WO2003000665A1 - Antibacterial uracil derivatives - Google Patents

Abstract

The invention relates to the uracils of the general formula (I), wherein R?1, R2 and R3¿ are defined as in the description. The invention further relates to methods for producing the novel uracils, to pharmaceutical compositions containing them, and to their use in the treatment of diseases in humans and animals.

Description

 ANTIBACTERIAL URACIL DERIVATIVES

The present invention relates to uraciles, processes for their preparation, they include pharmaceutical compositions and their use in the treatment of diseases in humans or animals.

Gram-positive eubacteria contain three different DNA polymerase ex-nucleases, which are referred to as Pol 1, Pol 2 and Pol 3. Pol 3 is an enzyme that is necessary for the replicative synthesis of DNA.

WO 01/29 010 describes 3-aminocarbonyl-substituted phenylaminouracils.

WO 96/06614 describes 3-alkylidene-substituted uracils.

WO 00/71523 describes 3-alkanoyloxyalkyl uracils.

WO 00/20556 describes Uracile with a zinc finger active unit as antibacterial compounds.

In J. Med. Chem., 1999, 42, 2035, Antimicro. Agents and Chemotherapy, 1999, 43,

1982 and Antimicro. Agents and Chemotherapy, 2000, 44, 2217, phenylaminouracile are described as antibacterial compounds.

Although there are other structurally different antibacterial agents on the market, resistance can regularly develop.

New means for better and more effective therapy are therefore desirable.

An object of the present invention is therefore to provide new compounds with the same or improved antibacterial activity for the treatment of bacterial diseases in humans and animals. Surprisingly, it has been found that derivatives of this class of compounds in which the amide is replaced by cyclic amides are highly antibacterial.

The present invention therefore relates to compounds of the general

Formula (I)

embedded image in which

R ¹ and R ² together with the nitrogen atom to which they are attached form a heterocycle,

where this heterocycle can be optionally substituted with 1 to 3 substituents independently selected from the group halogen, trifluoromethyl, trifluoromethoxy, nitro, dC ₆ alkyl, dC _ö alkoxy, C ₃ -C ₆ cycloalkyl, - (CH ₂ ) _P -C ₆ -Cι ₀ aryl, - (CH ₂ ) _n heteroaryl, - (CH ₂ ) _m heterocyclyl, 1,2- (methylenedioxy) benzene, oxo, formyl, dC ₆ alkylcarbonyl, dC ₆ -alkoxy-carbonyl, amino, d-Cβ-alkylamino, -C-C ₆ -dialkylamino, phenylamino, aminocarbonyl, Cι-C ₆ -alkylaminocarbonyl, dC ₆ -dialkylarninocarbonyl,

Aminosulfonyl, alkylaminosulfonyl _ö dC, dC _ό dialkylaminosulfonyl, C ₃ - C ₈ -Cycloalkylaminosulfonyl, C ₃ -C ₈ -Dicycloalkylaminosulfonyl, C ₆ -C ₁₀ - arylaminosulfonyl, heteroarylaminosulfonyl, -CH ₂ CH ₂ OCH ₂ CH ₂ OH and

-NR '-' R ¹ - ² .

wherein p, n and m are identical or different and are 0, 1, 2, 3 or 4, wherein Cι-C ₆ -alkyl, C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, phenylamino, - (CH _{2) P} - C ₆ -C ₁₀ aryl, - (CH _{2) m} -heterocyclyl and - (CH ₂ ) _n -Heteroaryl can in turn be substituted with 1 to 4 substituents selected from the group Ci-Cβ-alkyl, hydroxy, Ci-C _ö alkoxycarbonyl, amino, dC _ό -alkylamϊno, dC _ö -dialkylamino, dC _ö - Alkylcarbonylamino, oxo, cyano, nitro, heterocyclicl, dC _ö alkoxy and Ci-C _ö thioalkyl,

and wherein R ^{1 "1} and R ^{1" 2} are identical or identical and are selected from the group consisting of hydrogen, Ci-Cβ-alkyl, -OCH ₂ CH ₂ OH, C ₃ -C ₆ cycloalkyl, C ₆ -C _10- aryl, heteroaryl, -CC ₆ alkylcarbonyl, CC ₆ -

Alkoxycarbonyl, arylcarbonyl C ₃ -C ₈ cycloalkylcarbonyl, C ₆ -do-arylcarbonyl, hetero, aminocarbonyl, alkylaminocarbonyl _ö dC, dC ₆ dialkyl aminocarbonyl, dC ₆ alkylsulfonyl, C ₃ -C ₈ cycloalkylsulfonyl, C ₆ -do-aryl-sulfonyl and heteroarylsulfonyl,

R ^ is a substituent of the following formula

wherein

R ^ -l and R3 "2 are independently selected from the group -C-C ₆ alkyl, C2-C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl and halogen, or

R3 ^~ l and R ^ '2 together with the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl or heterocyclyl ring which can optionally be substituted by up to 3 halogen, A is a Ci-Cß-alkanediyl chain, which optionally contains one or more double or triple bonds and in which one carbon atom is optionally replaced by a nitrogen or oxygen atom, with at least 2 carbon atoms between the hetero atom in A and the nitrogen atom in the uracil ring , and where the

Heteroatom in A and the carbonyl carbon atom, which is adjacent to A, must have at least 1 carbon atom,

and optionally with up to 3 substituents selected from the group halogen, nitro, amino, dC ₆ alkylamino, C ₁ -C ₆ dialkylamino, dC ₆ -

Acylamino, trifluoromethyl, trifluoromethoxy is substituted,

and their pharmaceutically acceptable salts, solvates and hydrates.

The compounds of the general formula (I) according to the invention can occur in various stereoisomeric forms which either behave like images and mirror images (enantiomers) or do not behave like images and mirror images (diastereomers). The invention relates to both the enantiomers and the diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.

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 the invention.

The substances of the general formula (I) according to the invention can also be present as salts. Physiologically acceptable salts are preferred in the context of the invention. Physiologically acceptable (pharmaceutically acceptable) salts can be salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid are preferred, or salts with organic carboxylic or sulfonic acids such as acetic acid, propionic acid,

Maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts can also be salts of the invention

Be compounds with bases, such as metal or ammonium salts. Preferred examples are alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), and also ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di- or Triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.

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

The compounds of the present invention are distinguished by a broad spectrum of activity against Gram-positive bacteria, it also being possible to detect multi-resistant germs, in particular staphylococci, pneumococci and

Enterococci, including vancomycin-resistant strains.

The compounds generally have sufficient solubility to produce solutions for parenteral administration. Alkyl and the alkyl parts in alkoxy, mono- and dialkylamino stand for straight-chain or branched alkyl and, unless stated otherwise, comprise dC ₆ -alkyl, in particular dC-alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert -butyl..

Alkenyl stands for a straight-chain or branched alkenyl radical with 2 to 6 carbon atoms. A straight-chain or branched alkenyl radical having 2 to 4, particularly preferably 2 to 3, carbon atoms is preferred. For example and preferably, the following may be mentioned: vinyl, allyl, n-Proρ-1-en-l-yl and n-but-2-en-l-yl.

Alkynyl is a straight-chain or branched alkenyl radical with 2 to 6 carbon atoms. A straight-chain or branched alkenyl radical having 2 to 4, particularly preferably 2 to 3, carbon atoms is preferred. For example and preferably, the following may be mentioned: n-prop-1-in-1-yl and n-but-2-in-1-yl.

Cycloalkyl comprises polycyclic saturated hydrocarbon radicals with up to 14 C atoms, namely monocyclic C3-C12, preferably C ₃ -C ₈ alkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and polycyclic alkyl , ie preferably bicyclic and tricyclic, optionally spirocyclic C -C -alkyl, such as bicyclo [2.2.1] -hept-l-yl,

Bicyclo [2.2.1] -hept-2-yl, bicyclo [2.2.1] -hept-7-yl, bicyclo [2.2.2] -oct-2-yl, bicyclo [3.2.1] -oct-2 -yl, bicyclo [3.2.2] -non-2-yl and adamantyl.

