DE10061541A1 - New arylamino-substituted dihydropyrimidinone derivatives, useful as broad-spectrum antibacterial agents with strong activity against Gram positive bacteria - Google Patents

Abstract

5-(Diaminoalkanoylamino)-3,4,5,6-tetrahydro-2-((hetero)aryl-amino)-pyr imidin-4-one derivatives (I) are new. Dihydropyrimidinones of formula (I) and their salts, solvates, hydrates and hydrated salts are new. R1 = H or T; A = -NR4R5, -NR5-C(Q)-NR6R7 or -N(R5)-C(R8)=NR9; R4 - R7, R9 = H, T, COT, benzyl or pyridylmethyl; R8 = H or T; Q = O, S or NR9; D = 2-6C alkanediyl (optionally substituted by 1 or 2 of OH, OT, OCOT or =O); E = direct bond or CH2; R2 = H or T; R3 = 6-10C aryl or Het (both optionally substituted by 1-3 of T, halo, CF3, COOT, COOH, CONH2, Ph, NHPh, CONHT and/or CONT2; T = 1-6C alkyl; Het = 5-10 membered mono- or bicyclic, partially unsaturated or aromatic heterocycle, containing 1-3 of N, O and/or S as heteroatom(s). An Independent claim is included for the preparation of (I).

Description

The present invention relates to new arylamino-substituted dihydropyrimines dinon derivatives, a process for their preparation, pharmaceutical comprising them Compositions and their use in the treatment of diseases in humans or animals.

EP-A-0339596 discloses antibiotics of the formula

obtained by cultivating a microorganism belonging to the genus Flexibacter will.

The following compounds are also specifically described there

in which the A carbon atom has the S configuration (TAN-1057A) or the R configuration (TAN-1057B). Y. Funabashi et al., Tetrahedron 49, 13, 1993 describe the chemical and structural characterization of TAN-1057A and TAN-1057B. N. Katayama et al., J. Antibiotics 46, 606, 1993 report on the taxonomy of the TAN-1057-producing organisms and the biological properties of the TAN-1057. Total syntheses of the TAN-1057 compounds have been reported by C. Yuan and RM Williams in J. Am. Chem. Soc. 119, 11777, 1997 and A. de Meijere et al. published in Eur. J. Org. Chem. 1998, 777. The first derivatives of the TAN-1057 compounds were described by RM Williams in J. Antibiotics 51, 189, 1998. The derivatizations largely affect the cyclic amidinourea part of the molecule. So z. B. derivatives of the type

wherein R is Ac, COPh, COOMe, SO ₂ Me and CO ₂ CH ₂ Ph is described.

WO-A-99/07685 and US-6,110,925 disclose acylated and, moreover, phosphorylated derivatives of the general formula on the cyclic amidino urea part of the molecule

Two derivatizations (J. Antibiotics 51, 189, 1998) concern the (S) -β-homoarginine part:

However, these derivatizations led to a complete loss of the biolo gical activity.

WO-A-00/12484 discloses antibiotics of the general formula

in which, among other things
X represents a group of the formula - (CH ₂ ) _m -, in which m is 0, 1 or 2,
and
D is selected from groups of the formulas D ₁ to D ₃

The inventors of the present invention set themselves the task of further derivatives to synthesize the TAN-1057 compounds to their biological or pharma to investigate ecological effects. They managed to get more new ones at Dihydro pyrimidinone ring of TAN 1057 modified compounds according to a new, generally applicable method to produce the surprising way about a have better effectiveness and a broader spectrum of activity.

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

in which
R ^{1 represents} hydrogen or (C ₁ -C ₆ ) -alkyl,
A for a group of the formula

wherein
R ⁴ , R ⁵ , R ⁶ and R ^{7 are} each independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkanoyl, benzyl and pyridylmethyl,
R ^{8 is} hydrogen or (C ₁ -C ₆ ) -alkyl,
Q stands for double-bonded O or S or for a double-bonded group of the formula NR ⁹ ,
R ^{9 in} each case has the meaning given above for R ⁴ ,
D stands for a (C ₂ -C ₆ ) -alkanediyl group which, if appropriate, can be substituted one or two _{times, identically or differently, by hydroxy, (C 1} -C ₆ ) -alkoxy, (C ₁ -C ₆ ) -alkanoyl oxy or by an oxo group is substituted,
E stands for a bond or for the group of the formula -CH ₂ -,
R ^{2 represents} hydrogen or (C ₁ -C ₆ ) -alkyl,
and
R ^{3 represents} (C ₆ -C ₁₀ ) aryl or a 5- to 10-membered, partially unsaturated or aromatic, mono- or bicyclic heterocycle which contains up to three heteroatoms from the series N, O and / or S. , where both aryl and the heterocycle are optionally up to three identical or different by (C ₁ -C ₆ ) -alkyl, halogen, trifluoromethyl, (C ₁ -C ₆ ) -alkoxy carbonyl, carboxyl, aminocarbonyl, phenyl, phenylamino and / or are substituted by mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl,
and their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts.

The compounds of the invention also include their prodrugs.

The compounds of the general formula (I) according to the invention can be used in ver Different stereoisomeric forms occur, either like image and mirror image (enantiomers), or which are not like image and mirror image (diastereomers) behavior. The invention relates to both the enantiomers and the diastereomers as well as their respective mixtures. The racemic forms can be just like the Diastereomers in a known manner into the stereoisomerically uniform constituents separate.

Furthermore, certain compounds can exist in tautomeric forms. This is known to those skilled in the art, and such compounds are also within the scope of Invention includes.

The substances of the general formula (I) according to the invention can also be used as salts are present. In the context of the invention, physiologically harmless salts are present admitted.

Physiologically acceptable salts can be salts of the compounds according to the invention Chemicals with inorganic or organic acids. Salts are preferred with inorganic acids such as hydrochloric acid, bromine water chemical acid, phosphoric acid or sulfuric acid, or salts with organic carbon or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, Ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphtha lindisulfonic acid.

Physiologically acceptable salts can also be salts of the salts according to the invention Be compounds with bases, such as metal or ammonium salts. Preferred examples are alkali metal salts (e.g. sodium or potassium salts), earth alkali salts (e.g. magnesium or calcium salts), as well as ammonium salts, the ab are derived from ammonia or organic amines, such as ethylamine, Di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di- or tri ethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methyl morpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, Ethylenediamine or 2-phenylethylamine.

The compounds according to the invention can also be used in the form of their solvates, in particular others in the form of their hydrates.

In the context of the invention, (C ₁ -C ₆ ) -alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. The following may be mentioned as examples and preferred: methyl, ethyl, n-propyl, isopropyl and t-butyl.

In the context of the invention, (C ₂ -C ₆ ) -alkanediyl represents a straight-chain or branched alkanediyl radical having 2 to 6 carbon atoms. A straight-chain or branched alkanediyl radical having 3 to 5 carbon atoms is preferred, a 1, ω-alkanediyl radical having 3 to 5 carbon atoms is particularly preferred. Examples include: propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl.

In the context of the invention, (C ₆ -C ₁₀ ) -aryl stands for an aromatic radical having 6 to 10 carbon atoms. The preferred aryl radical is phenyl.

In the context of the invention, (C ₁ -C ₆ ) -alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. For example and before given, there may be mentioned: methoxy, ethoxy, n-propoxy, isopropoxy and t-butoxy.

In the context of the invention, (C ₁ -C ₆ ) -alkanoyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, which carries a doubly bonded oxygen atom in the 1-position and is linked via the 1-position. Examples include: formyl, acetyl, propionyl, n-butyryl, i-butyryl and pivaloyl.

In the context of the invention, (C ₁ -C ₆ ) -alkanoyloxy stands for a straight-chain or branched alkyl radical with 1 to 6 carbon atoms which carries a double-bonded oxygen atom in the 1-position and an additional oxygen in the 1-position atom is linked. Examples include: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy and n-hexanoyloxy.

In the context of the invention, (C ₁ -C ₆ ) -alkoxycarbonyl represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms which is linked via a carbonyl group. A straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred. The following may be mentioned as examples and preferred: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.

In the context of the invention, mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl represents an amino group which is linked via a carbonyl group and which has one straight-chain or branched or two identical or different straight-chain or branched alkyl substituents, each with 1 to 6 Has carbon atoms. Examples include: methylaminocarbonyl, n-propylaminocarbonyl, isopropylamino carbonyl, t-butylaminocarbonyl, N, N-dimethylaminocarbonyl, N-methyl-Nn-propyl aminocarbonyl, Nt-butyl-N-methylaminocarbonyl and Nn-hexyl-N-methyl-amino carbonyl .

