarction, stroke, and transient ischemic attacks, for cardioprotection in coronary artery bypass grafting (CABG), primary percutaneous transluminal

Coronary angioplasties (PTCAs), PTCAs after thrombolysis, rescue PTCA, heart transplants and open heart surgery, as well as for organ protection during transplantation, bypass

Surgery, catheterization and other surgical procedures.

Further indications for which the compounds according to the invention can be used are, for example, the prophylaxis and / or treatment of diseases of the genitourinary area, such as, for example, acute renal failure, irritable bladder, urogenital incontinence, erectile dysfunction and female sexual dysfunction, but also the prophylaxis and / or treatment of inflammatory diseases, such as inflammatory dermatoses and arthritis, in particular rheumatoid arthritis, of diseases of the central nervous system and neurodegenerative disorders (post-stroke conditions, Alzheimer's disease, Parkinson's disease, dementia, Huntington's chorea, epilepsy, depression, multiple sclerosis), pain conditions and migraine, liver fibrosis and cirrhosis, cancer and nausea and vomiting associated with cancer treatments, and wound healing.

Another indication is, for example, the prophylaxis and / or treatment of respiratory diseases such as asthma, chronic obstructive pulmonary diseases (COPD, chronic bronchitis), pulmonary emphysema, bronchiectasis, cystic fibrosis (cystic fibrosis) and pulmonary hypertension, especially pulmonary arterial hypertension.

Finally, the compounds according to the invention are also suitable for the prophylaxis and / or treatment of metabolic diseases, for example diabetes, in particular diabetes mellitus, gestational diabetes, insulin-dependent diabetes and non-insulin-dependent Diabetes, diabetic sequelae such as retinopathy, nephropathy and neuropathy, metabolic disorders such as metabolic syndrome, hyperglycemia, hyperinsulinemia, insulin resistance, glucose intolerance and obesity, as well as atherosclerosis and dyslipidaemias (hypercholesterolemia, hypertriglyceridemia, increased levels of postprandial plasma triglycerides, hypoalphalipoproteinemia, combined hyperlipidaemias), in particular diabetes, metabolic syndrome and dyslipidaemias.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the erfϊndungsgemäßen compounds for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.

The compounds of the invention may be used alone or as needed in combination with other agents. Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.

Examples of suitable combination active ingredients are lipid metabolism-changing active substances, antidiabetics, hypotensives, circulation-promoting and / or antithrombotic agents, antiarrhythmics, antioxidants, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, Orexin agonists, anorectics, PAF-AH inhibitors, anti-inflammatory drugs (COX inhibitors, LTB ₄ receptor antagonists) and analgesics such as aspirin.

The present invention particularly relates to combinations of at least one of the compounds according to the invention with at least one active substance which alters the lipid metabolism. substance, an antidiabetic agent, a hypotensive agent, an antiarrhythmic agent and / or an antithrombotic agent.

The compounds of the invention may preferably be with one or more

The lipid metabolism-changing active substances, by way of example and preferably from the group of HMG-CoA reductase inhibitors, inhibitors of HMG-CoA reductase expression,

Squalene synthesis inhibitors, ACAT inhibitors, LDL receptor inducers, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, MTP inhibitors, lipase inhibitors, LpL activators, fibrates, niacin, CETP inhibitors, PPAR-α-, PPAR-γ and / or PPAR-δ agonists, RXR modulators, FXR modulators, LXR modulators, thyroid hormones and / or thyroid mimetics, ATP citrate lyase inhibitors,

Lp (a) antagonists, cannabinoid receptor 1 antagonists, leptin receptor agonists, bomberin receptor agonists, histamine receptor agonists, and antioxidants / free radical scavengers;

• antidiabetic agents mentioned in the Red List 2004 / π, chapter 12, as well as by way of example and preferably those from the group of sulfonylureas, biguanides, meglitinide derivatives,

Glucosidase inhibitors, inhibitors of dipeptidyl peptidase IV (DPP-IV inhibitors), oxadiazolidinones, thiazolidinediones, GLP 1 receptor agonists, glucagon antagonists, insulin sensitizers, CCK 1 receptor agonists, leptin receptor Agonists, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake and potassium channel openers, such as those in

WO 97/26265 and WO 99/03861 are disclosed;

Antihypertensive agents, by way of example and with preference from the group of calcium antagonists, angiotensin Aü antagonists, ACE inhibitors, renin inhibitors, beta adrenoceptor antagonists, alpha adrenoceptor antagonists, diuretics, aldosterone antagonists, Mineralocorticoid receptor antagonists, ECE inhibitors and the vasopeptidase

inhibitors;

Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors or anticoagulants;

Antiarrhythmics, especially those for the treatment of supraventricular arrhythmias and tachycardias;

• substances for the prophylaxis and treatment of ischemia and reperfusion injury; Vasopressin receptor antagonists;

• organic nitrates and NO donors;

• positive inotropic compounds;

Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of

Phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil and PDE 3 inhibitors such as milrinone;

Natriuretic peptides, e.g. "atrial natriuretic peptide" (ANP, anaritide), "B-type natriuretic peptide" or "brain natriuretic peptide" (BNP, nesiritide), "C-type natriuretic peptide" (CNP) and urodilatin;

Agonists of the prostacyclin receptor (IP receptor), such as iloprost, beraprost and cicaprost;

Calcium sensitizers, such as by way of example and preferably levosimendan;

• potassium supplements;

Guanylate cyclase NO- and heme-independent activators, in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;

NO-independent, but heme-dependent guanylate cyclase stimulators, in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

• inhibitors of human neutrophil elastase (HNE), such as Sivelestat and DX-890 (Reltran);

The signal transduction cascade inhibiting compounds, such as tyrosine kinase inhibitors, especially sorafenib, imatinib, gefitinib and erlotinib;

• compounds affecting the energy metabolism of the heart, such as estimoxir, dichloroacetate, ranolazines and trimetazidines;

• painkillers; and or • substances for the prophylaxis and treatment of nausea and vomiting

be combined.

Among the lipid metabolism-changing active compounds are preferably compounds from the group of HMG-CoA reductase inhibitors, squalene synthesis inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, MTP inhibitors, lipase inhibitors, thyroid hormones and / or thyroid mimetics, niacin receptor Agonists, CETP inhibitors, PPAR-α agonists, PPAR-γ agonists, PPAR-δ agonists, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, antioxidants / free-radical scavengers, and the cannabinoid receptor 1 antagonists.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin ,

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid hormone and / or thyroid mimetic, such as by way of example and preferably D-thyroxine or 3,5,3'-triiodothyronine (T3). In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an agonist of the niacin receptor, such as by way of example and preferably niacin, Acipimox, Acifran or Radecol.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, for example and preferably, torcetrapib, JTT-705, BAY 60-5521, BAY 78-7499 or CETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-γ agonist, by way of example and preferably pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-δ agonist, such as by way of example and preferably GW-501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.

In a preferred embodiment of the invention, the compounds of the invention are used in combination with a bile acid reabsorption inhibitor, such as by way of example and preferably ASBT (= IBAT) inhibitors such as e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an antioxidant / radical scavenger, such as, by way of example and by way of preference, probucol, AGI-1067, BO-653 or AEOL-10150.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cannabinoid receptor 1 antagonist, such as by way of example and preferably rimonabant or SR-147778.

Antidiabetic agents are preferably understood as meaning insulin and insulin derivatives as well as orally active hypoglycemic agents. Insulin and insulin derivatives here include both insulins of animal, human or biotechnological origin as well as mixtures thereof. The orally active hypoglycemic agents preferably include sulphonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors, DPP-IV inhibitors and PPAR-γ agonists. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with insulin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a sulphonylurea, such as, by way of example and by way of preference, butylidamide, glibenclamide, glimepiride, glipizide or gliclazide.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a biguanide, such as by way of example and preferably metformin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a meglitinide derivative, such as by way of example and preferably repaglinide or nateglinide.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a glucosidase inhibitor, such as by way of example and preferably migolith or acarbose.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a DPP-IV inhibitor, such as by way of example and preferably sitagliptin or vildagliptin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-γ agonist, for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.

The blood pressure lowering agents are preferably understood as meaning compounds from the group of the calcium antagonists, angiotensin Aü antagonists, ACE inhibitors, renin inhibitors, beta adrenoceptor antagonists, alpha adrenoceptor antagonists and diuretics.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AH antagonist, such as by way of example and preferably losartan, valsartan, candesartan, embusartan, olmesartan or telmisartan. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a beta-adrenoceptor antagonist, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-adrenoceptor antagonist, such as by way of example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone, Acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an aldosterone or mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vasopressin receptor antagonist, such as, by way of example and by way of preference, conivaptan, tolvaptan, lixivaptan or SR-121463.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an organic nitrate or NO donor, such as by way of example and preferably sodium nitroprusside, glyceryl nitrate, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-I, or in combination with inhaled NO. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a positive inotropically active compound such as by way of example and preferably cardiac glycosides (digoxin) as well as beta-adrenergic and dopaminergic agonists such as isoproterenol, epinephrine, norepinephrine, dopamine or dobutamine.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with antisympathotonics such as reserpine, clonidine or alpha-methyl-dopa, or in combination with potassium channel agonists such as minoxidil, diazoxide, dihydralazine or hydralazine.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors or anticoagulants.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPUb / IHa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No. 3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin. Antiarrhythmics are preferably substances from the class Ia antiarrhythmics (eg quinidine), class Ic antiarrhythmics (eg flecainide, propafenone), class II antiarrhythmics (eg metoprolol, atenolol, sotalol, oxprenolol and other beta-antiarrhythmics). Receptors-B), class III antiarrhythmics (eg, sotalol, amiodarone), and class IV antiarrhythmics (eg, digoxin, verapamil, diltiazem, and other calcium antagonists).

Particularly preferred in the context of the present invention are combinations containing at least one of the compounds according to the invention and one or more further active compounds selected from the group consisting of HMG-CoA reductase inhibitors (statins), diuretics, beta-adrenoceptor antagonists, alpha-adrenoceptor Antagonists, organic nitrates and NO donors, calcium antagonists, ACE inhibitors, angiotensin Aue antagonists, aldosterone and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, platelet aggregation inhibitors, anticoagulants and antiarrhythmics, and their use for the treatment and / or prophylaxis of the aforementioned diseases.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent. For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For the oral administration are according to the prior art functioning, the inventive compounds rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention), tablets or wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, Granules, pellets, powders, emulsions, suspensions, aerosols or solutions. The parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration, suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example Inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions , Ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.