Alkanediyl (alkylidene) stands for a carbon chain that is terminally substituted at both terms. It can optionally be mono- or polyunsaturated, in the form of double or triple bonds. Saturated chains having 1 to 6 carbon atoms, in particular 2 to 4 carbon atoms, are preferred, unless stated otherwise. (CH ₂ stands as a prefix for substituents for an alkanediyl chain with chain length n. In the context of the invention, alkoxy preferably represents a straight-chain or branched alkoxy radical, in particular having 1 to 6, 1 to 4 or 1 to 3 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is preferred. The following may be mentioned by way of example and preferably: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, i-butoxy, n-pentoxy and n-hexoxy.

In the context of the invention, monoalkylamino represents an amino group with a straight-chain or branched alkyl substituent which preferably has 1 to 6, 1 to 4 or 1 to 2 carbon atoms. A straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms is preferred. The following may be mentioned as examples and preferably: methylamino, ethylamino, n-propylamino, isopropylamino, t-butylamino, n-pentylamino and n-hexylamino.

In the context of the invention, dialkylamino stands for an amino group with two identical or different straight-chain or branched alkyl substituents, which preferably each have 1 to 6, 1 to 4 or 1 to 2 carbon atoms. Straight-chain or branched dialkylamino radicals each having 1 to 4 carbon atoms are preferred. The following may be mentioned by way of example and preferably: NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N- isopropyl-Nn-propylamino, Nt-butyl-N-methylamino, N- Ethyl-Nn-pentylamino and

N-n-hexyl-N-methylamino.

In the context of the invention, mono- or dialkylaminocarbonyl represents an amino group which is linked via a carbonyl group and which has a straight-chain or branched or two identical or different straight-chain or branched alkyl substituents, each preferably having 1 to 4 or 1 to 2 carbon atoms , The following may be mentioned by way of example and preferably: methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, t-butylaminocarbonyl, NN-dimethylaminocarbonyl, NN-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl and Nt-butyl-N-methylaminocarbonyl. In the context of the invention, alkylcarbonylamino (acylamino) represents an amino group having a straight-chain or branched alkanoyl substituent which preferably has 1 to 6, 1 to 4 or 1 to 2 carbon atoms and is linked via the carbonyl group. A monoacylamino radical having 1 to 2 carbon atoms is preferred. The following may be mentioned as examples and preferably: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.

-Cio-aryl generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

Heteroaryl represents a 5- to 10-membered, in particular a 5- to 6-membered aromatic, optionally bonded via a nitrogen atom mono- or polycyclic heterocycle with up to 3 heteroatoms from the series S, O and / or N, for example for Pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, N-triazolyl, oxazolyl or imidazolyl. Pyridyl, furyl,

Thiazolyl and N-triazolyl. The term "nitrogen heteroaryl", such as in "6-, 9 or 10-membered nitrogen (CH ₂ ) _n heteroaryl", stands for a heteroaryl ring which has no other heteroatoms apart from nitrogen.

Heterocyclyl (heterocycle) stands for a mono- or polycyclic, heterocyclic radical with 3 to 11 ring atoms and up to 3, preferably 1 heteroatoms or hetero groups from the series N, O, S, SO, SO _{2, which} is optionally bonded via a nitrogen atom. In the case of polycyclic radicals, the rings can be condensed (for example with a [0] bridge) or spiro-linked. 4- to 8-membered, in particular 5- and 6-membered, heterocyclyl is preferred. Mono- or bicyclic

Heterocyclyl is preferred. Monocyclic heterocyclyl is particularly preferred. N and O are preferred as heteroatoms. The heterocyclyl residues can be saturated or partially unsaturated. The unsaturated representatives can contain one or more double bonds in the ring or, in the case of polycyclic systems, can be aromatic in a ring, such as, for example, benzoxazine. Saturated heterocyclyl residues are preferred. The heterocyclyl radicals can have a carbon atom or a heteroatom be bound. It can be formed from two substituent groups together with the nitrogen atom to which they are attached. 5- to 7-membered, monocyclic, saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S are particularly preferred. Examples and, preferably, are: oxetanyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidinyl , Thiopyranyl, Mo holinyl, Perhydroazepinyl, Thio- moφholinyl, Piperazinyl, Bicyclo [2.2.1] diazaheptyl. The term “nitrogen-heterocyclyl”, as for example in “6-membered nitrogen- (CH ₂ ) _π -heterocyclyl”, stands for a heterocyclyl ring which has no other heteroatoms apart from nitrogen.

Halogen represents fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred unless otherwise stated.

Two substituents can also be attached to the same carbon atom.

Likewise, cyclic substituents (cycloalkyl, heterocyclyl), when bound to cyclic substituents, can be spiro-linked.

A symbol * on a bond means the point of attachment in the molecule.

The general or preferred radical definitions given above apply both to the end products of the formula (I) and correspondingly to the starting materials or intermediates required in each case for the preparation.

The radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of other combinations, regardless of the respectively specified combinations of the radicals.

In the context of the present inventions, preference is given to compounds of the general formula (I) embedded image in which

1 ^* ) • ■

R and R together with the nitrogen atom to which they are attached form a heterocycle,

where this heterocycle can be optionally substituted with 1 to 3 substituents independently selected from the group halogen, trifluoromethyl, trifluoromethoxy, nitro, dC ₆ alkyl, Ci-C _ö alkoxy, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl, - (CH ₂ ) _n heteroaryl, - (CH ₂ ) _m heterocyclyl, dC ₆ alkoxycarbonyl, aminocarbonyl, dC _δ alkylaminocarbonyl, dC ₆ dialkyl aminocarbonyl, aminosulfonyl, dC ₆ -Alkylaminosulfonyl, dC _ö -dialkyl-aminosulfonyl, d-Cs-cycloalkylaminosulfonyl, C ₃ -C ₈ -dicycloalkylaminosulfonyl, Ce-do-arylaminosulfonyl, heteroarylaminosulfonyl, -CH ₂ CH ₂ OCH ₂ CH ₂ OH, or -NR ^{1 "} 'R ¹ - ² ,

in which n and m are identical or different and are 2, 3 or 4,

wherein dC _ö alkyl, Ci-C _ö alkoxy, C ₃ -C ₆ cycloalkyl, C ₆ -Cι ₀ aryl, hetero- aryl in turn may be substituted with 1 to 3 substituents selected from the group of hydroxy, dC ₆ - Alkoxycarbonyl, amino, dC ₆ -alkylamino, C _\ -C ₆ -dialkylamino, C \ -C ₆ - alkylcarbonylamino,

and wherein R ^{1 '1} and R ^{1' 2} are the same or identical, and Cι-C ₆ are selected from the group consisting of hydrogen, - alkyl, -OCH ₂ CH ₂ OH, dC _ö cycloalkyl, C _ö -do-aryl , Heteroaryl, dC ₆ -alkylcarbonyl, CrC ₆ - alkoxycarbonyl, C ₃ -C ₈ -cycloalkylcarbonyl, C ₆ -do-arylcarbonyl, hetero-arylcarbonyl, aminocarbonyl, Cj-C _ό -alkylaminocarbonyl, Cι-C ₆ -dialkyl-aminocarbonyl, Ci-C _ö alkylsulfonyl, C ₃ -C ₈ cycloalkylsulfonyl, C _ö -Cio-arylsulfonyl and heteroarylsulfonyl, R3 is a substituent of the following formula

embedded image in which

R3-1 and R3-2 are independently selected from the group dC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl or halogen, or

R3 ^_ l and R3-2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl-dC _ö ring which may be optionally substituted with up to 3 halogen,