In the context of the invention, halogen includes fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.

A 5- to 10-membered, partially unsaturated or aromatic, mono- or bicyclic heterocycle with up to three heteroatoms from the series N, O and / or In the context of the invention, S generally represents a mono- or bicyclic one Heterocycle containing one or more double bonds or being aromatic can, one to three identical or different heteroatoms from the series N, O and / or S contains and which has a ring carbon atom or optionally a Ring nitrogen atom is linked. Examples include: pyridyl, 1,2-dihydro pyridinyl, 1,4-dihydropyridinyl, furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, oxa zolyl, triazolyl, pyrazolyl, pyrazinyl, 3,4,5,6-tetrahydropyrimidinyl, pyrimidinyl, Pyridazinyl, indolyl, benzimidazolyl, benzo [b] thienyl, benzo [b] furyl, indazolyl, Quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl. Pyridyl are preferred, Pyrimidinyl, pyrazinyl and quinolinyl.

The compounds of the general formula (I) according to the invention are preferred,
in which
R ^{1 represents} (C ₁ -C ₄ ) -alkyl,
A for a group of the formula

wherein
R ⁴ , R ⁵ , R ⁶ and R ^{7 are} each independently selected from the group consisting of hydrogen, (C ₁ -C ₄ ) -alkyl or acetyl,
R ^{8 is} (C ₁ -C ₄ ) -alkyl,
Q represents a double bonded O or a double bonded group of the formula NR ⁹ ,
R ^{9 in} each case has the meaning given above for R ⁴ ,
D is (C ₃ -C ₅ ) -alkanediyl, which is optionally substituted by hydroxy or by an oxo group,
E represents a bond or represents the group of the formula -CH ₂ -,
R ^{2 represents} hydrogen or (C ₁ -C ₄ ) -alkyl,
and
R ^{3 stands} for phenyl or for a 6- to 10-membered, partially unsaturated or aromatic, mono- or bicyclic heterocycle with up to three nitrogen atoms, both phenyl and the heterocycle, where appropriate, up to two times identical or different through (C ₁ -C ₄ ) -alkyl, fluorine, chlorine, bromine, trifluoromethyl, (C ₁ -C ₄ ) -alkoxycarbonyl, carboxyl, amino carbonyl, phenyl or phenylamino are substituted,
and their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts.

The compounds of the general formula (I) according to the invention are particularly preferred,
in which
R ^{1 represents} methyl,
A for a group of the formula

wherein
R ⁴ , R ⁵ , R ⁶ and R ^7, independently of one another, are each hydrogen or methyl,
R ^{8 is} (C ₁ -C ₄ ) -alkyl,
Q stands for a double bonded group of the formula NR ⁹ ,
R ^{9 in} each case has the meaning given above for R ⁴ ,
D is straight-chain (C ₃ -C ₅ ) -alkanediyl,
E stands for the group of the formula -CH ₂ -,
R ^{2 represents} hydrogen,
and
R ^{3 represents} pyridyl, pyrimidinyl, pyrazinyl or quinolinyl, each of which can be substituted one to two times, identically or differently, by methyl, trifluoromethyl, fluorine, chlorine or bromine,
and their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts.

The compounds according to the invention of the general formula (Ia),

in which
A, D, R ¹ , R ² and R ^{3 have} the meanings given above.

Likewise very particularly preferred are the compounds of the general formula (I) according to the invention,
in which
R ^{1 represents} methyl.

Likewise very particularly preferred are the compounds of the general formula (I) according to the invention,
in which
R ^{2 represents} hydrogen.

Likewise very particularly preferred are the compounds of the general formula (I) according to the invention,
in which
E stands for the group of the formula -CH ₂ -.

Likewise very particularly preferred are the compounds of the general formula (I) according to the invention,
in which,
A represents the group of the formula H ₂ N-.

In addition, a process for the preparation of the compounds of the general formula (I) according to the invention has been found, characterized in that first
Compounds of the general formula (II)

or their salts,
in which
R ^{3 has} the meaning given above,
by reaction with compounds of the general formula (III)

in which
R ^{1 has} the meaning given above
and
Z represents a suitable amino protective group, preferably benzyloxycarbonyl,
in the presence of a base in compounds of the general formula (IV)

in which
R ¹ , R ³ and Z have the meaning given above,
convicted,
then split off the amino protective group Z according to customary conditions and with compounds of the general formula (V)

in which
D, E and R ^{2 have} the meaning given above,
R ^{10 represents} an amino protective group, preferably tert-butoxycarbonyl or benzyloxycarbonyl,
and
A ^{* stands} for one of the formulas listed above under A, with any free amino and / or imino groups present in these, preferably in a form protected by tert-butoxycarbonyl or benzyloxycarbonyl,
is reacted in inert solvents in the presence of an amide coupling reagent and, if appropriate, in the presence of a base, and if appropriate, in a final cut, the respective amino protective groups are split off by customary methods.

The process according to the invention can be exemplified by the following equation explained:

Reaction scheme

As a coupling agent in the reaction of compounds of the general formula (IV) after cleavage of the protective group derived amine and the carboxylic acid of general formula (V) can known reagents such. B. [O- (7-Azabenzo triazol-1-yl) -1,1,3,3-tetramethyluronium] hexafluorophosphate (HATU) or [bromine trispyrrolidino-phosphonium] hexafluorophosphate (PyBroP) can be used because with them the coupling proceeds smoothly and with high yields.

As an amino protective group, the customary ones in peptide chemistry can be used in each case Deten amino protecting groups are used. These include preferably: benzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, Methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, Phthaloyl, 2,2,2-trichloroethoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, Acetyl, isovaleroyl, 2-chloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromo-benzoyl, 4- Nitrobenzoyl, benzyloxymethylene, benzyl, 4-nitrobenzyl, 2,4-dinitrobenzyl, 4- Nitrophenyl, 4-methoxyphenyl or triphenylmethyl, with tert-butoxycarbonyl and benzyloxycarbonyl are particularly preferred.

The splitting off of the amino protective group takes place in each case according to conventional Ver drive (see T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York, 1991), preferably tertiary Butoxycarbonyl with hydrochloric acid in dioxane or with trifluoroacetic acid, fluorenyl-9- methoxycarbonyl with piperidine and benzyloxycarbonyl by hydrogenolysis in Presence of catalysts such. B. Raney nickel, palladium, palladium Carbon, palladium (II) chloride or platinum, or with hydrogen bromide in glacial acetic acid.

In the present invention, the reactions are carried out in inert organic solutions solvents carried out that do not change under the reaction conditions. These include ethers such as diethyl ether, 1,4-dioxane or tetrahydrofuran, halogen hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-di chloroethane, trichloroethane or tetrachloroethane, hydrocarbons such as benzene, Toluene, xylene, hexane, cyclohexane or petroleum fractions, alcohols such as methanol, Ethanol or iso-propanol, nitromethane, dimethylformamide, acetonitrile or Dimethyl sulfoxide. It is also possible to use mixtures of the solvents. Dichloromethane, tetrahydrofuran, dioxane, methanol, Dimethylformamide or acetonitrile.

The reactions are generally carried out in a temperature range from 0 ° C to 150 ° C, preferably from 0 ° C to 70 ° C carried out. The implementations can be carried out at normal, increased or reduced pressure (e.g. 0.5 to 5 bar). In general, normal pressure is used.

Suitable bases for the process of this invention generally sodium or lithium bistrimethylsilylamide, alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide, alkali metal carbonates such as sodium carbonate or bicarbonate, alkali metal acetates such as sodium acetate or potassium acetate, sodium hydride, organic tri (C ₁ -C ₆₎ alkylamines such as triethylamine or Diisopropyl ethylamine, or heterocycles such as 1,4-diazabicyclo [5.4.0] undec-7-en (DBU), pyridine, N, N-dimethylaminopyridine, N-methylpiperidine or N-methylmorpholine can be used. Lithium hydroxide, sodium hydrogen carbonate, sodium acetate, pyridine, diisopropylethylamine and triethylamine are preferred.

The compounds of the general formula (III) are known or can, as in WO-A-00/12484 and A. de Meijere et al., Eur. J. Org. (Chem., 1998, 777 described ben.