Preference is given to oral or parenteral administration, in particular oral and intravenous administration.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. When administered orally, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases, it may be sufficient to make do with less than the aforementioned minimum amount, while in other cases, the said upper limit is exceeded got to. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The following embodiments illustrate the invention. The invention is not limited to the examples.

The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume.

A. Examples

Abbreviations and acronyms:

Ac Acetyl aq. Aqueous, aqueous solution

Boc /e .- / - butoxycarbonyl

DMAP 4-N, N-dimethylaminopyridine

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide d. Th. Of theory (at yield)

EDC 1 - ^ - dimethylaminopropyl O-S-ethylcarbodiimide hydrochloride

ESI electrospray ionization (in MS)

EtOH ethanol sat. saturated h hour (s)

HOAc acetic acid

HPLC high pressure, high performance liquid chromatography conc. concentrated

LC-MS liquid chromatography-coupled mass spectrometry min minute (s)

MS mass spectrometry

NMM N-methylmorpholine

NMR nuclear magnetic resonance spectrometry

P para quant. quantitative (at yield)

RT room temperature

Retention time (on HPLC) tert. tertiary

TFA trifluoroacetic acid

THF tetrahydrofuran

UV ultraviolet spectrometry v / v volume-to-volume ratio (of a solution)

Z is benzyloxycarbonyl LC-MS methods:

Method 1:

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 50 mm x 4.6 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 10% B -> 3.0 min 95% B → 4.0 min 95% B; Flow: 0.0 min 1.0 ml / min → 3.0 min 3.0 ml / min → 4.0 min 3.0 ml / min; Oven: 35 ° C; UV detection: 210 nm.

Method 2:

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3μ 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 5.5 min 10% A; Oven: 50 ^° C .; Flow: 0.8 ml / min; UV detection: 210 nm.

Method 3:

Device Type MS: Waters ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Onyx Monolithic Cl 8, 100 mm x 3 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2 min 65% A → 4.5 min 5% A → 6 min 5% A; Flow: 2 ml / min; Oven: 40 ^° C; UV detection: 210 nm.

Method 4:

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; UV DAD; Column: Phenomenex Gemini 3μ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min - → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 208-400 nm.

Method 5:

Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 μ 50 mm x 1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 0.1 min 90% A → 1.5 min 10% A → 2.2 min 10% A; Flow: 0.33 ml / min; Oven: 50 ° C; UV detection: 210 nm. Method 6:

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex syn ergi 2.5 μ MAX-RP 100A Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 0.1 min 90% A → 3.0 min 5% A → 4.0 min 5% A → 4.01 min 90% A; Flow: 2 ml / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 7:

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3μ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A - »4.5 min 5% A; Flow: 0.0 min 1 ml / min -> 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 8:

Instrument: Waters Acquity SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8μ 50mm x 1mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; Flow: 0.40 ml / min; Oven: 50 ^° C .; UV detection: 210-400 nm.

Method 9:

Device type MS: M-40 DCI (NH ₃ ); Device type HPLC: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ (70%) / liter water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B → 6.7 min 2% B → 7.5 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ^° C .; UV detection: 210 nm.

Method 10:

Instrument: Micromass Quattro Micro MS with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3μ 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.01 min 100% A (flow 2.5 ml / min) → 5.00 min 100% A; Oven: 50 ^° C .; Flow: 2 ml / min; UV detection: 210 nm. Method 11:

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 208-400 nm.

Method 12:

Device Type MS: Waters ZQ; Device type HPLC: Waters Alliance 2795; Column: Merck Chromolith RP-18e, 100 mm x 3 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min- 90% A → 2 min 65% A → 4.5 min 5% A → 6 min 5% A; Flow: 2 ml / min; Oven: 40 ^° C; UV detection: 210 nm.

Starting compounds and intermediates:

Example IA

4- {[(4S> 2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} benzaldehyde

12.5 g (102.4 mmol) of 4-hydroxybenzaldehyde were initially charged under argon in 166 ml of dry DMF and at RT with 42.4 g (307.1 mmol) of potassium carbonate and 20.05 g (133.1 mmol) of (R) - (-) - 3-chloro-1, 2-propanediol acetonide added. The mixture was stirred at 160 ^° C. for 16 h. The reaction was then combined with water and extracted twice with ethyl acetate. The combined organic phases were washed with sat. washed aqueous sodium chloride solution and dried over magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator and the residue was purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 2).

Yield: 20.0 g (82% of theory)

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.89 (s, IH), 7.85 (d, 2H), 7.03 (d, 2H), 4.50 (q, IH), 4.22- 4.09 (m, 2H), 4.04 (dd, IH), 3.92 (dd, IH), 1.48 (s, 3H), 1.41 (s, 3H).

LC-MS (Method 9): R. = 4.02 min; MS (ESIpos): m / z = 254 [M + NHJ ^* .

Example 2A

A- {[(4R) -2,2-Dimethyl-1,3-dioxolan-4-yl] methoxy} benzaldehyde

31.2 g (255.4 mmol) of 4-hydroxybenzaldehyde were initially charged in 400 ml of dry DMF and treated at RT with 105.7 g (766.1 mmol) of potassium carbonate and 50.0 g (332.0 mmol) of (S) - (-) - 3 -chloro-1,2- propanediol acetonide. The mixture was stirred at 160 ^° C. for 16 h. The batch was then treated with 4000 ml of water and extracted three times with 500 ml of ethyl acetate. The combined organic phases were washed once with 500 ml of water and 500 ml of sat. washed aqueous sodium chloride solution. After drying over magnesium sulfate, the solvent was removed on a rotary evaporator and the residue was purified by column chromatography on silica gel 60 (mobile phase gradient: ethyl acetate / petroleum ether 1: 9 → 2: 8).

Yield: 40.4 g (63% of theory)

¹ H NMR (400 MHz, DMSO- (I ₆ ): δ = 9.90 (s, IH), 7.85 (d, 2H), 7.03 (d, 2H), 4.50 (q, IH), 4.22-4.09 (m , 2H), 4.04 (dd, IH), 3.92 (dd, IH), 1.48 (s, 3H), 1.41 (s, 3H).

LC-MS (Method 9): R, = 3.97 min; MS (ESIpos): m / z = 254 [M + NHJ *.

Example 3A

2-Amino-4- (4 - {[(4iS) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} phenyl) -6-mercaptopyridine-3,5-dicarbonitrile

44.0 g (186.2 mmol) of the compound from Example IA and 37.3 g (372.5 mmol) of cyanothioacetamide were initially charged in 800 ml of ethanol. The reaction mixture was admixed at room temperature with 37.6 g (372.5 mmol) of 4-methylmorpholine and heated to reflux with stirring for 3 h. After cooling to RT, the mixture was stirred at this temperature for a further 16 h. The precipitate was filtered off, washed with ethanol and dried in vacuo. The product was used without further purification in the subsequent reaction.

Yield: 22.8 g (32% of theory) ¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 7.69-7.37 (br.s, 2H), 7.42 (d, 2H), 7.10 (d, 2H), 4.48-4.39 (m, IH) , 4.15-4.02 (m, 2H), 3.78 (dd, IH), 3.66 (dd, IH), 2.77-2.68 (br s, IH), 1.37 (s, 3H), 1.31 (s, 3H).

LC-MS (method 1): R ₄ = 1.75 min; MS (ESIpos): m / z = 383 [M + H] ⁺ .

Example 4A

2-Amino-4- (4 - {[(4i) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} phenyl) -6-mercaptopyridine-3,5-dicarbonitrile

40.4 g (171.0 mmol) of the compound from Example 2A and 34.2 g (342.0 mmol) of cyanothioacetamide were initially charged in 700 ml of ethanol. The reaction mixture was admixed with 34.5 g (342.0 mmol) of 4-methylmorpholine and heated to reflux with stirring for 3 h. After cooling to RT, the mixture was stirred at this temperature for a further 16 h. The precipitate was filtered off, washed with about 100 ml of ethanol and dried in a drying oven. The product was used without further purification in the subsequent reaction.

Yield: 19.5 g (29% of theory)

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.63-7.31 (br.s, 2H), 7.41 (d, 2H), 7.09 (d, 2H), 4.49-4.38 (m, IH), 4.15- 3.99 (m, 2H), 3.78 (dd, IH), 3.66 (dd, IH), 2.77-2.68 (br, s, IH), 1.37 (s, 3H), 1.32 (s, 3H).

LC-MS (method 11): R, = 1.95 min; MS (ESIpos): m / z = 424 [M + H + CH ₃ CN] ⁺ .

Example 5A

4- (chloromethyl) -2- (4-chlorophenyl) -l, 3-oxazol

123.8 g (795.5 mmol) of 4-chlorobenzenecarboxamide and 101.0 g (795.5 mmol) of 1,3-dichloroacetone were stirred at 135 ° C. for one hour. It formed a melt. The mixture was then cooled with stirring to RT, at this temperature cautiously with 200 ml of conc. Sulfuric acid and stirred for 30 min. The suspension obtained was poured into ice-water and stirred for a further 30 min. The resulting precipitate was then filtered off, washed with water and purified by flash chromatography on silica gel (eluent: dichloromethane). The solvent was removed on a rotary evaporator and the residue was dried in vacuo. 95.5 g (53% of theory) of the target compound were obtained.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.30 (s, IH), 7.99 (d, 2H), 7.62 (d, 2H), 4.75 (s, 2H).

LC-MS (Method 2): R, = 3.78 min; MS (ESIpos): m / z = 228 [M + H] ⁺ .

Example 6A

2-amino-6 - ({[2- (4-chloφhenyl) -l, 3-oxazol-4-yl] methyl} sulfanyl) -4- (4 - {[(4S) -2,2-dimethyl-l , 3-dioxolan-4-yl] methoxy} phenyl) pyridine-3,5-dicarbonitrile

150 mg (0.39 mmol) of the compound from Example 3 A and 98 mg (0.43 mmol) of the compound from Example 5 A were suspended together with 99 mg (1.18 mmol) of sodium bicarbonate in 2 ml of dry DMF. The reaction mixture was stirred at RT for 20 h. The mixture was then purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm, mobile phase gradient: acetonitrile / water 10:90 → 95: 5).

Yield: 147 mg (65% of theory) ¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.37 (s, IH), 8.29-7.91 (br, s, 2H) ₅ 7.97 (d, 2H), 7.61 (d, 2H), 7.47 ( d, 2H), 7.12 (d, 2H), 4.48-4.39 (m, IH), 4.42 (s, 2H), 4.16-4.03 (m, 3H), 3.77 (dd, IH), 1.37 (s, 3H) , 1.31 (s, 3H).