A is a C 1 -C 6 -alkylidene chain, which optionally contains one or more double or triple bonds and in which one carbon atom is optionally replaced by a nitrogen or oxygen atom, both of the hetero atom in A and the nitrogen atom in the uracil ring having to have at least 2 carbon atoms , and where the hetero atom in A and the carbonyl carbon atom which is adjacent to A must have at least 1 carbon atom,

and which is optionally substituted with up to 3 substituents selected from the group halogen, nitro, amino, dC ₆ alkylamino, C ₁ -C ₆ dialkylamino, C ₁ -C ₆ acylamino, trifluoromethyl, trifluoromethoxy,

and their pharmaceutically acceptable salts, solvates and hydrates. In the context of the present inventions, preference is also given to compounds of the general formula (I)

embedded image in which

R ¹ and R ² together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycle,

where this heterocycle can be optionally substituted with 1 to 3 substituents independently selected from the group halogen, trifluoromethyl, nitro, CC ₆ alkyl, Ci-C _ö alkoxy, C ₃ -C ₆ cycloalkyl, - (CH ₂ ) _P -C ₆ - aryl, - (CH _{2) n} -heteroaryl, - (CH _{2) m} -heterocyclyl, l, 2- (methylenedioxy) benzene, oxo, formyl, methylcarbonyl, dC _ö alkoxycarbonyl, amino, methylamino, Dimethylamino, phenylamino, aminocarbonyl, CrC ₆ alkylaminocarbonyl, d -C ₆ dialkylaminocarbonyl and -CH ₂ CH ₂ OCH ₂ CH ₂ OH

in which p, n and m are identical or different and are 0, 1 or 2,

(CH _{2) n} - where _Cι-C6 alkyl, dC ₆ alkoxy, dC _ό cycloalkyl, phenylamino, - (CH _{2) P} - C _ö -Cjo-aryl, - (CH _{2) m} -heterocyclyl and - Heteroaryl in turn can be substituted with 1 to 3 substituents selected from the group Ci-C _ό alkyl, hydroxy, Ci-C _ö alkoxycarbonyl, amino, dimethylamino, oxo, cyano, nitro, heterocyclyl, C ₁ -C ₆ alkoxy and dC thioalkyl,

R ^ is a substituent of the following formula

embedded image in which R ^ -l and R3-2 are independently selected from the group -C-C ₆ - alkyl, fluorine and chlorine, or

R3 "1 and R3- together with the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl or 3- to 6-membered heterocyclic ring which is optionally substituted with up to 3 fluorine or chlorine can be,

A is a Ci -C4 alkanediyl chain,

which is optionally substituted with a substituent selected from the group consisting of fluorine, chlorine and amino,

and their pharmaceutically acceptable salts, solvates and hydrates.

In the context of the present inventions, preference is also given to compounds of the general formula (I)

wherein

R ¹ and R ² together with the nitrogen atom to which they are attached form a six-membered heterocycle, where this heterocycle can optionally be substituted with 1 to 3 substituents selected from the group halogen, dC ₆ -alkyl, dC ₆ -alkoxy, C ₃ -C ₆ cycloalkyl, C ₆ -Cι ₀ -

Aryl, heteroaryl, dC ₆ -alkoxycarbonyl, aminocarbonyl, dC ₆ -alkyl-aminocarbonyl, -C-C ₆ -dialkylaminocarbonyl, aminosulfonyl, -C-C ₆ -alkylaminosulfonyl, Cι-C ₆ -dialkylaminosulfonyl, C ₃ -C ₈ -cyclo - sulfonyl, C ₃ -C ₈ dicycloalkylaminosulfonyl, C ₆ -Cι ₀ arylaminosulfonyl, heteroarylaminosulfonyl, -CH ₂ CH ₂ OCH ₂ CH ₂ OH, or -NR ^ 'R ^{1 "2} , wherein dC ₆ - alkyl, Cι-C ₆ - alkoxy, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl, hetero- aryl in turn may be substituted with 1 to 3 substituents selected from the group amino, dC _ö - Alkylamino, Ci-C _ö dialkylamino, dC _ö - alkylcarbonylamino,

and wherein R ^'and R ^"are the same or identical, and Cι-C ₆ are selected from the group consisting of hydrogen, - alkyl, -OCH ₂ CH ₂ OH, dC _ö cycloalkyl, C _ö -do-aryl, heteroaryl, Cι -C ₆ -alkylcarbonyl, dC ₆ - alkoxycarbonyl, C ₃ -C ₈ -cycloalkylcarbonyl, C ₆ -Cιo-arylcarbonyl, hetero-arylcarbonyl, aminocarbonyl, CrC _ό -alkylaminocarbonyl, Cι-C ₆ -dialkyl-aminocarbonyl, dC ₆ -alkylsulfonyl , C ₃ -C ₈ cycloalkylsulfonyl, C ₆ -Cιo-arylsulfonyl and heteroarylsulfonyl,

R3 is a substituent of the following formula

embedded image in which

R -1 and R ^ "are independently selected from the group

C] -C ₆ - alkyl or halogen, or

R3-1 and R3-2 together with the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl ring,

A is a -C-C3 alkylidene chain.

In the context of the present inventions, preference is also given to compounds of the general formula (I) embedded image in which

R ¹ and R ² together with the nitrogen atom to which they are attached form a pyrrolidine-piperidine, piperazine or thiomopholine ring,

where this pyrrolidine-piperidine, piperazine or thiomophole ring may optionally be substituted with 1 to 3 substituents independently selected from the group fluorine, chlorine, nitro, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, - (CH ₂ ) _P - Phenyl, 6-, 9- or 10-membered

Nitrogen (CH ₂ ) _n heteroaryl, 5- or 6-membered - (CH ₂ ) _m - heterocyclyl, 1,2- (methylenedioxy) benzene, oxo, formyl, methylcarbonyl, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, dimethylamino , Phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl and -CH ₂ CH ₂ OCH ₂ CH ₂ OH

in which p, n and m are identical or different and are 0, 1 or 2,

wherein methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, phenylamino, - (CH ₂ ) _P -phenyl, 6-, 9- or 10-membered nitrogen- (CH ₂ ) _n -heteroaryl and 5- or 6-membered - (CH2) - Heterocyclyl in turn can be substituted with 1 to 2 substituents selected from the group methyl, ethyl, isopropyl, hydroxy, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, amino, dimethylamino, oxo, cyano, nitro, 5- or 6 -linked heterocyclyl and thiomethyl,

R ^ is a substituent of the following formula

embedded image in which

R ^ -l and R-3- are independently selected from the group methyl, ethyl, fluorine and chlorine, or

R3 ^_ 1 and R3-2 together with the carbon atom to which they are attached form a cyclopentyl ring,

A is a Ci -C4 alkanediyl chain,

which is optionally substituted with a substituent selected from the group consisting of fluorine, chlorine and amino,

and their pharmaceutically acceptable salts, solvates and hydrates.

Also preferred within the scope of the present inventions are compounds of the general formula (I) in which R ¹ and R ² together with the nitrogen atom to which they are attached form a piperidine or piperazine ring, this piperidine or piperazine ring optionally being as stated above can be substituted.

In the context of the present inventions, preference is also given to compounds of the general formula (I) in which R ¹ and R ² together with the nitrogen atom to which they are bonded form a piperazine ring, which piperazine ring can optionally be substituted with 1 to 3 substituents from the group dC ₆ - alkyl, heteroaryl or -CH ₂ CH ₂ OCH ₂ CH ₂ OH.

In the context of the present inventions, preference is also given to compounds of the general formula (I) in which R ^ is selected from the group consisting of:

In the context of the present inventions, preference is also given to compounds of the general formula (I) in which R is a group

In the context of the present inventions, preference is also given to compounds of the general formula (I) where R is a group

In the context of the present inventions, preference is also given to compounds of the general formula (I) in which A is ethylene or propylene. In the context of the present inventions, preference is also given to compounds of the general formula (I) in which A is propane-1,3-diyl or butane-1,4-diyl, in particular propane-1,3-diyl.

The active substance can act systemically and / or locally. For this purpose it can be applied in a suitable way, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as an implant.

The active ingredient can be administered in suitable administration forms for these administration routes.

Known application forms which release the active ingredient quickly and / or modified, such as e.g. Tablets (non-coated and coated tablets, e.g. tablets or film-coated tablets provided with enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions and solutions.

Parenteral administration can be done by bypassing a resorption step (intravenously, intraarterially, intracardially, intraspinally or intralumbally) or by switching on a resection (intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

For the other application routes, e.g. Inhalation drug forms (e.g.

Powder inhalers, nebulizers), nose drops / solutions, sprays; tablets or capsules to be administered lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants.

The active compounds can be converted into the application forms mentioned in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients. These include Carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), dispersants (e.g. polyvinylpyrrolidone), synthetic and natural biopolymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), dyes (e.g. inorganic pigments such as

Iron oxides) or taste and / or smell.