The compounds of the general formula (V) are known or can be found in Ana logic to processes known from the literature are produced [cf. WO-A-00/12484 and Bastiaans, H.M.M. et al., Tetrahedron Lett. 35, 7659 (1994)].

Some of the compounds of the general formula (II) are new and can be prepared by adding amines of the general formula (VI)

R ³ -NH ₂ (VI),

in which
R ^{3 has} the meaning given above,
with a compound of the formula (VII)

to compounds of the general formula (VIII)

in which
R ^{3 has} the meaning given above,
implements,
in a next step in the presence of a base, the benzoyl group to compounds of the general formula (IX)

in which
R ^{3 has} the meaning given above,
split off and finally with alkylating agents of the general formula (X)

CH ₃ -X (X),

in which
X is a leaving group such as chlorine, bromine, iodine, tosylate or mesylate, preferably iodine,
implements.

The reactions are carried out in inert organic solvents, which do not change under the reaction conditions. These include ethers such as diethyl ether, 1,4-dioxane or tetrahydrofuran, halogenated hydrocarbons such as dichloro methane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane or Tetrachloroethane, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, alcohols such as methanol, ethanol or iso-propanol, nitro methane, acetone, acetonitrile, dimethylformamide or dimethyl sulfoxide. Likewise is it is possible to use mixtures of solvents or mixtures of individual solvents To use water. Particularly preferred for process steps (VI) + (VII) are → (VIII) and (IX) + (X) → (II) acetone or acetonitrile.

The reactions are generally carried out in a temperature range from 0 ° C to 150 ° C, preferably from 0 ° C to 100 ° C carried out. The implementations can be carried out at normal, increased or reduced pressure (e.g. 0.5 to 5 bar). In general, normal pressure is used.

As a base for splitting off the benzoyl group in process step (VIII) → (IX) can generally be alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkali metal carbonates such as sodium carbonate or potassium carbonate can be used. Lithium hydroxide and are preferred Sodium hydroxide.

The compounds of the general formulas (VI), (VII) and (X) are known per se or can be prepared by customary methods.

The compounds of the general formulas (VIII) and (IX) are known or new and can be produced, for example, as described above.

The natural product derivatives of the present invention have interesting pharma ecological effects on. In particular, the compounds of the present Invention have an antibacterial effect and are therefore useful in combating bacterial infections in humans and animals.

Determination of the minimum inhibitory concentration (MIC)

The MIC was determined in the liquid dilution test. Overnight cultures of most Test germs were diluted 1: 1000 in AOAC medium (Difco) with 4% dextrose and incubated with dilutions of the test substances (dilution levels 1: 2). Only one The exception was the test with S. pneumoniae, which was carried out in 10% BHI with the addition of 10% Bovine serum was performed.

Results

The cultures were incubated at 37 ° C for 18-24 hours. The lowest in each case Substance concentration at which no more visible bacterial growth occurred, was defined as an MIC. The MIC values in µg / ml of some ver according to the invention bindings to a number of test germs are shown in the table below listed as an example. The compounds showed a very good antibacterial effect against most of the test germs and thus a broad gram-positive effect.

The compounds according to the invention have a broad antibacterial spectrum, especially against gram-positive germs. These properties enable their ver Use as chemotherapeutic agents in human and veterinary medicine. With Their help can fight gram-positive germs as well as those caused by these pathogens caused diseases can be prevented, improved and / or cured.

They are good for the prophylaxis and chemotherapy of local and systemic infections functions in human and veterinary medicine that result from such pathogens be called.

The present invention includes pharmaceutical preparations, in addition to non-toxic, inert, pharmaceutically acceptable carriers or excipients contain one or more compounds according to the invention, or from one or more active ingredients according to the invention exist, as well as methods for Her position of these preparations.

For the application of the compounds of the general formula (I) all of the above come common forms of application into consideration, d. H. i.e. oral, parenteral, inhalative, nasal, sublingual, buccal, rectal or external such as B. transdermal, especially before is given orally or parenterally. In the case of parenteral administration, intra to name venous, intramuscular, subcutaneous application, z. B. as subcutaneous Depot. Oral application is very particularly preferred.

Here, the active ingredients can be administered alone or in the form of preparations will. Preparations suitable for oral administration include: Tablets, Capsules, pellets, coated tablets, pills, granulates, solid and liquid aerosols, syrups, Emulsions, suspensions and solutions. Here, the active ingredient must be in a be present in such an amount that a therapeutic effect is achieved. In general can mean the active ingredient in a concentration of 0.1 to 100 wt .-%, esp especially 0.5 to 90% by weight, preferably 5 to 80% by weight, are present. In particular the concentration of the active ingredient should be 0.5-90% by weight, d. H. the active substance should be in amounts that are sufficient to the stated dosage range space to reach.

For this purpose, the active ingredients can be converted into the customary ones in a manner known per se Preparations are transferred. This is done using inert, non- toxic, pharmaceutically suitable carriers, auxiliaries, solvents, Vehicles, emulsifiers and / or dispersants.

The active ingredient (s) can optionally be used in one or more of the above given carrier substances are also present in microencapsulated form.

Examples of auxiliaries are: water, non-toxic organic Solvents such as B. paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. Ethanol, glycerine), glycols (e.g. polyethylene glycol), solid carriers such as natural lich or synthetic powdered rock (e.g. talc or silicates), sugar (e.g. Milk sugar), emulsifiers, dispersants (e.g. polyvinylpyrrolidone) and lubricants medium (e.g. magnesium sulfate).

In the case of oral administration, tablets can of course also contain additives like sodium citrate along with additives like starch, gelatin and the like included. Aqueous preparations for oral administration can still be used can be added with flavor enhancers or colorings.

The pharmaceutical preparations listed above can in addition to the inven compounds according to the invention also contain further active pharmaceutical ingredients.

In general, it has been used in both human and veterinary medicine Proven to be advantageous, the active ingredient (s) according to the invention in the case of oral Application in total amounts of about 0.01 to about 100, preferably 0.5 to 50 mg / kg body weight per 24 hours, possibly in the form of several To be given single doses to achieve the desired results. One Single dose contains the active ingredient (s) according to the invention, preferably in Amounts from about 0.1 to about 50, in particular 0.5 to 30 mg / kg, body weight.

However, it may be advantageous to deviate from the amounts mentioned soft, depending on the type and body weight of the treated object, the individual behavior towards the drug, the Type and severity of the disease, the type of preparation and application, as well as the time or interval at which the administration takes place.

The compounds of the invention can be used for the purpose of expanding the Spectrum of effects and to achieve an increase in effectiveness, also with others Antibiotics are combined.

Output connections Example I. 1-Benzoyl-3-pyrimidin-2-yl-thiourea

Lit .: DT Hurst, Aust. J. Chem. 41, 1988, 1221-1229

1.72 mg (10.5 mmol) of benzoyl isothiocyanate are dissolved in 30 ml of abs. Dissolve acetone, cool in an ice bath and add 1 g (10.5 mmol) of 2-aminopyrimidine in 20 ml of abs. Acetone added. The mixture is left to stir overnight at room temperature and the product obtained (1.5 g) is filtered off. A further 630 mg of substance are obtained from the mother liquor.
Fbl. Crystals, m.p .: 194 ° C; R _f (dichloromethane / ethyl acetate 1/1) = 0.8
Yield: 2.13 g (78.5% of theory)
MS (M + H) = 259

Example II Pyrimidin-2-yl-thiourea

Lit .: CR Rasmussen, Synthesis, 1988, 456-459

In an oil bath set to 90 ° C., 2 g (7.74 mmol) of the compound from Example I are heated with 17.2 ml of 5% sodium hydroxide solution. After about 30 minutes, the mixture is allowed to cool, the precipitated product is filtered off, washed with water and the crystals are dried.
Fbl. Crystals, m.p .: <250 ° C; R _f (dichloromethane / ethyl acetate 4/1) = 0.5
Yield: 1.07 g (89.3% of theory)
MS (M + H) = 155

Example III 2-methyl-1-pyrimidin-2-yl-isothiourea-hydroiodide

Lit .: CR Rasmussen, Synthesis 1988, 460-466

1 g (6.5 mmol) of the compound from Example II are suspended in 15 ml of acetonitrile, mixed with 0.48 ml (1.1 g) (7.78 mmol) of methyl iodide and initially at 40 ° C. for 30 minutes then stirred at 90 ° C. for 1 h. After cooling, the precipitate which has separated out is filtered off. Further product is obtained from the mother liquor by extensive evaporation of the solvent.
Fbl. Crystals, m.p .: approx. 230 ° C; R _f (dichloromethane / ethyl acetate 4/1) = 0.1
Yield: 1.73 g (90.2% of theory)
MS (M + H) = 169

