EP1480958A1

EP1480958A1 - Uracil-thioether

Info

Publication number: EP1480958A1
Application number: EP03704624A
Authority: EP
Inventors: Niels Svenstrup; Alexander Kuhl; Dietmar Flubacher; Michael Brands; Kerstin Ehlert; Christoph Ladel; Michael Otteneder; Jörg Keldenich; Marcus Bauser
Original assignee: Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2002-02-27
Filing date: 2003-02-14
Publication date: 2004-12-01
Also published as: WO2003072551A1; US20060122201A1; AU2003206902A1; CA2477287A1; DE10208460A1; JP2005528347A

Abstract

The invention relates to uracil-thioethers, pharmaceutical compositions containing said compounds and to a method for the production thereof. The invention also relates to the use of said substances in the treatment of diseases in humans and animals.

Description

Uracil thioether

The present invention relates to uracil thioethers, processes for their preparation, they comprise 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.

The suitability of uracil derivatives for the treatment of bacterial. Infections have been known for some time. For example, WO 01/29010 describes 3-aminocarbonyl-substituted phenylaminouracils, WO 96/06614 describes 3-alkylidene-substituted uracils, WO 00/71523 describes 3-alkanoyloxyalkyluracils and WO 00/20556 describes uracils 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.

There are other structurally different antibacterial agents on the market

Medium available, but resistance development can occur regularly. New means for better and more effective therapy are therefore desirable.

An object of the present invention is therefore to develop new compounds with the same or improved antibacterial activity for the treatment of bacterial

To provide diseases in humans and animals.

Surprisingly, it has been found that derivatives of this class of compounds in which the uracil is substituted by a thioether are highly antibacterial. The present invention therefore relates to compounds of the general formula (I) in which

R ^{1 represents} hydroxy, alkoxy, alkenyl, cycloalkyl, aryl, heterocyclyl or heteroaryl,

where R ¹ may be optionally substituted aryl with 1 to 3 substituents independently selected from the group halogen, cyano, nitro, alkyl, alkoxy, alkanoyl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, aminosulfonyl and alkylaminosulfonyl .

and

where R ¹ may be heterocyclyl optionally substituted with 1 to 3 substituents independently selected from the group oxo, alkyl, alkoxy, aryl, heteroaryl, alkanoyl and alkylsulfonyl,

wherein aryl can be optionally substituted with 1 to 3 substituents independently selected from the group halogen, nitro, alkyl and alkoxy,

and where R ¹ may be heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group halogen, alkyl, alkoxy, alkylthio, cycloalkyl, aryl, oxo, alkanoyl, alkanoyla ino, alkoxycarbonyl, aminq, alkylamino, aminocarbonyl and alkylaminocarbonyl,

R2 is a substituent of the following formula wherein

R2-1 and R2-2 are selected independently of one another from the group -C ₆ - alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl and halogen, or

R2-1 _and R2-2 together with the carbon atom to which they are attached form a C ₆ -C ₆ -cycloalkyl or heterocyclyl ring which can optionally be substituted with up to 3 halogen,

and

A is a C3-C6 alkanediyl chain in which a carbon atom is represented by a

Sulfur atom is replaced, where there must be at least 2 carbon atoms between the sulfur atom in A and the nitrogen atom in the uracil ring, and where R ¹ is hydroxy or alkoxy between the sulfur atom in A and the oxygen atom in R ¹ at least 2 carbon atoms must be located

and which is optionally substituted with up to 2 substituents selected from the group consisting of hydroxy, alkoxy, oxo or amino. The compounds according to the invention can also be present in the form of their salts, solvates or solvates of the salts.

Depending on their structure, the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and their respective mixtures. The stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.

Depending on the structure of the compounds, the invention also relates to

Tautomers of the compounds.

In the context of the invention, preferred salts are physiologically acceptable salts of the compounds according to the invention.

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

Physiologically acceptable salts of the compounds (I) also include salts of conventional bases, for example and preferably alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 C - Atoms, such as, by way of example and by way of preference, ethylamine, the ylamine, triemylamine, ethyldiisopropylamine, monoe anolarnine, diethanolamine, triethanolamine, dicyclo-hexylamine, dimemylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroamine ylaminendinine, ajin methylpiperidine. In the context of the invention, solvates are those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water.