In general, it has proven to be advantageous to administer amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 1 mg / kg body weight in the case of parenteral administration, in order to achieve effective results. In the case of oral administration, the amount is approximately 0.01 to 500 mg / kg, preferably approximately 1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the quantities mentioned, depending on the 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.

Parenteral, in particular intravenous, e.g. as an iv bolus injection (i.e. as a single dose, e.g. by syringe), short-term infusion

(ie infusion over a period of up to one hour) or long-term infusion (ie infusion over a period of more than one hour). The volume applied can, depending on the special conditions, between 0.5 to 30, in particular 1 to 20 ml in the case of the iv bolus injection, between 25 to 500, in particular 50 to 250 ml in the case of the short-term infusion and between 50 to 1000. in particular 100 to 500 ml for long-term infusion. For this it can be advantageous be to provide the active substance in solid form (eg as a lyophilisate) and to dissolve it in the solution medium only immediately before application.

The application forms must be sterile and pyrogen-free. They can be based on aqueous or mixtures of aqueous and organic solvents.

These include e.g. aqueous solutions, mixtures of aqueous and organic solvents (in particular ethanol, polyethylene glycol (PEG) 300 or 400), aqueous solutions containing cyclodextrins or aqueous solutions containing emulsifiers (surface-active solubilizers, e.g. lecithin or Pluronic

F 68, Solutol HS 15, Cremophor). Aqueous solutions are preferred.

Isotonic and euhydric formulations are largely suitable for parenteral administration, e.g. those with a pH between 3 and 11, especially 6 and 8, especially around 7.4.

The injection solutions are packed in suitable containers made of glass or plastic, e.g. in vials. These can have a volume of 1 to 1000, in particular 5 to 50 ml. The solution can be taken directly from these and applied. In the case of a lyophilizate, it is dissolved in the vial by injecting a suitable solvent and then removed.

The infusion solutions are packed in suitable glass or plastic containers, e.g. in bottles or collapsing plastic bags. These can have a volume of 1 to 1000, in particular 50 to 500 ml.

The present invention further relates to a process for the preparation of the compounds of the general formula (I) by reacting compounds of the general formula (II)

embedded image in which

A and R ^{3 have} the meaning given above,

and the carboxylic acid is optionally present in activated form,

with compounds of the general formula (III)

, NL (III)

R ¹ - ^* H woπn

R> ι "and R have the meaning given above.

The reaction is carried out in inert solvents, in the presence of customary condensing agents, if appropriate in the presence of a base, preferably in a temperature range from room temperature to 50 ° C. at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol such as benzyl xylene glycol such as benzyl xylene glycol, such as xylene glycol, such as xylene glycol , Toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, Dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dimethyl sulfoxide, acetonitrile or pyridine, tetrahydrofuran, dimethylformamide, 1,2-dichloroethane or methylene chloride are preferred.

Common condensing agents are, for example, carbodiimides such as e.g. N, N'

Diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide -N'-propyloxymethyl polystyrene (PS carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulfate or 2-tert.-butyl -5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis- (2-oxo-3-oxazolidinyl) phosphoryl chloride or 1-benzotriazolyloxytripyrrolidium - hexafluorophosphate (PyBOP) or O- (benzotriazol-l-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-l- (2H) -pyridyl) -l, l, 3,3-tetramethyl uronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-l-yl) -N, N, N ^l , N'-tetra-methyluronium hexafluorophosphate (HATU), or 1-hydroxybenztriazole ( HOBt), or Benzotriazol-1 -yloxytris (dimethyla mino) -phosphonium hexafluorophosphate (BOP), or mixtures of these.

Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-Methylmoφholin, N-Methylpiperidin, 4-Dimethylaminopyridin or Diisopropylethylamin.

The combination of N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) and triethylamine in dimethylformamide or HATU and diisopropylethylamine in dimethylformamide or 1-benzotriazolyloxytripyrrolidinophosphonium phosphonium phosphonium is particularly preferred (PyBOP) and diisopropylethylamine in dimethylformamide. The amines (III) are known or can be prepared by methods known from the literature.

A process for the synthesis of the compounds of the formula (II) can be found in part A. Examples (see general working instructions 1 to 6).

A production route is to be explained by the following scheme 1:

(V)

(VIII)

H ₂ N - R ^J

(VI)

R ^< I

R ^ H

(HI)

(I)

Scheme 1 The compounds according to the invention show an unforeseeable, valuable pharmacological and pharmacokinetic spectrum of action. They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.

The compounds according to the invention are particularly effective against bacteria and bacteria-like microorganisms, in particular Gram-positive bacteria. They are therefore particularly well suited for the prophylaxis and chemotherapy of local and possibly systemic infections in human and veterinary medicine, which are caused by these pathogens.

For example, local and / or systemic diseases that are caused by the following pathogens or by mixtures of the following pathogens can be treated and / or prevented:

Gram-positive cocci, e.g. Staphylococci (Staph. Aureus, Staph. Epidermidis) and Streptococci (Strept. Agalactiae, Strept. Faecalis, Strept. Pneumoniae, Strept. Pyogenes) as well as strictly anaerobic bacteria such as e.g. Clostridium, also mycoplasma (M. pneumoniae, M. hominis, M. ureaiyticum).

The above list of pathogens is only an example and is in no way to be interpreted as limiting. Examples of diseases which can be caused by the pathogens or mixed infections mentioned and which can be prevented, improved or cured by the compounds according to the invention are:

Infectious diseases in humans such. B. septic infections, bone and joint infections, skin infections, postoperative wound infections, abscesses, phlegmon, wound infections, infected burns, burns, infections in the mouth area, infections after dental operations, septic arthritis, mastitis, tonsillitis, genital infections and eye infections. In addition to humans, bacterial infections can also be treated in other species. Examples include:

Pig: sepsis, metritis-mastitis-agalaktiae syndrome, mastitis;

Ruminants (cattle, sheep, goats): sepsis, bronchopneumonia, mycoplasmosis, genital infections;

Horse: bronchopneumonia, pueφerale and postpueφerale infections;

Dog and cat: bronchopneumonia, dermatitis, otitis, urinary tract infections, prostatitis;

Poultry (chicken, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, chronic respiratory diseases, psittacosis.

Bacterial diseases in the rearing and keeping of farmed and ornamental fish can also be treated, the antibacterial spectrum extending beyond the previously mentioned pathogens to other pathogens such as e.g. Brucella, Campylobacter, Listeria, Erysipelothris, Nocardia expanded.

A. Assessment of pharmacological effectiveness

in vftro effect

The in vitro effect of the compounds according to the invention can be shown in the following assays:

Cloning, Expression and Purification of Pol III from S. aureus To clone polC with an N-terminal His tag, the structural gene polC is amplified with the help of PCR from genomic DNA from S. aureus. With help the primers SAPol31 5'-GCGCCATATGGACAGAGCAACAAAAATTTAA-3 'and SAPolrev 5'-GCGCGGATCCTTACATATCAAATATCGAAA-3' the restriction sites Ndel and BamHI are introduced before and after the amplified gene. After the 4300 bp PCR product has been digested with Ndel and BamHI, it is converted into the vector pET15b, also digested with Ndel and BamHI

(Novagen, USA) ligated and transformed into E. coli XL-1 Blue.

After transformation into E. coli BL21 (DE3) cells for the expression of PolC at 30 ° C in LB medium to be cultured with 100 ug / ml ampicillin to an OD ₅₉₅ "of 0.5 _m, cooled to 18 ° C and incubated for 20 hours after the addition of 1 mM IPTG. The cells are harvested by centrifugation, washed once in PBS with 1 mM PMSF and taken up in 50 mM NaH ₂ PO ₄ pH 8.0, 10 mM imidazole, 2 mM β-mercaptoethanol, 1 mM PMSF, 20% glycerol. The cells are disrupted using a French press at 12,000 psi, the cell debris centrifuged (27,000xg, 120 min, 4 ° C) and the supernatant with an appropriate

Amount of Ni-NTA agarose (from Quiagen, Germany) stirred at 4 ° C. for 1 hour. After filling into a column, the gel matrix is washed with 50 mM NaH ₂ PO pH 8.0, 2 mM β-mercaptoethanol, 20 mM imidazole, 10% glycerol and the purified protein is then washed with the same buffer containing 100 mM imidazole. eluted. The purified protein is mixed with 50% glycerol and stored at -20 ° C.