Example IV (R, S) -5- (N-Benzyloxycarbonyl-N-methylamino) -3,4,5,6-tetrahydro-2- (pyrimidine-2- yl-amino) pyrimidin-4-one

Lit .: A. de Meijere, Eur. J. Org. Chem. 1998, 777-783

320 mg (1.08 mmol) of the compound from Example III, 327 mg (1.08 mmol) of 3-amino-2- (N-benzyloxycarbonyl-N-methylamino) propionic acid methyl ester hydrochloride and 177.3 mg (82.16 mmol) of sodium acetate are suspended in 7 ml of acetonitrile and stirred in a 70 ° C. oil bath overnight. After cooling, 50 ml of water are added and the precipitate which has separated out is filtered off. It is dissolved in ethyl acetate and separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/5).
Fbl. Crystals; R _f (dichloromethane / methanol 100/5) = 0.2
Yield: 272 mg (80% pure) = 56.8% of theory. Th.
MS (M + H) = 355

Example V

(R, S) -5- (N-methylamino) -3,4,5,6-tetrahydro-2- (pyrimidin-2-yl-amino) -pyrimidin-4-one

0.5 g (1.41 mmol) of the compound from Example IV are dissolved in 20 ml of HBr in glacial acetic acid (33%) and the mixture is stirred at RT for 30 min. It is then evaporated to dryness and the residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol / saturated ammonia solution in water, approx. 25% strength = 85/15/3).
Foam; R _f (solvent as above) = 0.5
Yield: 0.2 g (64.4% of theory)
MS (M + H) = 221

Example VI

(R, S) -5- (N-methylamino) -2- (2-pyridinylamino) -5,6-dihydro-4 (1H) -pyrimidinone

Production takes place analogously to Examples I to V.
Fbl. Crystals;
MS (M + H) = 220

Example VII

(3'S, 5R, S) -5- (N-3'-7'-dibenzyloxycarbonylaminoheptanoyl-N-methylamino) - 3,4,5,6-tetrahydro-2- (pyrimidin-2-yl-amino) -pyrimidin- 4-on

1.00 mg (0.45 mmol) of the compound from Example V, 194.5 mg (0.45 mmol) (S) -3,7-di-benzyloxycarbonylamino-heptanoic acid, 345.3 mg (0.91 mmol) are added under an argon atmosphere ) O- (7-Azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) and 117.4 mg (0.91 mmol) N, N-diisopropylethylamine (Hünig base) in 3 ml of dried DMF dissolved and stirred at RT overnight. One steams i. V. to dryness, taken up in 5 ml of ethyl acetate, extracted twice with 2 ml of 1N hydrochloric acid each time, the organic solvent evaporated i. V. and separates the residue by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/7).
Fbl. Crystals, R _f (mobile phase as above) = 0.5
Yield: 192 mg (92%) = 61.9% of theory. Th.
MS (M + H) = 631

Example VIII

(3'S, 5R, S) -5- (N-3'-6'-dibenzyloxycarbonylamino-hexanoyl-N-methyl) -amino-3,4,5,6-tetrahydro-2- (pyrimidin-2-yl) - amino-pyrimidin-4-one

Production analogous to Example VII from 30 mg (0.14 mmol) of the compound from Example V, 56.5 mg (0.14 mmol) (S) -3,6-dibenzyloxycarbonylaminohexanoic acid, 103.6 mg (0.27 mmol ) HATU and 35.2 mg (0.27 mmol) of Hünig's base in 3 ml of dried DMF.
Pale crystals, R _f (dichloromethane / methanol 9/1) = 0.3
Yield: 49 mg (90% pure) = 52.5% of theory. Th.
MS (M + H) = 617

Example IX

(3'R, S, 5R, S) -5- (N-3'-8'-dibenzyloxycarbonylamino-octanoyl-N-methyl) -amino-3,4,5,6-tetrahydro-2- (pyrimidine-2 -yl) -amino-pyrimidin-4-one

Production analogous to Example VII from 30 mg (0.14 mmol) of the compound from Example V, 60.3 mg (0.14 mmol) (R, S) -3,8-dibenzyloxycarbonylamino-octanoic acid, 103.6 mg (0, 27 mmol) of HATU and 35.2 mg (0.27 mmol) of Hunig base in 3 ml of dried DMF.
Pale crystals, R _f (dichloromethane / methanol 9/1) = 0.3
Yield: 55 mg (92%) = 57.6% of theory. Th.
MS (M + H) = 645

Example X

(3'S, 5R, S) -5- [N- (N ^β , N ^ε , N ^ω -tribenzyloxycarbonyl-3-amino-6-guanidino-hexanoyl) -N-methyl] -amino-3,4,5,6 Tetrahydro-2- (pyrimidin-2-yl) -amino-pyrimidin-4-one

Production analogous to Example VII from 30 mg (0.14 mmol) of the compound from Example V, 80.45 mg (0.14 mmol) (S) -N ^β , N ^ε , N ^ω -tribenzyloxycarbonyl-3-amino-6- guanidinohexanoic acid, 103.6 mg (0.27 mmol) of HATU and 35.2 mg (0.27 mmol) of Hunig's base in 3 ml of dried DMF.
Pale crystals, R _f (dichloromethane / methanol 100/5) = 0.4
Yield: 63 mg (99% pure) = 57.8% of theory. Th.
MS (M + H) = 793

Example XI

(3'S, 5R, S) -5- [N-methyl-N- (3'-benzyloxycarbonylamino-6'-tert -butyloxycarbonylamino-hexanoyl) -amino] -5,6-dihydro-2- (pyridyl-2 ) -amino-4 (1H) -pyrimidone

1 g (4.56 mmol) of the compound from Example VI, 1.7352 g (4.56 mmol) (3S) -3-benzyloxycarbonylamino-6-tert-butyloxycarbonylamino-hexanoic acid, 3.4685 g (9.12 mmol ) HATU and 2.358 g (18.24 mmol) of Hünig's base (3.18 ml) are dissolved in 10 ml of dried dimethylformamide and stirred under an argon atmosphere at room temperature overnight. After neutralization with 1N hydrochloric acid, everything is evaporated to dryness in vacuo and taken up in 15 ml of ethyl acetate and 1 ml of water. The water is separated off, the organic phase is washed twice with 3-5 ml of water each time, dried with sodium sulfate and the organic residue evaporated in vacuo is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 100/7).
R _f (dichloromethane / methanol = 100/7) = 0.27
fbl. Product, yield: 1.1275 g (88%) = 36.55% of theory. Th.
MS (M + H) = 582

Example XII

(3'S, 5R, S) -5- [N-methyl-N- (3'-benzyloxycarbonylamino-6'-amino-hexanoyl) -amino] -5,6-dihydro-2- (pyridyl-2) -amino- 4 (1H) -pyrimidone hydrochloride

In a flask flushed with argon, 50 mg (0.09 mmol) of the compound from Example XI are suspended in 3 ml of a solution of 4 molar hydrochloric acid in dioxane and concentrated dropwise with 0.5 ml. Hydrochloric acid added. The suspension dissolves into a clear solution. The mixture is left to stir for a further 1 hour at room temperature, everything is evaporated to dryness in vacuo and the colorless residue is stirred out with a little dichloromethane.
R _f (dichloromethane / methanol = 4/1) = 0.38
fbl. Crystals, yield: 60 mg (70%) = 94.32% of theory. Th.
MS (M + H) = 482

Example XIII

(3'S, 5R, S) -5- [N-methyl-N- (3'-benzyloxycarbonylamino-6'-acetimidoylamino hexanoyl) -amino] -5,6-dihydro-2- (pyridyl-2) -amino-4 (1H) -pyrimidone

200 mg (0.42 mmol) of the compound from Example XII, 70.43 mg (0.56 mmol) of S-methylacetimidate hydrochloride and 161 mg (1.25 mmol) of Hünig's base (0.22 ml) are mixed with 5 Dissolved in ethanol and stirred at 60 ° C. overnight. Everything is evaporated to dryness in vacuo and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol / ammonia conc. = 85/15/3).
R _f (dichloromethane / methanol / conc. Ammonia = 85/15/3) = 0.2
fbl. Product, yield: 188 mg (96%) = 83.15% of theory. Th
MS (M + H) = 523