LC-MS (Method 3): R, = 4.23 min; MS (ESIpos): m / z = 574 [M + H] ⁺ .

Example 7A

2-Amino-6- ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] -methyl} -sulfanyl) -4- (4- {[(4R) -2,2-dimethyl-1 , 3-dioxolan-4-yl] methoxy} phenyl) pyridine-3,5-dicarbonitrile

70 mg (0.18 mmol) of the compound from Example 4A and 46 mg (0.20 mmol) of the compound from Example 5A were suspended together with 46 mg (0.55 mmol) of sodium bicarbonate in 1.9 ml of dry DMF. The reaction mixture was stirred at RT for 20 h. The mixture was then freed from the solvent on a rotary evaporator and the residue was purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm, mobile phase gradient: acetonitrile / water 10:90 → 95: 5).

Yield: 79 mg (75% of theory)

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.37 (s, IH), 8.30-8.01 (br.s, 2H), 7.97 (d, 2H), 7.60 (d, 2H), 7.48 ( d, 2H), 7.12 (d, 2H), 4.48-4.40 (m, IH), 4.42 (s, 2H), 4.16-4.03 (m, 3H), 3.78 (dd, IH), 1.37 (s, 3H) , 1.31 (s, 3H).

LC-MS (method 7): R, = 2.99 min; MS (ESIpos): m / z = 574 [M + H] ⁺ .

Example 8A

2-Amino-6- ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -4- (4- {[(2R) -2,3-dihydroxypropyl] ] oxy} phenyl) pyridine-3,5-dicarbonitrile

127.1 g (221.4 mmol) of the compound from Example 6A were suspended in 800 ml of ethanol and treated with 800 ml of 37% hydrochloric acid. The mixture was stirred at reflux overnight. After cooling to room temperature, the resulting precipitate was filtered off, washed with ethanol and dried at 50 ⁰ C in a vacuum overnight. 108.3 g (92% of theory) of the target compound were obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.37 (s, IH), 8.30-7.89 (br.s, 2H), 7.98 (d, 2H), 7.61 (d, 2H), 7.48 ( d, 2H), 7.10 (d, 2H), 5.00 (d, IH), 4.70 (t, IH), 4.42 (s, 2H), 4.09 (dd, IH), 3.98-3.92 (m, IH), 3.81 (q, IH), 3.50-3.43 (m, 2H).

LC-MS (Method 4): R, = 2.51 min; MS (ESIpos): m / z = 534 [M + H] ⁺ .

Example 9A

2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -4- (4 - {[(25) -2,3-dihydroxypropyl ] oxy} phenyl) pyridine-3,5-dicarbonitrile

400 mg (0.70 mmol) of the compound from Example 7A were initially charged in 17 ml of acetic acid and then admixed carefully with 8.6 ml of water. It was stirred for 12 h at RT. After concentration of the reaction mixture on a rotary evaporator, the residue was purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm, mobile phase gradient: acetonitrile / water 10:90 -> 95: 5). After removal of the solvent on a rotary evaporator, the product was obtained as a white solid.

Yield: 340 mg (91% of theory)

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.37 (s, IH), 8.27-7.91 (br, s, 2H), 7.98 (d, 2H), 7.60 (d, 2H), 7.47 (d, 2H), 7.10 (d, 2H), 5.00 (d, IH), 4.70 (t, IH), 4.42 (s, 2H), 4.09 (dd, IH), 3.96 (dd, IH), 3.70 (q, IH ), 3.46 (t, 2H).

LC-MS (Method 7): R, = 2.48 min; MS (ESIpos): m / z = 534 [M + H] ⁺ .

Example IQA

(2S) -3- {4- [2-Amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl (2S, 2'5) bis {2 - [(/ er /.- butoxycarbonyl) propanoate amino]}

5 g (9.36 mmol) of the compound from Example 8A, 7.09 g (37.45 mmol) of N-Boc-L-alanine, 8.975 g (46.82 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1,144 g (9.36 g) mmol) of 4-N, N-dimethylaminopyridine were combined in 500 ml of dichloromethane and treated in an ultrasonic bath for 30 minutes. The mixture was then shaken out with 10% citric acid solution and then with 10% strength sodium bicarbonate solution until no more N-Boc-L-alanine was detectable in the organic phase. The organic phase was then dried over magnesium sulfate and concentrated in vacuo. The residue was chloromethane and treated with diethyl ether. The resulting precipitate was filtered off with suction. Drying of the solid left 6.01 g (73% of theory) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.36 (s, IH), 8.33-8.02 (br, m, 2H), 7.97 (d, 2H), 7.60 (d, 2H), 7.48 ( d, 2H), 7.30 (m, 2H), 7.12 (d, 2H), 5.34 (m, IH), 4.42 (s, 2H), 4.38-4.21 (m, 4H), 4.03 (m, 2H), 1.36 (s, 18H), 1.26-1.22 (m, 6H).

LC-MS (method 5): R, = 1.61 min; MS (ESIpos): m / z = 876 [M + H] ⁺ .

Example IIA

(2S) -3- {4- [2-amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propane-1, 2-diyl-bis {[{tert. -butoxycarbonyl) amino] acetate}

300 mg (0.562 mmol) of the compound from Example 8A were initially charged in 20 ml of dichloromethane and treated with 217 mg (1.236 mmol) of N- (tert-butoxycarbonyl) glycine, 237 mg (1.236 mmol) of 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride and 7 mg (0.056 mmol) of 4-N, N-dimethylaminopyridine. The mixture was stirred at room temperature overnight. The solvent was then stripped off in vacuo and the crude product purified directly by preparative HPLC. 448 mg (94% of theory) of the target compound were obtained.

LC-MS (method 7): R. = 3.07 min; MS (ESIpos): m / z = 848 [M + H] ⁺ .

Example 12A

(25) -3- {4- [2-Amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl-bis {5 - [(ter /.- butoxycarbonyl) amino] pentanoate}

150 mg (0.281 mmol) of the compound from Example 8A were initially charged in 10 ml of dichloromethane and mixed with 183 mg (0.843 mmol) of 5 - [(tert-butoxycarbonyl) amino] pentanoic acid, 162 mg (0.843 mmol) of 1- (3-dimethylaminopropyl ) -3-ethylcarbodiimide hydrochloride and 3.4 mg (0.028 mmol) of 4-N, N-dimethylaminopyridine. The mixture was stirred at room temperature overnight. The solvent was then removed in vacuo and the crude product purified directly by preparative HPLC. 201 mg (77% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 2.96 min; MS (ESIpos): m / z = 932 [M + H] ⁺ .

Example 13A

(2S) -3- {4- [2-Amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl (25 ', 2'5) -bis {2,5-bis [(/ er /.- butoxycarbonyl) amino] pentanoate}

The preparation of the title compound was carried out analogously to the preparation of Example 12A starting from the compound from Example 8A and commercially available N, N'-bist / er / -butoxycarbonyl-L-ornithine.

Yield: 85% d. Th.

LC-MS (Method 10): R, = 3.11 min; MS (ESIpos): m / z = 1162 [M + H] ⁺ .

Example 14A

(2iS) -3- {4- [2-amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl (2S, 2 \ S) -bis {2,4-bis [(/ e ^ butoxycarbonyl) amino] butanoate}

200 mg (0.375 mmol) of the compound from Example 8A were initially charged in 15 ml of dichloromethane and 412 mg (0.824 mmol) of (2> S) -2,4-bis [(/ e) -butoxycarbonyl) amino] butanoic acid dicyclohexyl - Amine salt, 158 mg (0.824 mmol) l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4.6 mg (0.037 mmol) of 4-N, N-dimethylaminopyridine. The mixture was stirred at room temperature overnight. Thereafter, another 187 mg (0.375 mmol) of (2S) -2,4-bis [(tert-butoxycarbonylamino-butanoic acid dicyclohexylamine salt and 72 mg (0.375 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure and the crude product was purified by preparative HPLC to give 262 mg (62% of theory) of the target compound.

LC-MS (Method 7): R, = 3.31 min; MS (ESIpos): m / z = 1134 [M + H] ⁺ . Example 15A

(2S) -3- {4- [2-Amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propane-1,2-diyl bis {3 - [(tert -butoxycarbonyl) amino] propanoate}

200 mg (0.375 mmol) of the compound from Example 8A were initially charged in 10 ml of dichloromethane / DMF (1: 1), with 213 mg (1,124 mmol) of N- (tert-butoxycarbonyl) -β-alanine, 215 mg (1,124 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4.6 mg (0.037 mmol) of 4-N, N-dimethylaminopyridine and stirred overnight at room temperature. The reaction mixture was then purified directly by preparative HPLC (acetonitrile / water gradient 10:90 → 95: 5). 126 mg (38% of theory) of the target compound were obtained.

LC-MS (Method 6): R, = 2.67 min; MS (ESIpos): m / z = 876 [M + H] ⁺ .

Example 16A

(2R) -3- {4- [2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridine-4- yl] phenoxy} propan-l, 2-diyl (2S, 2 \ S) -bis {2,5-bis [(ter /.- butoxycarbonyl) amino] pentanoate}

374 mg (1.124 mmol) N ^i, N ⁵ -bis (ter /.- butoxycarbonyl) -L-ornithine were initially charged in 3 ml of DMF and initially with 93 mg (0.487 mmol) l- (3-dimethylaminopropyl) -3-ethylcarbodiimide Hydrochloride and 23 mg (0.187 mmol) of 4-N, N-dimethylaminopyridine were added before 200 mg (0.375 mmol) of the compound from Example 9A were added. The mixture was stirred at room temperature overnight. Thereafter, 93 mg (0.487 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 23 mg (0.187 mmol) of 4-N, N-dimethylaminopyridine were added again. After three hours of stirring at room temperature, the reaction mixture was purified directly by preparative HPLC (acetonitrile / water gradient 10:90 -> 95: 5). There were obtained 344 mg (79% of theory) of the target compound.

LC-MS (Method 6): R, = 2.90 min; MS (ESIpos): m / z = 1163 [M + H] ⁺ .

Example 17A

(2S) -3- {4- [2-Amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl (2R, 27?) - bis {2 - [(ter /.- butoxycarbonyl) amino] propanoate}

1063 g (5.618 mmol) of N- (te / γ.-butoxycarbonyl) -D-alanine were initially charged in 10 ml of DMF and treated with 448 mg (2.341 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 114 mg (0.936 mmol) of 4-NN-dimethylaminopyridine. After stirring for 5 minutes, 500 mg (0.936 mmol) of the compound from Example 8A were added and the mixture was stirred at room temperature for 2 h. The product was then isolated by preparative HPLC (acetonitrile / water gradient 10:90 → 95: 5). 676 mg (82% of theory) of the target compound were obtained.