Inhibition assay

The activity of PolC is measured in an enzymatically coupled reaction, the pyrophosphate formed during the polymerization using the ATP

Sulfurylsae is converted into ATP, which is detected with the help of Firefly luciferase. The reaction mixture contains 50 mM Tris / Cl pH 7.5 in a final volume of 50 μl; 5 mM DTT, 10 mM MgCl ₂ , 30 mM NaCl, 0.1 mg / ml BSA, 10% glycerol, each 20 μM dATP, dTTP, dCTP, 2U / ml activated calf thymus DNA (Worthington, USA), 20 µM APS and 0.06 mM luciferin. The reaction is through

Addition of purified PolC in a final concentration of ~ 2 nM, started and Incubated for 30 min at 30 ° C. The amount of pyrophosphate formed is then converted to ATP by adding ATP sulfurylase (Sigma, USA) at a final concentration of 5 nM and incubating at 30 ° C for 15 min. After adding 0.2 nM Firefly luciferase, the luminescence is measured in a luminometer for 60 s. The concentration of an inhibitor is given as IC ₅₀ , which leads to a 50% inhibition of the enzyme activity of PolC.

Table A

in v vo effect

The suitability of the compounds according to the invention for the treatment of bacterial infections can be shown in the following animal models:

Determination of the minimum inhibitory concentrations (MIC) against a number of germs

The MIC values against various bacterial strains (S. aureus, S. pneumoniae, E. faecalis) are carried out using the microdilution method in BHI broth. The bacterial strains are grown overnight in BHI broth (staphylococci) or BHI broth + 10% bovine serum (streptococci, enterococci). The test substances are in a concentration range from 0.5 to 256 μg / ml checked. After serial dilution of the test substances, the microtite plates are inoculated with the test germs. The germ concentration is approx. LxlO ⁶ germs / ml suspension. The plates are incubated at 37 ° C under 8% CO2 (for streptococci, enterococci) for 20 h. The lowest concentration at which the visible growth of the bacteria is completely inhibited is recorded as the MIC value.

Systemic infection with S. aureus 133

S. aureus 133 cells are grown overnight in BH broth. The overnight culture is diluted 1: 100 in fresh bra broth and turned up for 3 hours. The bacteria in the logarithmic growth phase are centrifuged off and washed twice with buffered, physiological saline (303). A cell suspension with an absorbance of 50 units in 303 is then set on the photometer (model LP 2W, Dr. Lange, Germany). After a dilution step (1:15), this suspension is mixed 1: 1 with a 10% mucin suspension. 0.25 ml / 20 g mouse ip is applied from this infection solution. This corresponds to a cell count of approximately 1 x 10E ⁶ germs / mouse. The ip therapy takes place 30 minutes after the infection. Female CFW1 mice are used for the infection attempt. The survival of the animals is recorded over 6 days.

B. Examples

Abbreviations:

aq. watery

Bn benzyl

DΓPEA diisopropylamine (Hünig Base)

DMSO dimethyl sulfoxide

DMF dimethylformamide d. Th. Of theory eq. equivalent to

ESI electrospray ionization (for MS) in vacuo in a vacuum

HATU O- (7- azabenzotriazol-1-y 1) -N, N, N ', N'-tetramethy luronium-

Hexafluorophosphate h hour

HPLC high pressure, high performance liquid chromatography

LC-MS liquid chromatography-coupled mass spectroscopy

MeCN acetonitrile

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy

Pd / C palladium / carbon

PS trisamine resin Ν- [2-amino-Ν ^l , Ν'-bis (2-aminoethyl) ethyl] aminopolystyrene

PyBOP Benzotriazol- 1 -yl-oxy-tris-pyrrolidino-phosphonium-

hexafluorophosphate

RP-HPLC reverse phase HPLC

RT room temperature

R, retention time (with HPLC) HPLC and LC-MS methods:

Method 1:

Method 2:

Method 3:

Method 4:

General synthesis instructions

General working instructions 1:

amide coupling

Ammocarbonyl-substituted phenylaminouracils (I) are prepared starting from carboxy-substituted phenylaminouracils (II) by amide formation:

(M) (III) (l)

The carboxylic acid (0.10 mmol), the amine (0.11 mmol) and PyBOP (0.11 mmol) are dissolved in dry DMF (3 mL) under an argon atmosphere and stirred while Hünig's base (DIPEA; 0.2 mmol) is added dropwise. The reaction is stirred for 12 hours and the solvent is removed in vacuo. The residue is purified using preparative HPLC (standard program, gradient from 10% to 90% MeCN in water). After removal of the solvent, the products are obtained in vacuo as oils, glasses or foams in yields of 5 to 90%.

General working instruction 2:

Hydrolysis of Type IV Esters

The carboxy-substituted phenylaminouracils (II) are prepared from the corresponding alkoxycarbonyl-substituted phenylaminouracils (IV) by hydrolysis:

(IV) dl)

The corresponding ester IV (10 mmol) is dissolved in 4N sodium hydroxide solution under argon at room temperature and stirred until the reaction is complete by thin layer chromatography or HPLC, normally between half an hour and two hours. The resulting clear solution is acidified to pH 3 with concentrated hydrochloric acid, cooling so that the temperature does not rise above 30 ° C. The solution is cooled to 0 ° for one hour and the resulting precipitate is filtered off, washed with cold water and dried in vacuo at 50 ° C. in order to obtain the resulting carboxylic acid II as a white powder in yields between 60 and 100%.

General procedure 3: Alkoxycarbonyl-substituted phenylamino-uraciles (IV)

Starting from 3-alkoxycarbonyl-substituted 6-chloro-2,4- (1H, 3H) -pyrimide indions (V):

(V) (VI) (IV)

A mixture of 3-substituted 6-chloro-2,4- (1H, 3H) -pyrimidinedione (V) (1.0 eq.) And aniline derivative (VI) (1.5 to 2.5 eq) is added, optionally with the addition of a tertiary amine base (approx. 2.0 eq.), in a high-boiling solvent (e.g.: 1,4-dioxane, diglyme or 1-methylpyrrolidinone) for 1 h to 36 h at 100 to 150 ° C stirred before concentrating in vacuo after aqueous work-up. The crude product can be purified by chromatography on silica gel (eluent: mixtures of dichloromethane and methanol) or by preparative RP-HPLC.

General working instruction 4:

6-Chloruracile

The corresponding 3-substituted 6-chloro-2,4- (1H, 3H) -pyrimidinediones (V) (6-chlorouracile) can be prepared as follows:

(VIII) (V)

A mixture of 1-substituted 2,4,6 (1H, 3H, 5H) -pyrimidine trione (1.0 eq.), Benzyltriethylammonium chloride (approx. 2.0 eq.) And phosphorus oxychloride (approx. 8 to

12.0 eq.) Is heated to 50-60 ° C under inert gas for 2 to 4 h. After cooling, the reaction mixture is poured onto ice water and carefully adjusted to neutral with concentrated sodium hydroxide solution (alternatively with concentrated ammonia solution) (pΗ paper). The mixture is extracted thoroughly with dichloromethane. The organic phases are combined, dried and concentrated in vacuo. If necessary, the product can either be purified by chromatography on silica gel (eluent: mixtures of dichloromethane and methanol or ethyl acetate and ethanol) or by crystallization from dichloromethane.

Alternatively, 3-substituted 6-chloro-2,4- (1H, 3H) -pyrimidinediones (V) can be used according to

Literature regulations also by reaction with phenylphosphorus oxychloride (J Heterocyclic Chem., 1985, 22, 873) or by phosphorus oxychloride in the presence of less Amounts of water (J Am. Chem. Soc, 1980, 102, 5036; Tetrahedron Asymmetry, 1997, 8, 2319) from the corresponding 1 -substituted 2,4,6 (1H, 3H, 5H) pyrimide intrions.