Embodiments

example 1

(3'S, 5R, S) -5- (N-3 ', 7'-diaminoheptanoyl-N-methylamino) -3,4,5,6-tetrahydro-2- (pyrimidin-2-yl-amino) -pyrimidin- 4-one dihydrobromide

100 mg (0.16 mmol) of the compound from Example VII are stirred at RT for 30 min with 2 ml of glacial acetic acid / HBr (33%). Then everything is ok. V. evaporated to dryness and dried in a high vacuum.
Pale crystals, R _f (methanol / dichloromethane / conc. Ammonia water 5/3/2) = 0.6
Yield: quantitative
MS (M + H) = 363

Example 2

(3S, 5R, S) -5- (N-3 ', 7'-diaminoheptanoyl-N-methylamino) -3,4,5,6-tetrahydro-2- (pyrimidin-2-yl-amino) -pyrimidin- 4-on

128 mg (0.24 mmol) of the compound from Example 1 are converted into the free base by column chromatography (silica gel 60, mobile phase: methanol / dichloromethane / conc. Ammonia water 5/3/2).
Fbl. Foam, R _f (solvent as above) = 0.6
Yield: 63 mg (71.2% of theory)
MS (M + H) = 363

Example 3

(3'S, 5R, S) -5- (N-3 ', 7'-diaminoheptanoyl-N-methylamino) -3,4,5,6-tetrahydro-2- (pyrimidin-2-yl-amino) -pyrimidin- 4-one dihydrochloride

3.2 mg (0.01 mmol) of the compound from Example 2 are dissolved in 2 ml of methanol / 2N hydrochloric acid, i. V. evaporated to dryness, and the residue is dried in a high vacuum.
Fbl. Crystals
Yield: quantitative
MS (M + H) = 363

Example 4

(3'S, 5R, S) -5- (N-3 ', 7'-diaminoheptanoyl-N-methylamino) -3,4,5,6-tetrahydro-2- (pyrimidin-2-yl-amino) -pyrimidin- 4-one dihydroacetate

2.4 mg (0.007 mmol) of the compound from Example 2 are dissolved in 2 ml of methanol / glacial acetic acid, i. V. evaporated to dryness and the residue dried in a high vacuum.
Foam
Yield: quantitative
MS (M + H) = 363

Example 5

(3'S, 5R, S) -5- (N-3 ', 7'-diaminoheptanoyl-N-methylamino) -3,4,5,6-tetrahydro-2- (3,4,5,6-tetrahydropyrimidine -2-yl-amino) -pyrimidin-4-one

20 mg (0.03 mmol) of the compound from Example VII and 8.43 mg (1.5 equivalents) of palladium dichloride are suspended in 5 ml of dichloromethane / methanol (1/1) (partly in solution) and for one hour at RT and normal pressure hydrogenated with hydrogen. Then you steam everything i. V. to dryness and the residue is purified by column chromatography (silica gel 60, mobile phase: methanol / dichloromethane / conc. Ammonia water = 5/3/2).
Fbl. Crystals, R _f (mobile phase as above) = 0.6
Yield: 10 mg (86% of theory)
MS (M + H) = 367

Example 6

(3'S, 5R, S) -5- (N-3 ', 6'-Diaminohexanoyl-N-methylamino) -3,4,5,6-tetrahydro-2- (pyrimidin-2-yl-amino) -pyrimidin- 4-one dihydrobromide

Analogously to Example 1 from 30 mg (0.05 mmol) of the compound from Example VIII and 2 ml of glacial acetic acid / HBr (33%).
Pale crystals, R _f (methanol / dichloromethane / conc. Ammonia water = 5/3/2) = 0.6
Yield: quantitative
MS (M + H) = 349

Example 7

(3'R, S, 5R, S) -5- (N-3 ', 8'-diaminooctanoyl-N-methylamino) -3,4,5,6-tetrahydro-2- (pyrimidin-2-yl-amino) ) pyrimidin-4-one dihydrobromide

Analogously to Example 1 from 30 mg (0.05 mmol) of the compound from Example IX and 2 ml of glacial acetic acid / HBr (33%).
Pale crystals, R _f (methanol / dichloromethane / conc. Ammonia water = 5/3/2) = 0.6
Yield: quantitative
MS (M + H) = 377

Example 8

(3'S, 5R, S) -5- (N-3-Amino-6-guanidinohexanoyl-N-methyl) -amino-3,4,5,6-tetrahydro-2- (pyrimidin-2-yl) -amino- pyrimidin-4-one trihydrobromide

Analogously to Example 1 from 45 mg (0.06 ml) of the compound from Example X and 2 ml of glacial acetic acid / HBr (33%).
Pale crystals, R _f (methanol / dichloromethane / conc. Ammonia water = 5/3/2) = 0.3
Yield: 2 mg (9.0% of theory)
MS (M + H) = 391

Example 9

(3'S, 5R, S) -5- [N -methyl-N- (3'-amino-6'acetimidoylamino-hexanoyl) -amino] -5,6-dihydro-2- (pyridyl-2) -amino-4 (1H) -pyrimidone

100 mg (0.19 mmol) of the compound from Example XIII are dissolved in 3 ml of methanol, 100 mg of Pd-C (10%) catalyst are added and the mixture is hydrogenated with hydrogen at room temperature and normal pressure for two hours. After filtering off the catalyst, the solution is evaporated in vacuo.
R _f (dichloromethane / methanol / conc. Ammonia = 5/3/2) = 0.3
fbl. Foam, yield: 60 mg (80.72% of theory)
MS (M + H) = 389

The compounds of Examples 10 to 56 were prepared analogously:

Example 57

(3'R, S, 6'R, S, 5R, S) -5- [N-methyl-N- (3 ', 6'-diaminoheptanoyl) amino] -5,6-dihydro-2- (pyridyl -2) -amino-4 (1H) -pyrimidone trihydrochloride

Stage a)

Under argon, 0.62 g (5.04 mmol) is added to a solution of 10.0 g (101 mmol) of rac-5-methyl-2-pyrrolidinone and 24.2 g (111 mmol) of BOC anhydride in 120 ml of acetonitrile. DMAP was added and the mixture was stirred at RT overnight. The solvent is distilled off on a rotary evaporator and the residue is purified on a short flash chromatography column (mobile phase: ethyl acetate / cyclohexane = 1/1). 19.6 g (98%) of the desired product tert-butoxycarboxy-2-methyl-1-pyrrolidin-5-one are obtained as a yellow oil.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.32 (d, 3H), 1.55 (s, 9H), 1.68 (m, 1H), 2.20 (m, 1H), 2.34-2.72 (m, 2H) , 4.25 (m, 1H).

Stage b)

In an argon atmosphere at -78 ° C., a solution of 9.10 g (103 mmol) ethyl acetate in 40 ml THF is added dropwise to 51.6 ml (103 mmol) of a 1 molar LDA solution in THF. A solution of 19.6 g (98.3 mmol) of tert-butoxycarboxy-2-methyl-1-pyrrolidin-5-one (stage a) in 50 ml of THF is then added. The mixture is stirred for a further 30 min at -78 ° C., the ice bath is removed, allowed to come to RT and stirred for a further hour. The reaction mixture is made up to 100 ml of a sat. Ammonium chloride solution poured and it is extracted three times with 200 ml of dichloromethane each time. The combined organic phases are dried over magnesium sulfate and the solvent is distilled off on a rotary evaporator. The residue is purified on a short flash chromatography column (mobile phase: ethyl acetate / cyclohexane = 1/12 becoming more polar to 1/1). 10.5 g (37%) 6 - [(tert-butoxycarbonyl) amino] -3-oxo-heptanoic acid ethyl ester are obtained.
MS (DCI / NH ₃ ): [M + NH ₄ ] ⁺ = 305.4
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.13 (d, 3H), 1.29 (t, 3H), 1.45 (s, 9H), 1.59-1.87 (m, 2H), 2.61 (m, 2H), 3.45 (s, 2H), 3.62 (m, 1H), 4.19 (q, 2H), 4.30 (m, 1H).