LC-MS (Method 8): R, = 1.42 min; MS (ES Ineg): m / z = 874 [MH] ^" .

Example 18A

(? 2 /) - 3- {4- [2-amino-6 - ({[2- (4-chloφhenyl) -l, 3-oxazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridin- 4-yl] phenoxy} propan-l, 2-diyl (2S, 2 \ S) -bis {2 - [(te /-/.- butoxycarbonyl) amino] -3-methylbutanoate}

16.3 mg (0.075 mmol) of N- (tert-butoxycarbonyl) -L-valine were introduced into 10 ml of dichloromethane and successively mixed with 15.8 mg (0.082 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.5 mg (0.004 mmol) of 4-N, N-dimethylaminopyridine and 20 mg (0.037 mmol) of the compound from Example 9A. The mixture was then stirred overnight at room temperature. The product was then isolated by preparative HPLC. 24 mg (69% of theory) of the target compound were obtained.

LC-MS (method 7): R, = 3.43 min; MS (ES Ineg): m / z = 930 [MH] ^" .

Example 19A

(2R) -3- {4- [2-amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl (2S, 2'5) bis {2 - [(/ erΛ-butoxycarbonyl) amino] propanoate}

CH ₃

53 mg (0.28 mmol) of N- (tert-butoxycarbonyl) -L-alanine were introduced into 37 ml of dichloromethane and successively admixed with 59 mg (0.309 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride , 1.7 mg (0.014 mmol) of 4-N, N-dimethylaminopyridine and 75 mg (0.14 mmol) of the compound fertil from Example 9A added. Subsequently, the mixture was stirred at room temperature overnight. The mixture was then poured into a mixture of saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was separated, dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC (acetonitrile / water gradient 10:90 -> 95: 5). 77 mg (63% of theory) of the target compound were obtained.

LC-MS (Method 6): R, = 2.71 min; MS (ES Ineg): m / z = 874 [MH] ^" . Example 2OA

(2R) -3- {4- [2-amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl-bis {4 - [(/ er /.- butoxycarbonyl) butanoate amino]

57 mg (0.281 mmol) of 4 - [(tert-butoxycarbonyl) amino] butanoic acid were initially charged in 37 ml of dichloromethane and successively admixed with 59 mg (0.309 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1.7 mg (0.014 mmol) of 4-N, N-dimethylaminopyridine and 75 mg (0.14 mmol) of the compound from Example 9A were added. Subsequently, the mixture was stirred at room temperature overnight. The reaction was then poured into a mixture of saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was separated, dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC (acetonitrile / water gradient 10:90 → 95: 5). There were obtained 78 mg (61% of theory) of the target compound.

LC-MS (Method 5): R, = 1.59 min; MS (ES Ineg): m / z = 903 [MH] ^" .

Example 21A

(2S) -3- {4- [2-amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl (25 ', 2'5) -bis {2,6-bis [(/ e /-/.- butoxycarbonyl) amino] hexanoate}

649 mg (1.873 mmol) of N ² , N ⁵ -bis (te / - / - butoxycarbonyl) -L-lysine were initially charged in 200 ml of dichloromethane and successively treated with 449 mg (2.341 mmol) of 1- (3-dimethylaminopropyl) -3 Ethylcarbodiimide hydrochloride, 5.7 mg (0.047 mmol) of 4-N, N-dimethylaminopyridine and 250 mg (0.468 mmol) of the compound from Example 8A. Subsequently, the mixture was stirred at room temperature for 5 hours. The batch was then shaken twice with 10% citric acid solution and three times with 10% sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. 425 mg (76% of theory) of the target compound were obtained.

LC-MS (Method 5): R, = 1.76 min; MS (ESIpos): m / z = 1190 [M + H] ⁺ .

Example 22A

(2iS) -3- {4- [2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridine-4- yl] phenoxy} propan-l, 2-diyl-bis {4 - butanoate [(ter /.- butoxycarbonyl) amino]

342.5 mg (1.685 mmol) of 4 - [(tert.-butoxycarbonyl) amino] butanoic acid were initially introduced in 30 ml of dichloromethane and successively treated with 323 mg (1.685 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. Hydrochloride, 34 mg (0.281 mmol) of 4-N, N-dimethylaminopyridine and 300 mg (0.562 mmol) of the compound from Example 8A. Subsequently, the mixture was stirred for 2 hours at room temperature. The mixture was then diluted with 100 ml of dichloromethane and shaken out once with 10% citric acid solution and three times with 10% strength sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. 290 mg (57% of theory) of the target compound were obtained.

LC-MS (Method 7): R, = 3.18 min; MS (ESIpos): m / z = 904 [M + H] ⁺ .

Example 23A

(2 ₁ S) -3- {4- [2-amino-6 - ({[2- (4-chlorophenyl) -l, 3-oxazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridin- 4-yl] phenoxy} propan-l, 2-diyl-bis {6 - hexanoate [(tert-butoxycarbonyl) amino]

390 mg (1.685 mmol) of 6 - [(tert.-butoxycarbonyl) amino] hexanoic acid were initially charged in 30 ml of dichloromethane and successively treated with 323 mg (1.685 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 34 mg (0.281 mmol) of 4-N, N-dimethylaminopyridine and 300 mg (0.562 mmol) of the compound from Example 8A were added. Subsequently, the mixture was stirred for 1 h at room temperature. The mixture was then diluted with 100 ml of dichloromethane and shaken out once with 10% citric acid solution and three times with 10% strength sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. 279 mg (52% of theory) of the target compound were obtained.

LC-MS (method 7): R, = 3.30 min; MS (ESIpos): m / z = 960 [M + H] ⁺ .

Example 24A

(2S) -3- {4- [2-Amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl (2S, 3i, 2W, 3'R?) bis {3-re /-/.- butoxy-2 - [amino] (he .- butoxycarbonyl?) - butanoate

1.293 g (2.421 mmol) of the compound from Example 8A were initially charged in 26 ml of dichloromethane / DMF (1: 1) and, in succession, 2.00 g (7.262 mmol) of N- (tert.-butoxycarbonyl) -O-tert.-butyl -L-threonine, 1.625 g (8.474 mmol) of lP-dimethylaminopropyl O-ethylcarbodiimide hydrochloride and 59 mg (0.484 mmol) of 4-N, N-dimethylaminopyridine. The mixture was stirred at RT overnight. Thereafter, 0.667 g (2.42 mmol) of N- (tert-butoxycarbonyl) -O-tert-butyl-L-threonine were added again and the mixture was stirred at RT for a further 8 h. The reaction mixture was then diluted with water and dichloromethane and the phases separated. The aqueous phase was back-extracted twice with dichloromethane. The combined organic phases were washed once with water, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 7: 3). 2.17 g (85% of theory) of the target compound were obtained.

LC-MS (Method 6): R, = 3.29 min; MS (ES Ineg): m / z = 1047 [MH] ^" .

Example 25A

2- (4-chlorophenyl) -4,5-dimethyl-1,3-oxazole-3-oxide

1.00 g (9.89 mmol) of diacetylmonoxime and 1.53 g (10.88 mmol) of 4-chlorobenzaldehyde were initially charged in 2 ml (34.94 mmol) of glacial acetic acid. Then hydrogen chloride gas was bubbled under ice for 30 min. Cooling of the reaction mixture initiated. Subsequently, the reaction mixture was mixed with 10 ml of diethyl ether. It precipitated out a precipitate, which was filtered off and washed twice with 2 ml of diethyl ether. The precipitate was resuspended in about 5 ml of water and the suspension basified with ammonia. It was then extracted four times with 10 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and the solvent was removed on a rotary evaporator. The residue was used without further purification in the subsequent reaction.

Yield: 1.85 g (84% of theory)

LC-MS (Method 12): R, = 2.29 min; MS (ESIpos): m / z = 224 [M + H] ⁺ .

Example 26A

4- (Chlorrnethyl) -2- (4-chlorophenyl) -5-methyl-l, 3-oxazol

1.00 g (4.47 mmol) of the compound from Example 25A were initially charged in 15 ml of chloroform and 1.5 ml (16.10 mmol) of phosphoryl chloride were added carefully. The reaction mixture was heated to reflux for 30 minutes with stirring. The mixture was then cooled to 0 ⁰ C and made weakly basic by the addition of ammonia. The mixture was extracted three times with 20 ml portions of ethyl acetate. The combined organic phases were washed twice with 5 ml of water and then dried over magnesium sulfate. The solvent was removed on a rotary evaporator. The residue was used without further purification in the subsequent reaction.

Yield: 1.33 g (96% of theory, 78% purity)

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.95 (d, 2H), 7.60 (d, 2H), 4.77 (s, 2H), 2.44 (s, 3H).

Example 27A

2-amino-6 - ({[2- (4-chloφhenyl) -5-methyl-l, 3-oxazol-4-yl] methyl} sulfanyl) -4- (4 - {[(4i?) - 2, 2-dimethyl-1,3-dioxolan-4-yl] methoxy} phenyl) pyridine-3,5-dicarbonitrile

4.00 g (10.46 mmol) of the compound from Example 4A and 2.79 g (11.51 mmol) of the compound from Example 26A were suspended together with 2.64 g (31.38 mmol) of sodium bicarbonate in 50 ml of dry DMF. The reaction mixture was stirred at RT overnight. The mixture was then treated with water and stirred for 30 min further. The resulting precipitate was filtered off with suction and washed with dichloromethane / methanol (3: 1). The filtrate was concentrated and the residue was stirred with dichloromethane / methanol (3: 1). The remaining solid was filtered off with suction, combined with the previously obtained precipitate and dried. This gave 5.0 g (81% of theory) of the target compound.

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.19-7.97 (br.s, 2H), 7.94 (d, 2H), 7.58 (d, 2H), 7.49 (d, 2H), 7.12 (d, 2H), 4.51 (s, 2H), 4.48-4.41 (m, IH), 4.16-4.03 (m, 3H), 3.79 (dd, 2H), 2.46 (s, 3H), 1.37 (s, 3H ), 1.32 (s, 3H).

LC-MS (method 7): R ₁ = 3.06 min; MS (ESIpos): m / z = 588 [M + H] ⁺ .