In the context of the present invention, unless otherwise specified, the substituents have the following meaning:

Alkyl per se and "alk" and "alkyl" in alkoxy, alkylthio, alkylamino, alkanoyl, alkanoylamino, alkylaminocarbonyl, alkylamirosulfonyl, alkoxycarbonyl, and

Alkylsulfonyl represent a linear or branched alkyl radical with generally 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl.

Cycloalkyl comprises polycyclic saturated hydrocarbon radicals with up to 14 C atoms, namely monocyclic C ₃ -C ₁₂ , 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 spiro-C _{_7-4} - 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 ₅ bicyclo [3.2.2] -non-2-yl and adamantyl. ,

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-prop-1-en-1-yl and n-but-2-en-1-yl.

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

Alkanediyl (alkylidene) stands for a carbon chain that is terminally substituted at both terms. Saturated chains with 1 to 6 carbon atoms, in particular 2 to 4 carbon atoms, are preferred.

Alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylthio is exemplary and preferably methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

Alkylamino stands for an AJ cylamino radical with one or two (independently selected) alkyl substituents, by way of example and preferably for methylamino, ethylamino, n-propylarnino, isopropylamino, tert-butylamino, n-pentylarnino, n-hexylamino, N, N-dimethylamino, ΛζN-diethylamino, NE yl-N-memylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, Nt-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl -7V-methylamino.

Alkanoyl is exemplary and preferably acetyl and propanoyl.

Alkanoylamino is an example and preferably acetylamino and ethylcarbonylamino.

Alkylaminocarbonyl stands for an alkylarninocarbonyl radical with one or two (independently selected) alkyl substituents, by way of example and preferably for methylaminocarbonyl, ethylarninocarbonyL n-propylaminocarbonyl, isopropylarninocarbonyl, tert.-butylarninocarbonyl, n-pentylaminocarbonyl, n-hexyl-, amin -Dimethylaminocarbonyl, N, N-die ylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-memyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propyl- aminocarbonyl, Nt-butyl-N-methylaminocarbonyl, N-emyl-Nn-pentylamino-carbonyl and Nn-hexyl-N-methylaminocarbonyl.

Alkylaminosulfonyl represents an alkylaminosulfonyl radical with one or two (independently selected) alkyl substituents, by way of example and preferably for methylinosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, tert-butylaminosulfonyl, n-pentylaminosulfonylamino, n sulfonyl, N, N-dimethylaminosulfonyl, N-diethylaminosulfonyl, N-ethyl-N-methylarninosulfonyl, N-memyl-Nn-propylaminosulfonyl, N-isopropyl-JV-n-propylaminosulfonyl, Nt-butyl-N-memylaminosulfonyl, Λ ethyl -Nn-pen1ylaminosulfonyl and Nn-hexyl-N-methylaminosulfonyl.

Alkoxycarbonyl exemplifies and preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkylsulfonyl is exemplified and preferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

Aryl stands for a mono- to tricyclic aromatic, carbocyclic radical with generally 6 to 14 carbon atoms; exemplary and preferably for phenyl, naphthyl and phenanthrenyl.

Heteroaryl is 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 are preferred. 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, in one

Ring aromatic, such as benzoxazine. Saturated heterocyclyl residues are preferred. The heterocyclyl radicals can be bonded via a carbon atom or a hetero atom. 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 , Thiopyranyl, morpholinyl, perhydroazepinyl, thiomorpholinyl, piperazinyl, bicyclo [2.2.1] diazaheptyl.

Halogen stands for fluorine, chlorine, bromine and iodine.

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 the respective combinations or preferred combinations of radicals are independent of the respective specified combinations of the residues can also be replaced by residue definitions of other combinations.

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

in which

R represents aryl, heterocyclyl or heteroaryl,

wherein R ¹ may be optionally substituted aryl with 1 to 2 substituents independently selected from the group halogen, cyano, nitro, alkyl, alkoxy, alkanoyl and amino,.

and

wherein aryl can be optionally substituted with 1 to 2 substituents independently selected from the group halogen, nitro, alkyl and alkoxy,

and

where R ¹ may be heteroaryl optionally substituted with 1 to 2 substituents independently selected from the group halogen, alkyl, alkoxy, alkylthio, cycloalkyl, aryl, oxo, alkanoyl, alkanoylamino, alkoxycarbonyl, amino, alkylamino, aminocarbonyl and alkylaminocarbonyl, R ^ is a substituent of the following formula wherein

R2-1 and R ^ -2 are independently selected from the group -C _ό - alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl and halogen, or

R2-1 and R ^ "2 together with the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl or heterocyclyl ring which can optionally be substituted with up to 3 halogen,

and

A is a C _ß -Cö alkanediyl chain, in which a carbon atom by a

and which is optionally substituted with up to 2 substituents selected from the group consisting of hydroxy or oxo.