Stage c)

A solution of 5.0 g (17.4 mmol) of 6 - [(tert-butoxycarbonyl) amino] -3-oxo-heptane acid ethyl ester (stage b) in 40 ml of a 7 molar ammonia solution in ethanol is in a closed flask Stirred for 72 h at RT. All volatile constituents are distilled off in vacuo, the residue (4.98 g) is taken up in 20 ml of methanol and the solution thus obtained is at 0 ° C to a solution of 3.28 g (52.2 mmol) of sodium cyanoborohydride in 25 ml abs. Methanol was added dropwise. 2.19 ml (60.1 mmol) of glacial acetic acid are added and the ice bath is removed. It is stirred for 1 h at RT. It is mixed with 5 ml of a sat. Sodium hydrogen carbonate solution and most of the methanol is distilled off on a rotary evaporator. The residue is extracted twice with 20 ml of dichloromethane each time. The combined organic phases are dried over sodium sulfate and the solvent is distilled off on a rotary evaporator. The residue is purified on a flash chromatography column (mobile phase: dichloromethane / methanol = 20/1 becoming more polar to 10/1). 2.84 g (56%) of rac-3-amino-6 - [(tert-butoxycarbonyl) amino] heptanoic acid ethyl ester are obtained.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.16 (d, 3H), 1.28 (t, 3H), 1.42 (s, 9H), 1.55-1.82 (m, H), 2.70 (d, 2H) , 3.55 (m, 2H), 4.21 (q, 2H), 4.64 (m, broad, 1H), 5.51 (m, broad, 2H).

Stage d)

A solution of 2.80 g (9.71 mmol) of rac-3-amino-6 - [(tert-butoxycarbonyl) -amino] -heptanoic acid ethyl ester (stage c) in 60 ml of THF is mixed with 120 ml of a saturated aqueous sodium hydrogen carbonate solution and 4.24 g (19.4 mmol) of BOC anhydride are added. It is stirred at RT overnight. It is extracted twice with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate and the solvent is distilled off on a rotary evaporator. The residue is purified on a flash chromatography column (mobile phase: dichloromethane / methanol = 1/0 becoming more polar to 15/1). 2.42 g (64%) of ethyl rac-3,6-bis [(tert-butoxycarbonyl) amino] heptanoate are obtained.
MS (ESI): [M + H] ⁺ = 389.3, [M + Na] ⁺ = 411.2
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.00 (d, 3H), 1.25 (t, 3H), 1.43 (s, 18H), 1.52 (m, 4H), 2.50 (m, 2H), 3.61 (m, 1H), 3.89 (m, 1H), 4.14 (q, 2H), 4.32 (m, 1H), 4.96 (m, 1H).

Stage e)

A solution of 0.39 g (1.00 mmol) rac-3,6-bis [(tert-butoxycarbonyl) -amino] -heptanoic acid ethyl ester (step d) and 0.19 g (1.50 mmol) potassium trimethylsilanoate in 4 ml of dichloromethane is stirred at RT for 1 h. Another 0.19 g of potassium trimethylsilanoate is added and the mixture is stirred at RT for 3 h. 1 ml of water is added and the aqueous phase is adjusted to pH 5 with 1 molar hydrochloric acid. The aqueous phase is extracted three times with 2 ml of dichloromethane each time. The combined organic phases are dried over sodium sulfate and the solvent is distilled off on a rotary evaporator. 0.38 g (quant.) Of rac-3,6-bis [(tert-butoxycarbonyl) amino] heptanoic acid, which is used without further purification, is obtained.
MS (ESI): [M + H] ⁺ = 361, [M + Na] ⁺ = 383.4, [2M + Na] ⁺ = 743.5

Stage f)

A solution of 73.0 mg (0.33 mmol) (R, S) -5- (N-methylamino) -2- (2-pyridinyl amino) -5,6-dihydro-4 (1H) -pyrimidinone (Example VI), 100 mg (0.28 mmol) rac-3,6-bis [(tert-butoxycarbonyl) -amino] heptanoic acid (stage e), 126 mg (0.33 mmol) [O- (7-azabenzotriazole- 1-yl) -1,1,3,3-tetramethyluronium] hexafluorophosphate (HATU) and 43.0 mg (0.33 mmol) of diisopropylethylamine in 5 ml of DMF are stirred at 23 ° C. for 16 h. The solvent is then distilled off in vacuo using a Kugelrohr and the residue is purified by preparative HPLC (Kromasil 100 C18, 5 μm; 50 × 20 mm; gradient: acetonitrile / water = 15/85 to 90/10, room temperature). 136 mg (97%) of the coupling product are obtained as a white solid [MS (ESI): [M + H] ⁺ = 562]. The product is taken up in 2 ml of a 4 molar HCl solution in dioxane and stirred at RT for 2 h. All volatile constituents are distilled off in vacuo. The residue is taken up in a little methanol and acetone is added until a voluminous precipitate occurs. It is decanted off and the residue is washed with acetone. It is freed from solvent residues in a high vacuum, and 89 mg (79%) of the target compound are obtained.
MS (ESI): [M + H] ⁺ = 362.5
¹ H-NMR (400 MHz, CD ₃ OD): δ = 1.36 (d, 3H), 1.67-1.87 (m, 4H), 2.82 (m, 1H), 3.01 (m, 1H), 3.19 (s, 3H ), 3.35 (m, 1H), 3.63 (m, 1H), 4.00 (m, 1H), 4.12 (m, 1H), 5.24 (m, 1H), 7.25 (d, 1H), 7.32 (m, 1H) , 7.98 (m, 1H), 8.42 (m, 1H).

Example 58

(3'S, 5R, S) -5- [N- (3,7-Diamino-5-oxoheptanoyl) -N-methylamino] -5,6-dihydro-2- (2-pyridinyl-amino) -4 (1H) pyrimidinone dihydrochloride

Stage a)

A suspension of 4.11 g (43.3 mmol) of anhydrous magnesium chloride and 11.5 g (67.2 mmol) of potassium ethyl malonate in 100 ml of tetrahydrofuran is stirred at 50 ° C. for 4 h. In a separate vessel, a solution of 10.0 g (44.8 mmol) of N-benzyl oxycarbonyl-β-alanine in 150 ml of tetrahydrofuran is cooled to 5 ° C. and treated with 8.72 g (53.7 mmol) of carbonyldiimidazole. After the addition has ended, the mixture is stirred at room temperature for 1 h. The solution of the imidazolide is transferred to a dropping funnel and added to the prepared solution of the magnesium malonate, which has been cooled to room temperature. The resulting suspension is stirred at room temperature overnight. Most of the THF is removed in vacuo. The residue is taken up in the two-phase system water-dichloromethane. The organic phase is separated off, dried over sodium sulfate and concentrated. Chromatography on silica gel (eluent: dichloromethane / ethyl acetate = 1/0 to 10/1) gives 9.8 g (75%) of ethyl 5- (benzyloxycarbonylamino) -3-oxo-pentanoate as a colorless oil.
¹ H NMR (200 MHz, DMSO): δ = 1.18 (t, 3H), 2.72 (t, 2H), 3.20 (q, 2H), 3.58 (s, 2H), 4.09 (q, 2H), 5.00 (s , 2H), 7.21 (br t, 1H), 7.33 (m, 5H).
MS (ESI): 294 [M + H] ⁺ .

Stage b)

A solution of 9.8 g (33.4 mmol) of the compound from step a, 4.15 g (66.8 mmol) of ethanediol and 160 mg (0.8 mmol) of p-toluenesulfonic acid hydrate in 200 ml of benzene is dissolved in a water separator heated to reflux for 16 h. After cooling to room temperature, sodium hydrogen carbonate solution is added and the aqueous phase is extracted with dichloromethane. The combined organic extracts are dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: dichloromethane / ethyl acetate = 1/0 to 5/1) gives 10.0 g (89%) of ethyl 5- (benzyloxycarbonylamino) -3- (1 ', 3'-dioxolano) pentanoate as a colorless oil .
¹ H NMR (200 MHz, DMSO): δ = 1.17 (t, 3H), 1.95 (dd, 2H), 2.62 (s, 2H), 3.09 (m, 2H), 3.96 (m, 4H), 4.05 (q , 2H), 5.00 (s, 2H), 7.11 (br t, 1H), 7.34 (m, 5H).
MS (ESI): 338 [M + H] ⁺ .