Example 28A

2-amino-6 - ({[2- (4-chlorophenyl) -5-methyl-l, 3-oxazol-4-yl] methyl} sulfanyl) -4- (4 - {[(2 S) -2,3 -di- hydroxypropyl] oxy} phenyl) pyridine-3,5-dicarbonitrile

5.00 g (8.50 mmol) of the compound from Example 27A were initially charged in 800 ml of acetic acid and then cautiously mixed with 100 ml of water. The reaction mixture was stirred at 70 ^° C. for 1 h. After removal of the solvent on a rotary evaporator, the residue was dried under high vacuum. 4.78 g (99% of theory) of the target compound were obtained.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.27-7.96 (br.s, 2H), 7.93 (d, 2H), 7.58 (d, 2H), 7.49 (d, 2H), 7.10 (d, 2H), 5.00 (d, IH), 4.70 (t, IH), 4.51 (s, 2H), 4.09 (dd, IH), 3.96 (dd, IH), 3.84-3.78 (m, IH), 3.47 (t , 2H), 2.49 (s, 3H).

LC-MS (Method 7): R, = 2.50 min; MS (ESIpos): m / z = 548 [M + H] ⁺ .

Example 29A

(2R) -3- {4- [2-amino-6 - ({[2- (4-chloφhenyl) -5-methyl-l, 3-oxazol-4-yl] methyl} sulfanyl) -3,5- dicyanopyridin-4-yl] phenoxy} propane-1,2-diyl (2S, 2'S) -bis {2 - [(/ er / -butoxycarbonyl) amino] propanoate}

CH ₃

2.07 g (10.95 mmol) of N- (tert-butoxycarbonyl) -L-alanine were initially charged in 17.5 ml of DMF and treated successively with 910 mg (4.74 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 223 mg (1.83 mmol) of 4-N, N-dimethylaminopyridine and 1.00 g (1.83 mmol) of the compound from Example 28A were added. The mixture was stirred for 2 h at RT and then treated with water. The mixture was extracted three times with ethyl acetate, and the combined organic layers were dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. 771 mg (43% of theory) of the target compound were obtained.

LC-MS (method 5): R, = 1.65 min; MS (ES Ineg): m / z = 888 [MH] ^" .

EXAMPLES

example 1

(25) -3- {4- [2-Amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propane-l, 2-diyl (2 _> S ', 2'S) -bis (2-aminopropanoate) dihydrochloride

Into a solution of 6014 mg (6.862 mmol) of the compound from Example 1OA methane in 500 ml of dichloroethane was added over 30 min introduced hydrogen chloride gas, the temperature was kept below +20 ⁰ C. The precipitated solid was filtered off, washed with dichloromethane and diethyl ether and dried overnight under high vacuum at +80 ⁰ C. 5080 mg (99% of theory) of the target compound were obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.7 (br. S, 6H), 8.4 (s, IH), 8.0 (d, 2H), 7.60 (d, 2H), 7.50 (d, 2H), 7.15 (d, 2H), 5.5 (m, IH), 4.60-4.50 (m, 2H), 4.44 (s, 2H), 4.40 (d, 2H), 4.15 (m, 2H), 1.5-1.4 (m, 6H).

LC-MS (Method 7): R, = 1.53 min; MS (ESIpos): m / z = 676 [M + H] ⁺ .

Example 2

(2iS) -3- {4- [2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridine-4- yl] phenoxy} propane-1,2-diyl (2S, 2'S) -bis (2-aminopropanoate) bis (trifluoroacetic acid) salt

6.520 g (7.440 mmol) of the compound from Example 10A were initially charged in 45 ml of dichloromethane, treated with 5.732 ml (74.396 mmol) of trifluoroacetic acid and stirred overnight at room temperature. The reaction mixture was then concentrated and the residue was slurried twice with dichloromethane and concentrated again. The residue was then stirred with diethyl ether, the remaining solid was filtered off, washed with diethyl ether and dried under high vacuum. 4.8 g (69% of theory) of the target compound were obtained.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.42 (br.s, 4H), 8.36 (s, IH), 8.19 (m, 2H), 7.97 (d, 2H), 7.60 (d, 2H) , 7.50 (d, 2H), 7.13 (d, 2H), 5.52-5.47 (m, IH), 4.59-4.50 (m, 2H), 4.41 (s, 2H), 4.39-4.31 (m, 2H), 4.19 -4.15 (m, 2H), 1.42-1.34 (m, 6H).

LC-MS (Method 5): R. = 0.94 min; MS (ESIpos): m / z = 676 [M + H] ⁺ .

Example 3

(25) -3- {4- [2-Amino-6- ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridine-4- yl] phenoxy} propane-1,2-diylbis (aminoacetate) dihydrochloride

440 mg (0.519 mmol) of the compound from Example IA were mixed with 5 ml of a 4 M solution of hydrogen chloride gas in dioxane and stirred for two hours at room temperature. The precipitated solid was filtered off with suction and dried for 4 days at + 50 ° C in vacuo. There were obtained 300 mg (79% of theory) of the target compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.47 (br, m, 6H), 8.39 (s, IH), 8.32-8.02 (br, s, 2H), 7.97 (d, 2H), 7.61 (d, 2H), 7.50 (d, 2H), 7.14 (d, 2H), 5.51 (m, IH), 4.52 (d, 2H), 4.42 (s, 2H), 4.35 (d, 2H), 3.88 (m, 4H).

LC-MS (Method 5): R, = 0.98 min; MS (ESIpos): m / z = 648 [M + H] ⁺ .

Example 4

(2S) -3- {4- [2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridine-4- yl] phenoxy} propan-l, 2-diyl-bis (5-aminopentanoat) dihydrochloride

200 mg (0.214 mmol) of the compound from Example 12A were introduced into 1.8 ml of dichloromethane and treated dropwise with 2.2 ml of a 2 M solution of hydrogen chloride gas in diethyl ether. It was stirred for one hour at room temperature and the precipitated solid was then filtered off. This was washed with dichloromethane and dried in vacuo. 137 mg (79% of theory) of the target compound were obtained.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.39 (s, IH), 8.35-8.02 (br, s, 2H), 7.97 (d, 2H), 7.93 (br, m, 6H), 7.61 ( d, 2H), 7.49 (d, 2H), 7.13 (d, 2H), 5.36 (m, IH), 4.42 (s, 2H), 4.40 (d, 2H), 4.37 (d, 2H), 2.77 (m , 4H), 2.38 (m, 4H), 1.57 (m, 8H).

LC-MS (Method 6): R, = 1.20 min; MS (ESIpos): m / z = 732 [M + H] ⁺ .

Example 5

(2S) -3- {4- [2-Amino-6- ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridine-4- yl] phenoxy} propan-l, 2-diyl (2S, 2 \ S) -bis (2,5-diaminopentanoat) tetrakis (trifluoroacetic acid) salt

276 mg (0.237 mmol) of the compound from Example 13A were introduced into 2 ml of dichloromethane and treated dropwise with 2.2 ml of a 2 M solution of hydrogen chloride gas in diethyl ether. It was stirred for one hour at room temperature and the precipitated solid was then filtered off. This was washed with dichloromethane and then purified by preparative HPLC (eluent: acetonitrile / water + 0.1% trifluoroacetic acid). There were obtained 96 mg (33% of theory) of the target compound. ¹ H NMR (400 MHz, DMSO- (I ₆ ): δ = 8.56 (br, m, 6H), 8.37 (s, IH), 8.26-8.06 (br, s, 2H), 7.97 (d, 2H) , 7.87 (br, m, 6H), 7.61 (d, 2H), 7.51 (d, 2H), 7.13 (d, 2H), 5.47 (m, IH), 4.54 (dd, IH), 4.47-4.30 (m , 5H), 4.16 (br, m, 2H), 2.81 (br, m, 4H), 1.93-1.55 (m, 8H).

LC-MS (method 7): R, = 1.31 min; MS (ESIpos): m / z = 762 [M + H] ⁺ .

Example 6

(25) -3- {4- [2-Amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl (2S, 2 \ S) -bis (2,4-diaminobutanoat) tetrakis (trifluoroacetic acid) salt

255 mg (0.225 mmol) of the compound from Example 14A were initially charged in 2 ml of dichloromethane and treated dropwise with 2.3 ml of a 2 M solution of hydrogen chloride gas in diethyl ether. It was stirred for one hour at room temperature and the precipitated solid was then filtered off. This was washed with dichloromethane and then purified by preparative HPLC (eluent: acetonitrile / water + 0.1% trifluoroacetic acid). There were obtained 44 mg (21% of theory) of the target compound.

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 8.66 (br, m, 6H), 8.37 (s, IH), 8.32-8.12 (br, s, 2H), 8.00 (br, m, 6H), 7.97 (d, 2H), 7.61 (d, 2H), 7.51 (d, 2H), 7.13 (d, 2H), 5.49 (m, IH), 4.54 (dd, IH), 4.49 (dd, IH), 4.42 (s, 2H), 4.40-4.23 (m, 4H), 3.00 (m, 4H), 2.18 (m, 2H), 2.09 (m, 2H).

LC-MS (Method 6): R, = 0.88 min; MS (ESIpos): m / z = 734 [M + H] ⁺ . Example 7

(2S) -3- {4- [2-Amino-6- ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridine-4- yl] phenoxy} propan-l, 2-diyl-bis (3-aminopropanoate) dihydrochloride

123 mg (0.140 mmol) of the compound from Example 15A were initially charged in 2 ml of dichloromethane and admixed with 1.4 ml (2.807 mmol) of a 2 M solution of hydrogen chloride gas in diethyl ether. After stirring for 1 h, the precipitated solid was filtered off, washed with dichloromethane and diethyl ether and dried in vacuo. 79 mg (75% of theory) of the target compound were obtained.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.38 (s, IH), 8.34-8.12 (br, s, 2H), 8.03 (br, m, 6H), 7.97 (d, 2H), 7.61 ( d, 2H), 7.49 (d, 2H), 7.14 (d, 2H), 5.40 (m, IH), 4.42 (s, 2H), 4.41-4.29 (m, 4H), 3.04 (br, m, 4H) , 2.75 (br. M, 4H).

LC-MS (Method 6): R, = 1.17 min; MS (ESIpos): m / z = 676 [M + H] ⁺ .