General working instruction 5:

The representation of the 1 -substituted 2,4,6 (1 H, 3H, 5H) -pyrimidintrione (VIII) starting from urea (LX) can be done in different ways (methods [5A] and [5B]):

(IX) (VIII)

[5 A] Basic reaction with ethanolate and malonic diester:

To a solution freshly prepared from sodium and absolute ethanol (1.0 to

1.8 mol / 1) of sodium ethanolate (1.8 to 2.5 eq.) In ethanol are added under an inert gas to urea derivative (1.0 eq.) And malonic acid diethyl ester (1.0 to 1.2 eq). The mixture is heated under reflux for about 4 to 8 h and, after cooling, is adjusted to about pH = 1 with hydrochloric acid. All volatile components are removed in a vacuum. The residue is taken up in dichloromethane and washed with water. The organic phase is dried and evaporated to dryness in vacuo. If necessary, the product can be purified by chromatography on silica gel (eluent: mixtures of dichloromethane and methanol with the addition of acetic acid).

[5B] Acidic reaction with acetic anhydride and malonic acid (J. Heterocyclic Chem., 1985, 22, 873): To a solution of the corresponding urea derivative (IX) (1.0 eq.) And malonic acid (1.3 to 1.8 eq) in glacial acetic acid (approx. 1 to 3 mol / 1), acetic anhydride (approx 3.0 eq.) Added. After the addition has ended, the temperature is raised and the mixture is stirred at about 90 ° C. for 4-8 h. After cooling, the volatile constituents of the reaction mixture are removed in vacuo. The product can be isolated from the residue by recrystallization (if necessary repeatedly) from alcoholic solvents (for example ethanol). Alternatively, the product can be obtained from the evaporation residue by RP-HPLC.

General working instruction 6:

Representation of urea (IX) starting from ammonium hydrochlorides (X)

(X) (IX)

Concentrated to a mixture of primary amine in water (about 0.5 to 2.0 mol / 1) with ice cooling. Hydrochloric acid entered until the reaction is slightly acidic. Alternatively, the hydrochloride of the primary amine can be used directly and dissolved in water (0.5 to 2.0 mol / 1). Potassium or sodium cyanate (1.0 to 1.25 eq.) Are added to the solution at room temperature and the solution is heated to reflux for 2.0 to 6.0 h. After cooling, it usually begins immediately or after the solid has failed. The solid is obtained by filtration, it is washed with water and dried thoroughly in vacuo. Alternatively, after removing the water in vacuo and taking up the residue, filter with ethanol while hot; from the residue of the filtrate can then pass through

Chromatography on silica gel (typically with solvent mixtures such as toluene / methanol or dichloromethane / methanol) the product can be obtained in pure form. starting compounds

Example I

(4-Chloro-2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl) ethyl acetate

1.5 g (7 mmol) (2,4,6-trioxotetrahydro-l (2H) -pyrimidinyl) ethyl acetate are mixed with 1.19 ml (8.41 mmol) phenylphosphorus oxychloride and stirred at 150 ° C for 20 minutes. The reaction solution is poured onto 10 g of ice and neutralized with ammonia. It is extracted twice with dichloromethane and dried over

Sodium sulfate and concentrated in vacuo. It is cleaned over silica gel 60

(Eluent: ethyl acetate).

Yield: 79% of theory Th.

1H-NMR (300MHz, DMSO-d ₆ ): δ = 1.2 (t, 3H), 4.13 (q, 2H), 4.48 (s, 2H), 6.0 (s, 1H), 12.63 (s, 1H).

MS (EI): m / z = 232 (M) ⁺

(see literature: J. Heterocycl. Chem., 1985, 22, 873-878)

Example II 4- (4-Chloro-2,6-dioxo-3, 6-dihydro-1 (2H) -pyrimidinyl) butanoic acid ethyl ester

The presentation is as described for Example I from the corresponding starting materials. Example III 1 - [(Benzyloxy) methyl] -6-chloro-2,4 (1H, 3H) pyrimidinedione

4.00 g (27.3 mmol) of chlorouracil are mixed with 100 ml of anhydrous dimethylformamide. It is cooled to 0 ° C. and 0.33 g (41.5 mmol) of lithium hydride is carefully added (strongly exothermic). Stir for 10 minutes. Then 7.26 g of chloromethylbenzyl ether are slowly added dropwise over a period of 10 minutes. The mixture is stirred at 0 ° C for 90 minutes. The reaction solution is diluted with 200 ml of 2% sodium hydroxide solution and extracted with 250 ml of toluene. The organic phase is washed once more with 100 ml of 2% sodium hydroxide solution. The combined aqueous phase is adjusted to pH 3 with 1 N sulfuric acid. The resulting precipitate is filtered and dried.

3.6 g (49% of theory) of product are obtained.

1H-NMR (200 MHz, CDCh): δ = 4.69 (s, 2H), 5.54 (s, 2H), 5.87 (s, 1H), 7.35 (m, 5H), 8.45 (s, 1H).

Example IV

5- [3 - [(Benzyloxy) methyl] -4-chloro-2,6-dioxo-3,6-dihydro-l (2H) -pyrimidinyl] ethyl pentanoate

1.33 g (5 mmol) of the compound from Example III are dissolved in 50 ml of dimethylformamide. 3.25 g (10 mmol) of cesium carbonate are added and stirring is continued for 10 minutes. Then 1,045 g (5 mmol) of 5-bromovaleric acid ethyl ester are added. The mixture is stirred for 3 days at room temperature.

The reaction solution is concentrated in vacuo and the residue is taken up in 50 ml of water. It is extracted once with 150 ml of ethyl acetate and dried over sodium sulfate.

It is cleaned over silica gel 60. (Mobile phase: cyclohexane / ethyl acetate = 2: 1).

1.04 g (53% of theory) of product are obtained.

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.24 (t, 3H), 1.63-1.66 (m, 4H), 2.33 (t, 2H), 3.87 (t, 2H), 4.11 (q, 2H), 4.69 (s, 2H), 5.56 (s, 2H), 5.88 (s, 1H), 7.32-7.33 (, 5H).

LCMS (method 1): R _t = 2.71 min MS (ESIpos): m / z = 395 (M + H) ⁺ Example V

5- (4-chloro-2,6-dioxo-3,6-dihydro-l (2H) -pyrimidinyl) pentanoate

0.99 g (2.5 mmol) of the compound from Example IV are mixed with 19 ml (250 mmol) of trifluoroacetic acid and stirred under reflux for 2 hours. The reaction solution is concentrated in vacuo. The residue is taken up in 10 ml of methanol and evaporated again. The solid obtained is recrystallized from 10 ml of methanol.

0.176 g (25% of theory) of product is obtained.

LCMS (method 3): R _t = 2.94 min MS (ESIneg): m / z = 273 (MH)

Example VI 4- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] butanoic acid, ethyl ester

7.67 g (29.42 mmol) of the compound from Example II and 15.68 g (117.69 mmol) of 5-aminoindane are heated together to 150 ° C. The mixture is stirred for 40 min. to. The reaction solution is mixed with 5 ml of ethanol and stored in the refrigerator overnight. It is concentrated in a vacuum. The residue is purified on silica gel (mobile phase: dichloromethane -> dichloromethane / methanol 100: 5).

10 g (95% of theory) of product are obtained. 1H-NMR (300 MHz, DMSO-d ₆ ): 5 = 1.17 (t, 3H), 1.75 (quintet, 2H), 2.02 (quintet, 2H), 2.26 (t, 2H), 2.85 (q, 4H), 3.72 (t, 2H), 4.03 (q, 2H), 4.70 (s, IH), 6.95 (d, IH), 7.06 (s, IH), 7.22 (d, IH), 8.06 (s, IH), 10.34 (s, IH).

Example VII

[4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] ethyl acetate

^H 3 ^C

The preparation is carried out as for example VI from 3.23 g (13.885 mmol) of the compound from example I and 7.39 g (55.54 mmol) of 5-aminoindane.

2.37 g (51% of theory) of product are obtained.

1H-NMR (200 MHz, DMSO-de): δ = 1.19 (t, 3H), 2.02 (quintet, 2H), 2.85 (q, 4H), 4.11 (q, 2H), 4.42 (s, 2H), 4.73 (s, IH), 6.97 (d, IH), 7.09 (s, IH), 7.23 (d, IH), 8.24

(s, IH), 10.66 (s, lH).