Stage c)

A solution of 4.9 g (14.5 mmol) of the compound from stage b in 50 ml of dichloromethane is mixed with 2.79 g (21.7 mmol) of potassium trimethylsilanolate at room temperature. After stirring for 2 hours, more potassium trimethylsilanolate (0.5 g) is added. The mixture is stirred for a further hour and the solvent is removed in vacuo. The residue is taken up in a two-phase system 1 M hydrochloric acid-ethyl acetate. After phase separation, the aqueous phase is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and concentrated in vacuo. 3.5 g (78%) of 5- (benzyloxycarbonylamino) -3- (1 ', 3'-dioxolano) pentanoic acid are obtained as a colorless oil.
¹ H NMR (400 MHz, DMSO): δ = 1.92 (s, 2H), 2.01 (m, 2H), 3.10 (m, 2H), 3.88 (m, 4H), 4.99 (s, 2H), 7.12 (br t, 1H), 7.35 (m, 5H), 12.06 (s, 1H).
MS (ESI): 310 [M + H] ⁺ .

Stage d)

Starting from 9.8 g (31.7 mmol) of the compound from stage c, another Clais condensation is carried out as described for the synthesis of ethyl 5- (benzyloxycarbonylamino) -3-oxopentanoate (stage a). After chromatography on silica gel (eluent: dichloromethane / ethyl acetate = 1/0 to 3/1), 7.8 g (65%) 7- (benzyloxycarbonylamino) -5- (1 ', 3'-dioxolano) -3-oxo are obtained -heptanoic acid ethyl ester.
¹ H NMR (200 MHz, DMSO): δ = 1.18 (t, 3H), 1.84 (dd, 2H), 2.82 (s, 2H), 3.06 (m, 2H), 3.60 (s, 2H), 3.89 (m , 4H), 4.07 (q, 2H), 5.00 (s, 2H), 7.15 (br t, 1H), 7.34 (m, 5H).
MS (ESI): 402 [M + Na] ⁺ .

Stage e)

A solution of 1.80 g (4.7 mmol) of the compound from stage d in 17 ml of saturated ethanolic ammonia solution is stirred overnight at room temperature. The volatile constituents are then removed in vacuo. The residue is dissolved in 50 ml of methanol, and a prepared solution of 897 mg (14.3 mmol) of sodium cyanoborohydride in 20 ml of methanol and then 628 mg (10.5 mmol) of acetic acid are added. The solution is stirred for 3 hours at room temperature. To complete the conversion, a further equivalent of sodium cyanoborohydride and acetic acid are added. After stirring for a further 30 minutes at room temperature, 50 ml of saturated aqueous sodium carbonate solution are added. Most of the methanol is removed under reduced pressure. The aqueous phase is extracted several times with ethyl acetate. The combined organic extracts are dried over sodium sulfate and concentrated in vacuo. 1.6 g (88%) of the amine are obtained, which is used for the next reaction without further purification (MS (ESI): 381 [M + H] ⁺ ). To do this, it is taken up in 80 ml of dichloromethane and the resulting solution is cooled to 0 ° C. 1.08 g (6.3 mmol) of benzyl chloroformate and 1.06 g (10.5 mmol) of triethylamine are added successively to the solution. Allow to warm to room temperature and stir overnight. After adding 20 ml of 1 M hydrochloric acid, the aqueous phase is extracted several times with dichloromethane. The combined organic extracts are dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (dichloromethane / ethyl acetate = 1/0 to 3/1) gives 1.4 g (65%) (3R, S) -3,7-bis (benzyloxycarbonylamino) -5- (1 ', 3'-dioxolano ) ethyl heptanoate as a colorless oil.
¹ H NMR (200 MHz, DMSO): δ = 1.18 (t, 3H), 1.74 (m, 4H), 2.48 (m, 2H), 3.05 (m, 2H), 3.80 (m, 4H), 4.02 (m , 3H), 5.00 (s, 4H), 7.16 (m, 2H), 7.34 (m, 10H).
MS (ESI): 515 [M + H] ⁺ .

Stage f)

Starting from 4.6 g (8.9 mmol) of the compound from stage e, ester cleavage is carried out with potassium trimethylsilanolate as described in stage c. 3.9 g (90%) (3R, S) -3,7-bis (benzyloxycarbonylamino) -5- (1 ', 3'-dioxolano) -heptanoic acid are obtained as a white solid.
¹ H NMR (200 MHz, DMSO): δ = 1.76 (m, 4H), 2.40 (m, 2H), 3.05 (m, 2H), 3.85 (m, 4H), 3.95 (m, 1H), 5.00 (s , 4H), 7.11 (m, 2H), 7.33 (m, 10H), 12.14 (br s, 1H).
MS (ESI): 487 [M + H] ⁺ .

The separation into the enantiomers takes place under the following conditions:
Stationary phase: poly (N-methacryloyl-L-isoleucine-3-pentylamide) grafted silica gel, based on 10 μm SH-modified silica gel;
Column dimensions 500 × 30 mm;
Eluent: ethyl acetate / methanol = 98/2;
Flow rate 25 ml / min.

First the 3R enantiomer elutes, then the 3S enantiomer.

Stage g)

A solution of 100 mg (0.21 mmol) (S) -3,7-bis (benzyloxycarbonylamino) -5- (1 ', 3'-dioxolano) -heptanoic acid (step f), 52 mg (0.21 mmol) (R, S) -5- (N-methyl amino) -5,6-dihydro-2- (2-pyridinylamino) -4 (1H) -pyrimidinone (Example VI); 156 mg (0.41 mmol) of HATU and 53 mg (0.41 mmol) of N, N-diisopropylethylamine in 10 ml of dimethylformamide are stirred overnight at room temperature. The volatile constituents are condensed off under reduced pressure. The residue is partitioned between 1 M hydrochloric acid and dichloromethane. The organic phase is separated off, dried over sodium sulfate and condensed. The residue obtained is dissolved in 3 ml of tetrahydrofuran and 3 ml of half-concentrated hydrochloric acid are added at 0 ° C. The mixture is allowed to warm to room temperature and stirred for 3 h. Water and ethyl acetate are added, the phases are separated and the aqueous phase is extracted several times with ethyl acetate. The combined organic extracts are dried over sodium sulfate and concentrated in vacuo to a yellow oil. 100 mg of (3'S, SR, S) -5- [N- (3,7-bis (benzyloxycarbonylamino) -5-oxoheptanoyl) -N methylamino] -5,6-dihydro-2- (2-pyridinylamino) - 4 (1H) -pyrimidinone.
MS (ESI): 644 [M + H] ⁺ .

Level h)

A solution of 55 mg (0.09 mmol) of the compound from stage g in 10 ml of dichloromethane / methanol (1/1) is admixed with 30 mg (0.17 mmol) of palladium (II) chloride. It is hydrogenated for 1 h at normal pressure and room temperature. It is filtered and the solvent is removed in vacuo. The residue is triturated with acetone. The white solid obtained is filtered off and dried in vacuo. 26 mg (68%) of the target compound are obtained.
¹ H-NMR (CD ₃ OD): δ = 2.75 (dd, 1H), 2.85 (dd, 1H), 2.96 (m, 2H), 3.08 (m, 2H), 3.16 (s, 3H), 3.20 (m , 2H), 3.98 (m, 2H), 4.12 (ddd, 1H), 5.25 (ddd, 1H), 7.24 (d, 1H), 7.32 (dd, 1H), 7.97 (dd, 1H), 8.42 (d, 1H).
MS (ESI): 376 [M + H] ⁺ .

Example 59

(3'R, 5R, S) -5- [N- (3,7-diamino-5-oxoheptanoyl) -N-methylamino] -5,6-dihydro-2- (2-pyridinyl-amino) -4 ( 1H) -pyrimidinone dihydrochloride

The compound is prepared analogously to Example 58 (stage gh) starting from (R) -3,7-bis (benzyloxycarbonylamino) -5- (1 ', 3'-dioxolano) -heptanoic acid (from stage f).
¹ H-NMR (CD ₃ OD): δ = 2.75 (dd, 1H), 2.86 (dd, 1H), 2.97 (m, 2H), 3.09 (m, 2H), 3.16 (s, 3H), 3.20 (m , 2H), 4.01 (m, 2H), 4.11 (ddd, 1H), 5.25 (ddd, 1H), 7.24 (d, 1H), 7.32 (dd, 1H), 7.96 (dd, 1H), 8.42 (d, 1H).
MS (ESI): 376 [M + H] ⁺ .