Example 8

(2R) -3- {4- [2-amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl (2S, 2 \ S) -bis (2,5-diaminopentanoat) -Tetrahydrochlorid

233 mg (0.201 mmol) of the compound from Example 16A were introduced into 1.9 ml of dichloromethane and treated dropwise with 2.01 ml (4.015 mmol) of a 2 M solution of hydrogen chloride gas in diethyl ether. It was stirred overnight at room temperature and then the solvent was removed on a rotary evaporator. The residue was added twice in succession with dichloromethane and the solvent was removed again in vacuo. The crude product was dissolved in 2 ml of water and lyophilized. 165 mg (91% of theory) of the target compound were obtained.

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 8.82 (br, m, 6H), 8.40 (s, IH), 8.15 (br, m, 8H), 7.98 (d, 2H), 7.61 (d, 2H), 7.50 (d, 2H), 7.19 (d, 2H), 5.53 (m, IH), 4.53 (d, 2H), 4.45-4.41 (m, 4H), 4.19 (m, 2H), 2.81 (m , 4H), 2.03-1.64 (m, 8H).

LC-MS (Method 5): R, = 0.73 min; MS (ESIpos): m / z = 762 [M + H] ⁺ .

Example 9

(2iy) -3- {4- [2-amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propane-1,2-diyl (2 /,, 27)) bis (2-aminopropanoate) dihydrochloride

675 mg (0.770 mmol) of the compound from Example 17A were initially charged in 8 ml of dichloromethane and admixed with 15.4 ml of a 1 M solution of hydrogen chloride gas in diethyl ether. After stirring for 4 h, the precipitated solid was filtered off with suction, washed with dichloromethane and diethyl ether and dried in vacuo. 577 mg (quant.) Of the target compound were obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 8.55 (br, m, 6H), 8.38 (s, IH), 8.33-8.02 (br, s, 2H), 7.97 (d, 2H), 7.61 (d, 2H), 7.50 (d, 2H), 7.13 (d, 2H), 5.51 (m, IH), 4.56-4.44 (m, 2H), 4.42 (s, 2H), 4.39-4.33 (m, 2H), 4.16 (m, 2H), 1.44 (d, 3H), 1.39 (d, 3H).

LC-MS (Method 8): R, = 0.87 min; MS (ESIpos): m / z = 676 [M + H] ⁺ .

Example 10

(2R) -3- {4- [2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridine-4- yl] phenoxy} propan-l, 2-diyl (2S, 2'5) -bis (2-amino-3-methylbutanoate) dihydrochloride

H ₃ C ^ CH ₃

A solution of 48 mg (0.051 mmol) of the compound from Example 18A in 1 ml of dichloromethane was admixed with 20 ml of a saturated solution of hydrogen chloride gas in dichloromethane and stirred at RT for 2 h. Thereafter, the mixture was concentrated and the residue was stirred with diethyl ether. The remaining solid was filtered off, washed with dichloromethane and diethyl ether and dried overnight under high vacuum at +80 ⁰ C. 28 mg (65% of theory) of the target compound were obtained.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.75-8.6 (br. S, 6H), 8.4 (s, IH), 7.96 (d, 2H), 7.60 (d, 2H), 7.50 (d, 2H), 7.1 (d, 2H), 5.6 (m, IH), 4.53 (d, 2H), 4.50-4.35 (m, 4H), 4.1-3.9 (m, 2H), 2.2 (m, 2H), 1.05 -0.95 (m, 6H).

LC-MS (method 7): R. = 1.62 min; MS (ESIpos): m / z = 732 [M + H] ⁺ .

Example 11

(2i?) - 3- {4- [2-amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl (2IS, 2'S) -bis (2-aminopropanoate) dihydrochloride

1090 mg (1.244 mmol) of the compound from Example 19A were treated with 125 ml of a saturated solution of hydrogen chloride gas in dichloromethane and treated for 2 h in an ultrasonic bath. Thereafter, the mixture was concentrated and the residue was stirred with diethyl ether. The remain- bene solid was filtered off, washed twice with diethyl ether and dried overnight under high vacuum at +80 ⁰ C. 770 mg (79% of theory) of the target compound were obtained.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.7-8.5 (br s, 6H), 8.35 (s, IH), 8.45 (d, 2H), 7.6 (d, 2H), 7.5 (d, 2H), 7.13 (d, 2H), 5.5 (m, IH), 4.59-4.30 (m, 6H), 1.45 (d, 3H), 1.40 (d, 3H).

LC-MS (Method 5): R, = 0.99 min; MS (ESIpos): m / z = 676 [M + H] ⁺ .

Example 12

(2R) -3- {4- [2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridine-4- yl] phenoxy} propane-1,2-diylbis (4-aminobutanoate) dihydrochloride

70 mg (0.077 mmol) of the compound from Example 2OA were mixed with 10 ml of a saturated solution of hydrogen chloride gas in dichloromethane and treated for 2 h in an ultrasonic bath. Thereafter, the mixture was concentrated and the residue was stirred with diethyl ether. The remaining solid was filtered off, washed twice with diethyl ether and dried overnight under high vacuum at +80 ⁰ C. 47 mg (75% of theory) of the target compound were obtained.

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.4 (s, IH), 8.1-8.0 (br, s, 6H), 7.95 (d, 2H), 7.6 (d, 2H), 7.45 (d, 2H), 7.1 (d, 2H), 5.4 (m, IH), 4.45-4.25 (m, 6H), 2.9-2.8 (m, 4H), 2.5-2.4 (m, 4H), 1.9-1.8 (m, 4H).

LC-MS (method 7): R, = 1.47 min; MS (ESIpos): m / z = 704 [M + H] ⁺ .

Example 13

(2S) -3- {4- [2-Amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl (2S, 2'S) -bis (2,6-diaminohexanoat) dihydrochloride

m a solution of 425 mg (0.357 mmol) methane of the compound from Example 21A in 200 ml of dichloroethane was added over 1 h of hydrogen chloride gas is introduced, the temperature was kept below +20 ⁰ C. The mixture was then stirred for 2 h at RT. It was then concentrated in vacuo and the remaining residue was taken up in 200 ml of water. It was extracted twice each with dichloromethane and ethyl acetate. The aqueous phase was filtered and then concentrated in vacuo to half of its volume. After lyophilization of the solution, 277 mg (83% of theory) of the target compound were obtained. ¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.9-8.7 (m, 6H), 8.38 (s, IH), 8.2-8.0 (m, 6H), 7.9 (d, 2H), 7.6 (d, 2H), 7.48 (d, 2H), 7.15 (d, 2H), 5.5 (m, IH), 4.6-4.4 (m, 6H), 4.1-4.0 (m, 2H), 2.8-2.7 (m , 4H), 1.9-1.8 (m, 4H), 1.7-1.4 (m, 8H).

LC-MS (Method 7): R, = 1.01 min; MS (ESIpos): m / z = 790 [M + H] ⁺ .

Example 14

(2ιS) -3- {4- [2-amino-6 - ({[2- (4-chlorophenyl) -1,3-oxazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridine-4- yl] phenoxy} propane-1,2-diylbis (4-aminobutanoate) dihydrochloride

In a solution of 290 mg (0.321 mmol) methane of the compound from Example 22A in 500 ml of dichloroethane was added over 1 h of hydrogen chloride gas is introduced, the temperature was kept below +20 ⁰ C. Subsequently, the mixture was stirred for a further 6 h at RT. It was then concentrated in vacuo. The residue was taken up in 10 ml of acetonitrile / water (1: 5) and purified by preparative HPLC. The product fractions were combined and concentrated. The residue was taken up in hydrochloric acid, which had been adjusted to pH 3, and the solution was subsequently lyophilized. 90 mg (36% of theory) of the target compound were obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.38 (s, IH), 8.0 (br, s, 6H), 7.95 (d, 2H), 7.6 (d, 2H), 7.45 (d, 2H), 7.1 (d, 2H), 5.38 (m, IH), 4.45-4.25 (m, 6H), 2.85-2.75 (m, 4H), 1.9-1.8 (m, 4H).

LC-MS (method 7): R ₁ = 1.51 min; MS (ESIpos): m / z = 704 [M + H] ⁺ .

Example 15

(2S) -3- {4- [2-Amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propane-1, 2-diyl-bis (6-aminohexanoate) dihydrochloride

In a solution of 275 mg (0.286 mmol) of the compound from Example 23A in 500 ml of dichloromethane, hydrogen chloride gas was passed in over 1 h, the temperature being kept below + 2O ⁰ C. Subsequently, the mixture was stirred for a further 6 h at RT. It was then concentrated in vacuo. The residue was taken up in 10 ml of acetonitrile / water (1: 5) and purified by preparative HPLC. The product fractions were combined and concentrated. The residue was taken up in hydrochloric acid adjusted to pH 3, and the solution was then lyophilized. 187 mg (78% of theory) of the target compound were obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.4 (s, IH), 7.95 (d, 2H), 7.9-7.7 (br, s, 6H), 7.6 (d, 2H), 7.45 ( d, 2H), 7.1 (d, 2H), 5.35 (m, IH), 4.45-4.2 (m, 6H), 2.8-2.7 (m, 4H), 2.32 (t, 4H), 1.6-1.5 (m, 8H), 1.35-1.25 (m, 4H).

LC-MS (Method 7): R, = 1.58 min; MS (ESIpos): m / z = 760 [M + H] ⁺ .

Example 16

(2S) -3- {4- [2-amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propan-l, 2-diyl (25 ', 2'5) -bis (2-amino-3-methylbutanoate) bis (trifluoroacetic acid) salt H ₃ C ^ CH ₃

400 mg (0.75 mmol) of the compound from Example 8A, 651 mg (3 mmol) of N-Boc-L-valine, 718 mg (3.745 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 91.5 mg (0.75 mmol) of 4-N, N-dimethylaminopyridine were combined under argon in 40 ml of dichloromethane and treated in an ultrasonic bath for 30 min. The mixture was then shaken out four times with 20 ml of 50% strength sodium bicarbonate solution and then four times with 20 ml of 0.5 M citric acid solution each time. The organic phase was dried over magnesium sulfate and concentrated. The residue was stirred with cyclohexane and the remaining solid was filtered off with suction. This was dissolved in dichloromethane and reprecipitated with cyclohexane. The precipitate was again filtered off with suction and dried in vacuo. There were obtained 801 mg of the Boc-protected intermediate.

This intermediate was taken up in 70 ml of dichloromethane, treated dropwise with 7 ml of anhydrous trifluoroacetic acid and stirred at RT for 30 min. Thereafter, the mixture was concentrated in a high vacuum. The residue was stirred with methyl tert-butyl ether, the solid was filtered off with suction and then recrystallised from hot isopropanol. After again vacuuming off and drying the filter residue in a high vacuum, 360 mg (47% of theory) of the title compound were obtained.