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

R ^{1 represents} heteroaryl, where the heteroaryl can be optionally substituted with 1 to 2 substituents independently selected from the group halogen, alkyl, alkoxy, alkylthio, cycloalkyl, aryl, oxo, alkanoyl, alkanoylamino, alkoxycarbonyl, amino, alkylamino, aminocarbonyl and alkylaminocarbonyl,

and R and A have the meaning given above.

R ^{1 represents} thiadiazole or isoxazole,

where the thiadiazole or isoxazole can be optionally substituted with 1 to 2 substituents independently selected from the group halogen, alkyl, alkoxy, alkylthio, cycloalkyl, aryl, oxo, alkanoyl, alkanoylamino,

Alkoxycarbonyl, amino, alkylamino, aminocarbonyl and alkylaminocarbonyl,

and R ² and A have the meaning given above.

R ^ is selected from the group consisting of:

and R ¹ and A have the meaning given above.

Preferred in the context of the present inventions are, in particular, compounds of the general formula (I) in which

R2 is selected from the group consisting of:

and R ¹ and A have the meaning given above.

In the context of the present inventions, preference is also given to compounds of the general formula (I) in which R ^{2 is} a group

and R ¹ and A have the meaning given above. Preferred in the context of the present inventions are, in particular, compounds of the general formula (I) in which R ^{2 is} a group

is, and R and A have the meaning given above.

Compounds of the general formula (I) in which R ^! -A soon

and R and R have the meaning given above.

Compounds of the general formula (I) in which R ^! -A soon

Is 1, and R and R have the meaning given above.

The active substance can act systemically and / or locally. For this purpose, it can be applied in a suitable manner, for example orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctivally, otically or as an implant. W

- 14 -

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 (intravenous, intraarterial, intracardial, intraspinal or intralumbal) or by switching on absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). 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. Inhaled drug forms (e.g. powder inhalers, nebulizers), nasal drops / solutions, sprays; tablets or capsules to be administered lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixes), 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 corrections. In general, it has proven to be advantageous to administer amounts of approximately 0.001 to 10 mg / kg, preferably approximately 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 amounts mentioned, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out.

Parenteral, in particular intravenous, e.g. as an iv bolus injection (i.e. as a single dose, e.g. by syringe), short-term infusion (i.e. infusion over a period of up to one hour) or long-term infusion

(i.e. infusion over a period of more than one hour). Depending on the special conditions, the volume applied can be between 0.5 to 30, in particular 1 to 20 ml for the iv bolus injection, between 25 to 500, in particular 50 to 250 ml for the short-term infusion and between 50 to 1000, in particular be a special 100 to 500 ml for long-term infusion. For this purpose, it may be advantageous to provide the active ingredient in solid form (e.g. as a lyophilisate) and to dissolve it in the solution medium just 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 (especially 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, for example those with a pH between 3 and 11, particularly 6 and 8, in particular around 7.4.

The injection solutions are packaged 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 packaged 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), characterized in that compounds of the general formula (II) in which

R ^{2 has} the meaning given above, and

A ^{1 represents} the part of A which is located between the sulfur atom and the uracil ring, with compounds of the general formula (III)

_R ι / ^A \ _χ ι (πi)

in which

R ^{1 has} the meaning given above,

A ^{2 stands} for the part of A which is between the sulfur atom and the rest

R ¹ is located

and

X ^{1 represents} halogen, preferably chlorine, bromine or iodine,

be implemented.

The reaction is carried out in inert solvents, optionally 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 dimethyl ether, or methyl ether such as diethylene glycol or other dimethyl ether , Dimethylacetamide, 1,2-

Dimethoxyethane, dimethyl sulfoxide, acetonitrile or pyridine, tetrahydrofuran, dimethylformamide or methylene chloride are preferred.