Example 60

(3'S, 5'R, S, 5R, S) -5- [N- (3,7-diamino-5-hydroxyheptanoyl) -N-methylamino] -5,6-dihydro-2- (2-pyridinyl-amino ) -4 (1H) -pyrimidinone dihydrochloride

A solution of 53 mg (0.08 mmol) (3'S, 5R, S) -5- [N- (3,7-bis (benzyloxycarbonyl amino) -5-oxoheptanoyl) -N-methylamino] -5,6-dihydro -2- (2-pyridinylamino) -4 (1H) -pyrimidinone (Example 58, stage g) in 0.3 ml of methanol is treated with 4.3 mg (0.11 mmol) of sodium borohydride at -78 ° C. The mixture is stirred for 3 h at -78 ° C., allowed to warm to room temperature, a few drops of 1 M hydrochloric acid and then water and ethyl acetate are added. After phase separation, the aqueous phase is extracted several times with ethyl acetate. The combined organic extracts are dried over sodium sulfate and concentrated in vacuo to a colorless oil. This is hydrogenated as described in Example 58 (stage h). 15 mg (42%) of the target compound are obtained as a white solid (mixture of two diastereomers in a ratio of 1: 1).
¹ H-NMR (CD ₃ OD): δ = 1.82 (m, 4H), 2.70-2.90 (m, 2H), 3.08 (m, 2H), 3.17 (s, 3H), 3.78 (m, 1H), 3.98 (m, 2H), 4.11 (dd, 1H), 5.23 (ddd, 1H), 7.25 (d, 1H), 7.32 (dd, 1H), 7.96 (dd, 1H), 8.42 (d, 1H).
MS (ESI): 378 [M + H] ⁺ .

Example 61

(3'R, 5'R, S, 5R, S) -5- [N- (3,7-diamino-5-hydroxyheptanoyl) -N-methylamino] -5,6-dihydro-2- (2-pyridinyl -amino) -4 (1H) -pyrimidinone dihydrochloride

The compound is prepared analogously to Example 60 starting from (3'R, 5R, S) -5- [N- (3,7-bis (benzyloxycarbonylamino) -5-oxoheptanoyl) -N-methylamino] -5,6-dihydro- 2- (2-pyridinyl-amino) -4 (1H) -pyrimidinone (see Examples 58 and 59) prepared as a mixture of two diastereomers.
¹ H-NMR (CD ₃ OD): δ = 1.85 (m, 4H), 2.70-2.90 (m, 2H), 3.08 (m, 2H), 3.17 (s, 3H), 3.78 (m, 1H), 3.96 (m, 2H), 4.13 (dd, 1H), 5.23 (ddd, 1H), 7.25 (d, 1H), 7.31 (dd, 1H), 7.96 (dd, 1H), 8.42 (d, 1H).
MS (ESI): 378 [M + H] ⁺

Claims (13)

1. Compounds of the general formula (T)
in which
R ^{1 represents} hydrogen or (C ₁ -C ₆ ) -alkyl,
A for a group of the formula
wherein
R ⁴ , R ⁵ , R ⁶ and R ^{7 are} each independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkanoyl, benzyl and pyridylmethyl,
R ^{8 is} hydrogen or (C ₁ -C ₆ ) -alkyl,
Q stands for doubly bonded O or S or for a doubly bonded group of the formula NR ⁹ ,
R ^{9 in} each case has the meaning given above for R ⁴ ,
D stands for a (C ₂ -C ₆ ) -alkanediyl group which can optionally be substituted one or two _{times, identically or differently, by hydroxy, (C 1} -C ₆ ) -alkoxy, (C ₁ -C ₆ ) -alkanoyloxy or by a Oxo group is substituted,
E stands for a bond or for the group of the formula -CH ₂ -,
R ^{2 represents} hydrogen or (C ₁ -C ₆ ) -alkyl,
and
R ^{3 represents} (C ₆ -C ₁₀ ) aryl or a 5- to 10-membered, partially unsaturated or aromatic, mono- or bicyclic heterocycle which has up to three heteroatoms from the series N, O and / or S contains, where both aryl and the heterocycle optionally up to three times identical or different by (C ₁ -C ₆ ) -alkyl, halogen, trifluoromethyl, (C ₁ -C ₆ ) -Allcoxycarbonyl, carboxyl, aminocarbonyl, phenyl, phenylamino and / or are substituted by mono- or di- (C ₁ -C ₆ ) -alkyl aminocarbonyl,
and their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts. 2. Compounds of the general formula (I) according to claim 1,
in which
R ^{1 represents} (C ₁ -C ₄ ) -alkyl,
A for a group of the formula
wherein
R ⁴ , R ⁵ , R ⁶ and R ^{7 are} each independently selected from the group consisting of hydrogen, (C ₁ -C ₄ ) -alkyl or acetyl,
R ^{8 is} (C ₁ -C ₄ ) -alkyl,
Q represents a double bonded O or a double bonded group of the formula NR ⁹ ,
R ^{9 in} each case has the meaning given above for R ⁴ ,
D is (C ₃ -C ₅ ) -alkanediyl, which is optionally substituted by hydroxy or by an oxo group,
E represents a bond or represents the group of the formula -CH ₂ -,
R ^{2 represents} hydrogen or (C ₁ -C ₄ ) -alkyl,
and
R ^{3 stands} for phenyl or for a 6- to 10-membered, partially unsaturated or aromatic, mono- or bicyclic heterocycle with up to three nitrogen atoms, both phenyl and the heterocycle, optionally up to two times, identically or differently by (C ₁ - C ₄ ) alkyl, fluorine, chlorine, bromine, trifluoromethyl, (C ₁ -C ₄ ) alkoxycarbonyl, carboxyl, aminocarbonyl, phenyl or phenylamino are substituted. 3. Compounds of the general formula (I) according to claim 1 or 2,
in which
R ^{1 represents} methyl,
A for a group of the formula
wherein
R ⁴ , R ⁵ , R ⁶ and R ^7, independently of one another, are each hydrogen or methyl,
R ^{8 is} (C ₁ -C ₄ ) -alkyl,
Q stands for a double bonded group of the formula NR ⁹ ,
R ^{9 in} each case has the meaning given above for R ⁴ ,
D is straight-chain (C ₃ -C ₅ ) -alkanediyl,
E stands for the group of the formula -CH ₂ -,
R ^{2 represents} hydrogen,
and
R ^{3 represents} pyridyl, pyrimidinyl, pyrazinyl or quinolinyl, each of which can be substituted one to two times, identically or differently, by methyl, trifluoromethyl, fluorine, chlorine or bromine. 4. Compounds of the general formula (Ia) according to claim 1, 2 or 3,
in which
A, D, R ¹ , R ² and R ^{3 have} the meanings given above. 5. Compounds of general formula (I) according to claim 1, 2, 3 or 4,
in which
R ^{1 represents} methyl. 6. Compounds of general formula (I) according to any one of claims 1 to 5,
in which
R ^{2 represents} hydrogen. 7. Compounds of general formula (I) according to any one of claims 1 to 6,
in which
E stands for the group of the formula -CH ₂ -. 8. Compounds of general formula (I) according to any one of claims 1 to 7,
in which
A represents the group of the formula H ₂ N-. 9. Process for the preparation of the compounds of the general formula (I), characterized in that first
Compounds of the general formula (II)
or their salts,
in which
R ^{3 has} the meaning given above,
by reaction with compounds of the general formula (III)
in which
R ^{1 has} the meaning given above
and
Z stands for a suitable amino protecting group,
in the presence of a base in compounds of the general formula (IV)
in which
R ¹ , R ³ and Z have the meaning given above,
convicted,
then split off the amino protective group Z according to customary conditions and with compounds of the general formula (V)
in which
D, E and R ^{2 have} the meaning given above,
R ^{10 stands} for an amino protecting group,
and
A ^{* stands} for one of the formulas listed above under A, with any free amino and / or imino groups present in these in protected form,
is reacted in inert solvents in the presence of an amide coupling reagent and, if appropriate, in the presence of a base and, if appropriate, in a last step the respective amino protective groups are split off by customary methods. 10. Compounds of the general formula (I) according to any one of claims 1 to 8 for use as a medicament. 11. Pharmaceutical composition that is a compound of general Formula (I) according to any one of claims 1 to 8 in admixture with one pharmaceutically acceptable carriers or excipients. 12. Use of a compound of the general formula (I) according to any one of claims 1 to 8 for the manufacture of a medicament. 13. Use of a compound of the general formula (I) according to any one of claims 1 to 8 for the manufacture of a medicament for treatment bacterial infections.