LC-MS (Method 6): R, = 1.24 min; MS (ESIpos): m / z = 732 [M + H] ⁺ .

Example 17

(2 ₁ S) -3- {4- [2-amino-6 - ({[2- (4-chloφhenyl) -l, 3-oxazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridin- 4-yl] phenoxy} propane-1,2-diyl- (2S, 2S) -bis (2-amino-4-methylpentanoate) -bis (trifluoroacetic acid) salt

400 mg (0.75 mmol) of the compound from Example 8A, 693 mg (3 mmol) of N-Boc-L-leucine, 718 mg (3.745 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 91.5 mg (0.75 mmol) of 4-N, N-dimethylaminopyridine were combined under argon in 40 ml of dichloromethane and treated in an ultrasonic bath for 30 min. The mixture was then extracted by shaking five times with 20 ml each of 0.5 M citric acid solution and then five times with 20 ml each of 50% strength sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated. The residue was taken up in dichloromethane and precipitated with cyclohexane. The precipitate was filtered off with suction and dried in vacuo. 715 mg of the Boc-protected intermediate were obtained.

This intermediate was taken up in 70 ml of dichloromethane, treated dropwise with 7 ml of anhydrous trifluoroacetic acid and stirred at RT for 75 min. Thereafter, the mixture was concentrated in a high vacuum. The residue was stirred for 2 days in 50 ml of methyl tert-butyl ether, the solid was then filtered off with suction and then recrystallized from hot isopropanol. After renewed aspiration and drying of the filter residue in a high vacuum, 512 mg (69% of theory) of the title compound were obtained.

LC-MS (Method 5): R, = 1.08 min; MS (ESIpos): m / z = 760 [M + H] ⁺ .

Example 18

(2iS) -3- {4- [2-amino-6 - ({[2- (4-chloro-phenyl) -l, 3-oxazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridine-4 yl] phenoxy} propane-l, 2-diyl (2S, 3 /,, 2'S, 3'A) -bis (2-amino-3-hydroxybutanoate) bis (trifluoroacetic acid) salt

916 mg (0.873 mmol) of the compound from Example 24A were initially charged in 10 ml of dichloromethane, treated with 1.35 ml (17.47 mmol) of trifluoroacetic acid and stirred overnight at room temperature. The reaction mixture was then concentrated and the residue was purified by preparative HPLC (eluent: acetonitrile / water + 0.1% trifluoroacetic acid). 574 mg (68% of theory) of the target compound were obtained.

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 8.42-8.25 (m, 5H), 8.15 (br, s, 2H), 7.98 (d, 2H), 7.61 (d, 2H), 7.51 (d, 2H), 7.12 (d, 2H), 5.68 (br s, IH), 5.50 (quint, IH), 4.50 (d, 2H), 4.42 (s, 2H), 4.38-4.32 (m, 2H), 4.24 -3.95 (m, 5H), 1.24-1.18 (m, 6H).

LC-MS (method 7): R. = 1.45 min; MS (ESIpos): m / z = 736 [M + H] ⁺ .

Example 19

(2Λ) -3- {4- [2-amino-6 - ({[2- (4-chloφhenyl) -5-methyl-l, 3-oxazol-4-yl] methyl} sulfanyl) -3,5- di-cyanopyridin-4-yl] phenoxy} propane-1,2-diyl- (2 ₁ S ', 2'S) -bis (2-aminopropanoate) dihydrochloride

CH ₃

3.1 g (3.48 mmol) of the compound from Example 29A were initially charged in 32 ml of dichloromethane and treated dropwise with 17 ml of a 2 M solution of hydrogen chloride gas in diethyl ether. The mixture was stirred at room temperature for six hours. The precipitated solid was filtered off, washed with dichloromethane and dried in vacuo. 2.65 g (98% of theory) of the title compound were obtained.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.80-8.50 (m, 6H), 8.10 (br, s, 2H), 7.92 (d, 2H), 7.59 (d, 2H), 7.51 (d, 2H), 7.14 (d, 2H), 5.56-5.48 (m, IH), 4.58-4.32 (m, 6H), 4.22-4.09 (m, 2H), 2.55 (s, 3H), 1.45 (d, 3H) , 1.41 (d, 3H).

LC-MS (method 7): R, = 1.73 min; MS (ESIpos): m / z = 690 [M + H] ⁺ .

B. Determination of solubility. Stability and release behavior

a) Determination of solubility;

The test substance is suspended in water or dilute hydrochloric acid (pH 4) or in 5% aqueous dextrose solution. This suspension is shaken for 24 h at room temperature. After ultra-centrifugation at 224000g for 30 min, the supernatant is diluted with DMSO and analyzed by HPLC. Quantification is via a two-point calibration curve of the test compound in DMSO.

HPLC method for acids:

Agilent 1100 with DAD (G1315A), quat. Pump (Gl 31 IA), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: Phenomenex Gemini C18, 5 μm, 50 mm x 2 mm; Temperature: 40 ^° C .; Eluent A: water / phosphoric acid pH 2, eluent B: acetonitrile; Flow rate: 0.7 ml / min; Gradient: 0-0.5 min 85% A, 15% B; Ramp 0.5-3 min 10% A, 90% B; 3-3.5 min 10% A, 90% B; Ramp 3.5-4 min 85% A, 15% B; 4-5 minutes 85% A, 15% B.

HPLC method for bases:

Agilent 1100 with DAD (G 1315 A), quat. Pump (G 1311 A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: VDSoptilab Kromasil 100 C18, 3.5 μm, 60 mm x 2.1 mm; Temperature: 30 ^° C .; Eluent A: water + 5 ml perchloric acid / liter, eluent B: acetonitrile; Flow rate: 0.75 ml / min; Gradient: 0-0.5 min 98% A, 2% B; Ramp 0.5-4.5 min 10% A, 90% B; 4.5-6 min 10% A, 90% B; Ramp 6.5-6.7 min 98% A, 2% B; 6.7-7.5 min 98% A, 2% B.

Table 1 shows the solubility values of representative embodiments in dilute hydrochloric acid (pH 4):

Table 1

Table 2 shows the solubility values of representative embodiments in 5% aqueous dextrose solution: Table 2

Decomposition of the exemplified compounds in these solutions was not observed.

The solubility of the active substance from Example 8A was determined to be <0.1 mg / liter in 0.1 M hydrochloric acid and <1.2 mg / liter in 5% strength aqueous dextrose solution.

b) Stability in buffer at different pH values:

Weigh 0.3 mg of the test substance in a 2 ml HPLC vial and add 0.5 ml of acetonitrile or acetonitrile / DMSO (9: 1). To dissolve the substance, the sample vessel is placed in the ultrasonic bath for approx. 10 seconds. Subsequently, 0.5 ml of the respective (buffer) solution is added and the sample is again treated in an ultrasonic bath.

Used (buffer) solutions:

pH 4: 1 liter of Millipore water is adjusted to pH 4.0 with 1 N hydrochloric acid;

pH 5: 0.096 mol of citric acid and 0.2 mol of sodium hydroxide ad 1 liter of water;

pH 7.4: 90.0 g of sodium chloride, 13.61 g of potassium dihydrogen phosphate and 83.35 g of 1 N sodium hydroxide ad 1 liter of water; this solution is then further diluted 1:10 with Millipore water;

pH 8: 0.013 mol of borax and 0.021 mol of hydrochloric acid ad 1 liter of water. Over a period of 24 hours at 37 ° C., 5 .mu.l each of the sample solution are analyzed per hour by HPLC for their content of unchanged test substance or on the parent compound of the formula (A). Quantification is made by the area percent of the corresponding peaks.

HPLC method for Example 1:

Agilent 1100 with DAD (G1315B), binary pump (G1312A), autosampler (G1329A), column oven (G1316A), thermostat (G1330B); Column: Kromasil 100 C18, 125 mm x 4 mm, 5 μm; Column temperature: 30 ^° C .; Eluent A: water + 5 ml perchloric acid / liter, eluent B: acetonitrile; Gradient: 0 min 90% A → 2.0 min 70% A → 18.0 min 70% A → 20.0 min 10% A → 21.0 min 10% A → 23.0 min 90% A → 26.0 min 90% A; Flow rate: 2.0 ml / min; UV detection: 294 nm.

HPLC method for Example 3:

Agilent 1100 with DAD (Gl 314A), binary pump (GI 312A), autosampler (G 1329A), column oven (G1316A), thermostat (G1330A); Column: Kromasil 100 C18, 125 mm x 4 mm, 5 μm; Column temperature: 30 ^° C .; Eluent A: water + 5 ml perchloric acid / liter, eluent B: acetonitrile; Gradient: 0 min 90% A → 2.0 min 64% A → 18.0 min 64% A → 20.0 min 10% A → 21.0 min 10% A → 23.0 min 90% A → 26.0 min 90% A; Flow rate: 2.0 ml / min; UV detection: 294 nm.

HPLC method for Example 11:

Agilent 1100 with DAD (G1315B), binary pump (G1312A), autosampler (G1329A), column oven (G1316A), thermostat (G1330B); Column: Kromasil 100 C18, 125 mm x 4 mm, 5 μm; Column temperature: 30 ^° C .; Eluent A: water + 5 ml perchloric acid / liter, eluent B: acetonitrile; Gradient: 0 min 90% A → 2.0 min 64% A → 18.0 min 64% A → 20.0 min 10% A → 21.0 min 10% A → 23.0 min 90% A → 26.0 min 90% A; Flow rate: 2.0 ml / min; UV detection: 294 nm.

HPLC method for Example 14:

Agilent 1100 with DAD (G1315B), binary pump (G1312A), autosampler (G1329A), column oven (G1316A), thermostat (G1330B); Column: Kromasil 100 C18, 250 mm × 4 mm, 5 μm; Column temperature: 30 ^° C; Eluent A: water + 5 ml perchloric acid / liter, eluent B: acetonitrile; Gradient: 0 min 90% A → 7.0 min 52% A → 18.0 min 52% A → 20.0 min 10% A → 21.0 min 10% A → 23.0 min 90% A → 26.0 min 90% A; Flow rate: 2.0 ml / min; UV detection: 288 nm.