Example VIII

4- [4 - [(3-chloro-4-methylphenyl) amino] -2,6-dioxo-3,6-dihydro-l (2H) pyrimidinyl] - butanoic acid, ethyl ester

The preparation is carried out as for example VI from 0.476 g (1.826 mmol) of the compound from example II and 1.03 g (7.3 mmol) of 3-chloro-4-methylaniline. 0.35 g (52% of theory) of product is obtained.

1H-NMR (300 MHz, DMSO-de): δ = 1.17 (t, 3H), 1.76 (quintet, 2H), 2.24-2.31 (m, 5H), 3.73 (t, 2 ^λ 4.03 (q, 2H), 4.78 (s, IH), 7.08-7.35 -. 3H), 8.31 (s, IH), 10.56 (s, IH).

LCMS (method 2): R, = 3.63 min MS (ESIpos): m / z = 366 (M + H) ⁺

Example IX

4- [4 - [(3-Ethyl-4-methylρhenyl): amino] -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] butanoic acid, ethyl ester

As for example VI, the preparation is carried out from 1.46 g (5.63 mmol) of the compound from example II, 1.16 g (6.75 mmol) of 3-ethyl-4-methylaniline hydrochloride and 2.15 ml (12.39 mmol) of N, N-diisopropylethylamine.

1.86 g (91% of theory) of product are obtained. 1H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.09-1.20 (m, 6H), 1.75 (quintet, 2H), 2.17-2.5

(m, 5H), 3.72 (t, 2H), 4.03 (q, 2H), 4.71 (s, IH), 6.97 (s, IH), 7.05 (dd, 2H), 8.10 (s, IH), 10.4 ( s, IH).

LCMS (method 3): R _t = 3.69 min MS (ESIpos): m / z = 360 (M + H) ⁺ Example X

5- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] - pentanoic acid, ethyl ester

The presentation is analogous to Example VI.

LCMS (method 2): R _t = 3.85 min MS (ESIpos): mz = 372 (M + H) ⁺

Example XI 4- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] - butanoic acid

0.3 g (0.84 mmol) of the compound from Example VI are mixed with 20 ml of 2M sodium hydroxide solution and stirred at room temperature for 1.5 hours. The reaction solution is filtered. The filtrate is adjusted to pH 3- with concentrated hydrochloric acid

4 placed and cooled in the refrigerator. The precipitate is filtered off and washed with water. It is dried in a high vacuum oven at 60 ° C.

0.256 g (99% of theory) of product is obtained. 1H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.72 (quintet, 2H), 2.02 (quintet, 2H), 2.19 (t,

2H), 2.84 (q, 4H), 3.72 (t, 2H), 4.72 (s, IH), 6.95 (d, IH), 7.06 (s, IH), 7.22 (d, IH), 8.43 (s, IH ), 10.47 (s, IH), 12.0 (s, IH). LCMS (method 2): R _t = 3.16 min MS (ESIpos): mz = 330 (M + H) ⁺ Example XII

[4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] acetic acid

The preparation is carried out as for example XI from 2.37 g (7.19 mmol) of the compound from example VII.

1.71 g (78% of theory) of product are obtained. 1H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.02 (quintet, 2H), 2.85 (q, 4H), 4.33 (s, 2H),

4.72 (s, IH), 6.96 (d, IH), 7.09 (s, IH), 7.23 (d, IH), 8.26 (s, IH), 10.65 (s, IH),

12.81 (s, IH).

LCMS (method 3): R _t = 3.06 min

MS (ESIpos): m / z = 302 (M + H) ⁺

Example XIII

4- [4 - [(3-chloro-4-methylphenyl) amino] -2,6-dioxo-3,6-dihydro -1 (2H) pyrimidinyl] butanoic acid

The preparation is carried out as for example XI from 10 g (27.33 mmol) of the compound from example VIII.

6.26 g (67% of theory) of product are obtained. LCMS (method 2): R _t = 3.13 min MS (ESIpos): m / z = 338 (M + H) ⁺ Example XIV

4- [4 - [(3-ethyl-4-methylρhenyl) amino] -2,6-dioxo-3,6-dihydro-l (2H) pyrimidinyl] butanoic acid

As for example XI, the preparation is carried out from 6.96 g (19.36 mmol) of the compound from example IX.

5.37 g (83% of theory) of product are obtained. LCMS (method 3): R _t = 3.23 min MS (ESIpos): m / z = 332 (M + H) ⁺

Example XV

5- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] pentanoic acid

545 mg (1.46 mmol) of the compound from Example X are dissolved in 54 ml of methanol and 27 ml of saturated sodium carbonate solution are added. The mixture is stirred for 6 hours at room temperature.

Methanol is distilled off in vacuo. The residue is stirred, added to 85 ml of 1 M sulfuric acid at 0 ° C. The resulting precipitate is filtered off and dried at 50 ° C in a high vacuum.

470 mg (93% of theory) of product are obtained.

LCMS (method 3): R, = 3.21 min MS (ESIpos): m / z = 344 (M + H) ⁺ Manufacturing examples

The following examples were produced from commercially available starting materials in accordance with the general working instructions:

Example 13

6- (2,3-Dihydro-1H-inden-5-ylamino) -3- [2-oxo-2- (4-phenyl-1-piperazinyl) ethyl] -2,4 (1H, 3H) -pyrimidinedione

0.043 g (0.143 mmol) of the compound from Example VII, 0.025 g (0.157 mmol) of 1-phenylpiperazine and 0.081 g (0.157 mmol) of 1-benzotriazolyloxytripyrrolidine-phosphonium hexafluorophosphate are combined in 4 ml of dimethylformamide and mixed with 0.037 g (0.285 mmol) of N, N -Diisopropylethylamine added. The mixture is stirred at room temperature for 24 hours. The reaction solution is concentrated in vacuo. The residue is mixed with acetonitrile and the precipitate formed is suction filtered. After drying under high vacuum, 42.7 mg (59 d. Th.) Of product are obtained. LCMS (method 3): R _t = 3.56 min MS (ESIpos): m / z = 446 (M + H) ⁺

The compounds listed in the following table are prepared from the corresponding starting materials in an analogous manner to Example 13:

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

m / z

= m / z

= m / z

= m / z

m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

= m / z

C. Examples of pharmaceutical compositions

The substances according to the invention can be converted into pharmaceutical preparations as follows:

Tablet;

Composition: 100 mg of the compound from Example 1, 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.

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

production:

The mixture of active ingredient, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are dried with the magnesium stearate for 5 min. mixed. This mixture is compressed with a conventional tablet press (tablet format see above). As a guideline for the

Pressing a pressure force of 15 kN is used.

Oral suspension:

Composition:

1000 mg of the compound from Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

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

The Rhodigel is suspended in ethanol, the active ingredient is added to the suspension. The water is added with stirring. The swelling of the Rhodigel is stirred for about 6 hours.

Solution that can be administered intravenously:

Composition:

1 mg of the compound of Example 1, 15 g of polyethylene glycol 400 and 250 g of water for injections.

production:

The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring. The solution is sterile filtered (pore diameter 0.22 μm) and filled into heat-sterilized infusion bottles under aseptic conditions. These are closed with infusion stoppers and crimp caps.

Claims

Patentansprttche

1. Compounds of the general formula (I)

Wonn

R and R together with the nitrogen atom to which they are attached form a heterocycle,

where this heterocycle can optionally be substituted with 1 to 3 substituents independently selected from the group halogen, trifluoromethyl, trifluoromethoxy, nitro, Cj-C _ό- alkyl, C] -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, - ( CH ₂ ) _P -C ₆ -C ₁₀ aryl, - (CH ₂ ) _n heteroaryl, - (CH ₂ ) _m - heterocyclyl, 1, 2- (methylenedioxy) benzene, oxo, formyl, CrC ₆ -

Alkylcarbonyl, dC _ό -alkoxycarbonyl, amino, C] -C ₆ -alkylamino, -C _ö -dialkylamino, phenylamino, aminocarbonyl, Cι-C ₆ -alkyl-aminocarbonyl, Cι-C ₆ -dialkylaminocarbonyl, aminosulfonyl, CrC ₆ - alkylaminosulfonyl, d- -dialkylaminosulfonyl, C ₃ -C ₈ -cycloalkylaminosulfonyl, C ₃ -C ₈ -dicycloalkylaminosulfonyl, C ₆ -C ₁₀ -arylaminosulfonyl, heteroarylaminosulfonyl, -CH ₂ CH ₂ OCH ₂ CH ₂ OH and -NR'- 'R ^{1 "2} ,

wherein p, n and m are the same or different and mean 0, 1, 2, 3 or 4, wherein Ci-C _ö alkyl, dC _ö alkoxy, C -C ₆ cycloalkyl, phenylamino, - (CH ₂ ) _P -C ₆ -C ₁₀ aryl, - (CH ₂ ) _m heterocyclyl and - (CH ₂ ) _n -Heteroaryl can in turn be substituted with 1 to 4 substituents selected from the group -C-C ₆ - alkyl, hydroxy, dC _ö alkoxycarbonyl, amino, Ci-C _ö alkylamino, dC _ö dialkylamino, dC _ö alkyl carbonylamino, oxo, cyano, nitro, heterocyclyl, dC ₆ - alkoxy and CrCe-thioalkyl,

1 1 1 and in which R ^" and R ^" are identical or identical and are selected from the group consisting of hydrogen, dC ₆ -alkyl,

-OCH ₂ CH ₂ OH, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl, heteroaryl, dC ₆ - alkylcarbonyl, dC _ό -alkoxycarbonyl, C -C ₈ cycloalkylcarbonyl, C ₆ - do-arylcarbonyl, heteroarylcarbonyl , Aminocarbonyl, dC ₆ alkyl aminocarbonyl, dC ₆ dialkylaminocarbonyl, Cj-C ₆ alkylsulfonyl, C ₃ -C ₈ cycloalkylsulfonyl, C ₆ -C ₁₀ arylsulfonyl and heteroaryl sulfonyl,

a substituent of the following formula

embedded image in which

Be R3-1 and R3 "2 are independently selected from the group Cι-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ - cycloalkyl and halogen, or

R3-1 and R->^" 2 together with the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl or heterocyclyl Ring, which may optionally be substituted with up to 3 halogen,

A is a Ci -Cö alkanediyl chain, optionally one or more

Contains double or triple bonds and in which a carbon atom is optionally replaced by a nitrogen or oxygen atom, where there must be at least 2 carbon atoms between the hetero atom in A and the nitrogen atom in the uracil ring, and where the hetero atom in A and the carbonyl carbon atom which is adjacent to A must have at least 1 carbon atom,

and which is stituiert optionally substituted with up to 3 substituents selected from the group halogen, nitro, amino, Cι-C ₆ -alkylamino, dC _ό dialkyl amino, Ci-C _ö acylamino, trifluoromethyl, trifluoromethoxy sub-,

and their pharmaceutically acceptable salts, solvates and hydrates.

2. Compounds of general formula (I) according to claim 1, wherein

R and R together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycle,

where this heterocycle can be optionally substituted with 1 to 3 substituents independently selected from the group halogen,

Trifluoromethyl, nitro, -C-C ₆ - alkyl, -C-C ₆ - alkoxy, C ₃ -C ₆ cycloalkyl, - (CH ₂ ) _P -C ₆ aryl, - (CH ₂ ) _n heteroaryl, - (CH ₂ ) _m -Heterocyclyl, 1,2- (methylenedioxy) benzene, oxo, formyl, methylcarbonyl, -C-C ₆ - alkoxycarbonyl, amino, methylamino, dimethylamino, phenylamino, aminocarbonyl, dC ₆ -alkylaminocarbonyl, Cι-C ₆ -Dialkyl-aminocarbonyl and -CH ₂ CH ₂ OCH ₂ CH ₂ OH in which p, n and m are identical or different and are 0, 1 or 2,

wherein -Cβ- alkyl, -C-C ₆ - alkoxy, dC _ö cycloalkyl, phenylamino,

- (CH ₂ ) _p -C ₆ -Cιo-aryl, - (CH ₂ ) _m heterocyclyl and - (CH ₂ ) „- heteroaryl may in turn be substituted with 1 to 3 substituents selected from the group Ci-Cβ-alkyl, Hydroxy, Ci-C _ö alkoxycarbonyl, amino, dimethylamino, oxo, cyano, nitro, heterocyclyl, -C-C ₆ - alkoxy and C i -C ₆ thioalky 1,

R3 is a substituent of the following formula

wherein

R3-1 and R3-2 are independently selected from the group dC ₆ - alkyl, fluorine and chlorine, or

R3-1 and R ^ -2 together with the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl or 3- to 6-membered heterocyclyl ring which is optionally substituted with up to 3 fluorine or chlorine can be,

A is a C] -C4-A] kandiyl chain,

which is optionally substituted with a substituent selected from the group consisting of fluorine, chlorine and amino, and their pharmaceutically acceptable salts, solvates and hydrates.

3. Compounds of general formula (I) according to claim 1 or 2, wherein

R ¹ and R ² together with the nitrogen atom to which they are attached form a pyrrolidine-piperidine, piperazine or thiomorpholine ring,

where this pyrrolidine-piperidine, piperazine or thiomorpholine ring can optionally be substituted with 1 to 3 substituents independently selected from the group fluorine, chlorine, nitro, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, - (CH ₂ ) _P -phenyl, 6-, 9- or 10-membered nitrogen (CH ₂ ) _n heteroaryl, 5- or 6-membered - (CH ₂ ) _m - heterocyclyl, l, 2- (methylenedioxy) benzene, oxo, Formyl, methylcarbonyl, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl and -CH ₂ CH ₂ OCH ₂ CH ₂ OH

in which p, n and m are identical or different and denote 0, 1 or 2,

wherein methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, phenylamino, - (CH ₂ ) _P -phenyl, 6-, 9- or 10-membered nitrogen- (CH ₂ ) _n -heteroaryl and 5- or 6-membered - (CH) _m - heterocyclyl in turn can be substituted with 1 to 2 substituents selected from the group methyl, ethyl, isopropyl, hydroxy, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, amino, dimethylamino, oxo, cyano, nitro, 5- or 6-membered heterocyclyl and thiomethyl,

R3 is a substituent of the following formula

embedded image in which

R3-1 and R3- are selected independently of one another from the group methyl, ethyl, fluorine and chlorine, or

R3 ^_ 1 and R3 "2 together with the carbon atom to which they are attached form a cyclopentyl ring,

A is a Ci -C4 alkanediyl chain,

which is optionally substituted with a substituent selected from the group consisting of fluorine, chlorine and amino,

and their pharmaceutically acceptable salts, solvates and hydrates.

4. Compounds of general formula (I) according to claim 1 to 3, wherein

R ¹ and R ² together with the nitrogen atom to which they are attached form a piperidine or piperazine ring, which piperidine or piperazine ring can optionally be substituted as stated in claim 1.

5. Compounds of general formula (I) according to any one of claims 1 to 4, wherein

R ^ is selected from the group consisting of:

Compounds of the general formula (I) according to one of Claims 1 to 5, in which A is propane-1,3-diyl or butane-1,4-diyl.

Process for the preparation of the compounds of the general formula (I) by reacting compounds of the general formula (II)

embedded image in which

A and R ^{3 have} the meaning given in claim 1,

and the carboxylic acid is optionally present in activated form,

with compounds of the general formula (III)

R ²

N ^(III)

embedded image in which 1 9

R and R have the meaning given in claim 1.

8. Compounds of general formula (I) one of claims 1 to 6 for the treatment and / or prophylaxis of diseases.

9. Medicament containing at least one compound according to one of claims 1 to 6 in combination with at least one pharmaceutically acceptable, pharmaceutically acceptable carrier or excipient.

10. Use of compounds of general formula (I) according to one of claims 1 to 6 for the manufacture of a medicament for the treatment of bacterial diseases.

11. Medicament according to one of claims 1 to 6 for treatment and / or

Prophylaxis of bacterial diseases.

12. A method for combating bacterial diseases in humans and animals by administering an antibacterially effective amount of at least one compound according to one of claims 1 to 6.