HPLC method for Example 18:

Agilent 1100 with DAD (G1315A), binary pump (G1312A), autosampler (G1329A), column oven (G1316A), thermostat (G1330A); Column: Kromasil 100 C18, 125 mm x 4 mm, 5 μm; Columns- temperature: 30 ^° C .; Eluent A: water + 5 ml perchloric acid / liter, eluent B: acetonitrile; Gradient: 0 min 90% A → 6.0 min 61% A → 18.0 min 61% A → 20.0 min 10% A → 21.0 min 10% A → 23.0 min 90% A → 26.0 min 90% A; Flow rate: 2.0 ml / min; UV detection: 294 nm.

Table 3 shows representative ratios of the peak areas (F) at the respective times in relation to the peak areas at the start time:

Table 3

In this test, an increase in the active compound compound of Example 8A or 9A was found simultaneously with a decrease in the content of the test substance.

c) In v / Vro stability in rat and human plasma;

Weigh 1 mg of the test substance in a 2 ml HPLC vial and add 1.5 ml of DMSO and 1 ml of water. To dissolve the substance, the sample vessel is placed in the ultrasonic bath for approx. 10 seconds. To 0.5 ml of this solution 0.5 ml 37 ° C warm rat or human plasma are given. The sample is shaken and taken for a first analysis about 10 .mu.l (time to). In the period up to 2 hours after the start of incubation, 4-6 additional aliquots are added Quantification taken. The sample is kept at 37 ° C over the test time. Characterization and quantification are by HPLC.

HPLC method:

Agilent 1100 with DAD (G1314A), binary pump (G1312A), autosampler (G1329A), column oven (G1316A), thermostat (G1330A); Column: Kromasil 100 C18, 250 mm × 4 mm, 5 μm; Column temperature: 30 ^° C .; Eluent A: water + 5 ml perchloric acid / liter, eluent B: acetonitrile; Gradient: 0- 8.0 min 53% A, 47% B; 8.0-18.0 min 53% A, 47% B; 18.0-20.0 min 90% A, 10% B; 20.0-21.0 min 90% A, 10% B; 21.0-22.5 min 98% A, 2% B; 22.5-25.0 min 98% A, 2% B; Flow rate: 2 ml / min; UV detection: 294 nm.

In Table 4, the respective times are given for representative embodiments in which after incubation with rat plasma 50% of the maximum possible amount of active ingredient compound (Example 8A or 9A) have arisen (tso _{% A} ) - Peak areas at the individual times compared to the start time used.

Table 4

d) IV pharmacokinetics in Wistar rats:

On the day before administration of the substance to the experimental animals (male Wistar rats, body weight 200-250 g) is implanted, a catheter for blood collection into the jugular vein under isoflurane im- ^® narcosis. On the day of the test, a defined dose of the test substance is administered as a solution with a Hamilton ^® glass syringe into the tail vein (bolus administration, application time <10 s). Within 24 hours of substance administration, blood samples (8-12 times) are taken sequentially across the catheter. For plasma collection, the samples are centrifuged in heparinized tubes. At each point in time, a defined plasma volume for protein precipitation is mixed with acetonitrile. After centrifugation, test substance and optionally known cleavage products of the test substance are quantitatively determined in the supernatant with a suitable LC / MS-MS method.

The pharmacokinetic parameters of the test substance or of the active substance compound (A) released therefrom, such as AUC, C _m3x , T _1/2 (half-life) and CL (clearance), are calculated from the measured plasma concentrations.

After i.v. application of the compound of Example 1, the substance could no longer be detected in the plasma at the first measurement point. Only the active ingredient (Example 8A) was also detectable until the time of 8 hours.

e) Hamodevnamische measurements on anesthetized rats:

Wistar rats (250-300 g body weight; Fa. Harlan- Winkelmann) are anesthetized with 5% isoflurane ^®. The anesthesia is maintained with 2% Isoflurane ^® and compressed air in an anesthesia mask. The carotid artery is dissected free and a tip catheter (Miliar micro-tip transducer, 2 French, HSE) is inserted and advanced into the left ventricle. Subsequently, a second catheter is inserted into the jugular vein. Placebo solution and test substance solutions are infused into the animals in ascending concentration via this catheter. At the same time, cardiac function (such as heart rate, left ventricular pressure, contractility (dp / dt), left ventricular end-diastolic pressure) is measured through the left ventricular catheter. By withdrawing the catheter from the left ventricle into the aorta, the systemic blood pressure can also be measured.

C. Embodiments of Pharmaceutical Compositions

The compounds according to the invention can be converted, for example, into pharmaceutical preparations as follows:

Tablet:

Composition:

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

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of the compound according to the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 mg of the inventive compound, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.

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

production:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h. Orally administrable solution:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention corresponds to 20 g of oral solution.

production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.

iv solution:

The compound according to the invention is dissolved in a concentration below the saturation solubility in a physiologically tolerated solvent (for example isotonic saline solution, glucose solution 5% and / or PEG 400 solution 30%, which are each adjusted to a pH of 3-5) , The solution is optionally filtered sterile and / or filled into sterile and pyrogen-free injection containers.

Claims

claims

1. Compound of formula (I)

in which

R is hydrogen or methyl

and

R is a group of the formula

stands in which

# means the point of attachment to the respective O atom,

L ^{1 is} a bond or -CH ₂ -,

L ^{2 is} straight-chain (C ₃ -C ₆ ) -alkanediyl which may be monosubstituted, identically or differently, by (C ₁ -C ₄ ) -alkyl, hydroxyl and / or (C 1 -C ₄ ) -alkoxy,

R ¹ and R ² are the same or different and are independently hydrogen or (Ci-C ₄₎ alkyl substituted with hydroxy, (Ci-C ₄₎ -alkoxy, amino, mono- (C _r C ₄₎ alkylamino or di - (Ci-C ₄ ) -alkylamino may be substituted mean or

R ¹ and R ² are linked to one another and together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocycle which contains a further ring heteroatom from the series N and O and one or two times, identical or different, with (C 1 -C ₄ ) -alkyl,

Amino, hydroxy and / or (Ci-Gι) alkoxy can be substituted,

or

R ^{3 is} linked to R ¹ and both together with the atoms to which they are attached form a 5- or 6-membered saturated heterocycle which is mono- or disubstituted, identical or different, with (Ci-G) -alkyl , Amino, hydroxy and / or (C 1 -C ₄ ) -alkoxy may be substituted,

R ^{4 is} hydrogen or methyl

or

and

R ⁵ and R ⁶ are identical or different and are independently hydrogen or (Ci-C ₄₎ alkyl substituted with hydroxy, (C _r _C4) alkoxy, amino, mono- (C _r C ₄₎ alkylamino or di - (C _r _C4) alkylamino may be substituted,

and their salts, solvates and solvates of the salts.

A compound of the formula (I) according to claim 1, in which

R ^{A is} hydrogen or methyl

and R ^{PD is} a group of the formula

stands in which

# means the point of attachment to the respective O atom,

L ^{1 is} a bond or -CH ₂ -,

L ² denotes straight-chain (C ₃ -C ₆ ) -alkanediyl,

R ¹ and R ² independently of one another denote hydrogen or methyl,

R ^{3 is} hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, benzyl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl,

2-aminoethyl, aminomethyl or 3-guanidino-propan-1-yl

or

R ^{4 is} hydrogen

and

R ⁵ and R ⁶ independently of one another denote hydrogen or methyl,

and their salts, solvates and solvates of the salts.

3. A compound of the formula (I) according to claim 1 or 2, in which

R ^{A is} hydrogen

and

R ^{PD is} a group of the formula stands in which

# means the point of attachment to the respective O atom,

L ^{1 means} a bond

L ² denotes straight-chain (C ₃ -C ₅ ) -alkanediyl,

R ¹ and R ^{2 are} each hydrogen,

R ^{3 is} hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, hydroxymethyl, 1-hydroxyethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 2-aminoethyl, aminomethyl or 3- Guanidinopropan-1-yl,

R ^{4 is} hydrogen

and

R ⁵ and R ^{6 are} each hydrogen,

and their salts, solvates and solvates of the salts.

4. A compound of formula (I) according to claim 1, 2 or 3, in which the two groups R ^{PD are} identical, and their salts, solvates and solvates of the salts.

5. A compound according to claim 1, 2, 3 or 4 having the formula (I-A)

(IA) and their salts, solvates and solvates of the salts.

6. A process for the preparation of compounds of formula (I) as defined in claims 1 to 5, in which the two groups R ^{PD are} each identical, characterized in that

[A] the compound of the formula (A)

in which

R ^{A is} hydrogen or methyl,

in an inert solvent with two or more equivalents of a compound of formula (II)

in which L ¹ , R ³ and R ^{4 have} the meanings given in claims 1 to 5

and

R ^1a and R ^{2a are the} same or different and have the meanings given in claims 1 to 5 of R ¹ or R ² or stand for a temporary amino-protecting group, with activation of the carboxyl group in (E) to give a compound of the formula (ffl)

in which L ¹ , R ⁶ , R ^1a , R ^2a , R ³ and R ^{4 have} the meanings given above,

wherein L ^1, R ^Λ, R ^1, R ^2, R ³ and R ⁴ have the meanings given in claims 1 to 5, away

respectively

[B] the compound of the formula (A) in an inert solvent with two or more equivalents of a compound of the formula (IV)

in which L ^{2 has} the meaning given in claims 1 to 5

and

R ^5a and R ^{6a are} identical or different and have the meanings given in claims 1 to 5 of R ⁵ or R ⁶ or stand for a temporary amino-protecting group,

activating the carboxyl group in (FV) to give a compound of the formula (V)

in which L, R, R ^a and R have the meanings given above,

in which L ² , R ^A , R ⁵ and R ^{6 have} the meanings given in claims 1 to 5,

away

and optionally converting the resulting compounds of the formula (I-C) or (I-D) with the corresponding (i) solvents and / or (ii) acids or bases into their solvates, salts and / or solvates of the salts.

7. A compound as defined in any one of claims 1 to 5, for the treatment and / or prophylaxis of diseases.

8. A compound as defined in any one of claims 1 to 5 for use in a method for the treatment and / or prophylaxis of cardiovascular diseases.

9. Use of a compound as defined in any one of claims 1 to 5, for the manufacture of a medicament for the treatment and / or prophylaxis of cardiovascular diseases.

10. A medicament containing a compound as defined in any one of claims 1 to 5, optionally in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

11. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 5, in combination with one or more further active ingredients.

12. Medicament according to claim 10 or 11 for the treatment and / or prophylaxis of cardiovascular diseases.

13. A method for the treatment and / or prophylaxis of cardiovascular diseases in humans and animals using at least one compound as defined in any one of claims 1 to 5, or a pharmaceutical composition as defined in any one of claims 10 to 12.