Bases are, for example, alkali carbonates, such as sodium or potassium carbonate, or organic bases such as trialkylamines, for example triethylamine or diisopropyl ethylamine, or other bases, such as N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or 1,8-diazabicyclo (5.4.0) undec-7-ene, preference is given to 1,8-diazabicyclo (5.4.0) undec- 7-ene.

The compounds of the general formula (III) are known or can be synthesized from the corresponding starting materials by known processes.

To prepare the compounds of the general formula (II), compounds of the general formula (JV) are used in which

A ^{1 has} the meaning given above,

with compounds of the general formula (V)

_{2 /} NH ₃ CI

R (V)

in which

R has the meaning given above, um.

The reaction is optionally carried out in inert solvents, in the presence of a base, preferably in a temperature range from 100 ° C. to 160 ° C. at normal pressure.

Inert solvents are, for example, ethers such as glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide, or hydrocarbons such as benzene, ethylbenzene, xylene or toluene, the reaction without solvent is preferred.

Bases are, for example, organic bases such as trialkylamines e.g. Triethylamine or diisopropylethylamine, or other bases such as e.g. N-methylmorpholine, N-

Methylpiperidine, 4-dimethylaminopyridine odbr l, 8-diazabicyclo (5.4.0) undec-7-ene, diisopropylethylamine is preferred.

The compounds of the general formula (V) are known or can be synthesized from the corresponding starting materials by known processes.

To prepare the compounds of the general formula (IV), compounds of the general formula (VI) are used in which

A ^{1 has} the meaning given above,

with aqueous alkali hydroxide solution.

The reaction is preferably carried out in a temperature range of 100 ° C. at normal pressure.

Alkali hydroxides are, for example, sodium, potassium or lithium hydroxide, sodium hydroxide is preferred. To prepare the compounds of the general formula (VI), compounds of the general formula (VIF) are used

(VI) x ^{2 / A} (vπ)

in which

A has the meaning given above, and

X rl represents halogen, preferably bromine or iodine,

With around.

The reaction takes place in inert solvents, optionally in the presence of a

Base, preferably in a temperature range from room temperature to 60 ° C at normal 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 ether such as dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dimethyl sulfoxide, acetonitrile or pyridine, preference is given to tetrahydrofuran, dimethylformamide or methylene chloride.

Bases are, for example, alkali carbonates, such as sodium, cesium or potassium carbonate, or organic bases such as trialkylamines, for example triethylamine or diisopropyl pylethylamine, or other bases such as N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or 1,8-diazabicyclo (5.4.0) undec-7-ene, preference is given to cesium carbonate.

The compounds of the general formula (VII) are known or can be synthesized from the corresponding starting materials by known processes.

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

NaOH / water

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.

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.

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. urealyticum).

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 as 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, puerperal and post-puerperal 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 commercial and ornamental fish can also be treated, the antibacterial spectrum extending beyond the previously mentioned pathogens to other pathogens such as Brucella, Campylobacter, Listeria, Erysipelothris, Nocardia. A. Assessment of pharmacological effectiveness

in vitro effects.

The vzYro activity 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 amphfected with the help of PCR from genomic DNA from S. aureus. With the help of the primers SAPoM 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 ligated into the vector pET15b (Novagen, USA), likewise digested with Ndel and BamHI, and transformed into E. coli XL-1 Blue.

After transformation in E. coli BL21 (DE3), the cells for expression of PolC at 30 ° C. in LB medium with 100 μg / ml ampicillin up to an OD _595nm of

0.5 cultured, cooled to 18 ° C and further incubated for 20 hours after adding 1 mM IPTG. The cells are harvested by centrifugation, once in PBS

1 mM PMSF washed and in 50 mM NaH ₂ PO ₄ pH 8.0, 10 mM imidazole, 2 mM β-

Mercaptoethanol, 1 mM PMSF, 20% glycerin added. The cells are disrupted using a French press at 12,000 psi, the cell debris centrifuged off (27,000xg, 120 min, 4 ° C) and the supernatant with an appropriate

Amount of Ni-NTÄ agarose (Quiagen, Germany) stirred at 4 ° C for 1 hour. After filling into a column, the gel matrix is washed with 50 mM NaH PO ₄ 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.

Determination of the ICgn against polymerase III The activity of PolC is measured in an enzymatically coupled reaction, the pyrophosphate formed during the polymerization being converted with the aid of the ATP-Sulfurylsae into ATP, which is detected with the help of the 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 (Fa.

Worthington, USA), 20 µM APS and 0.06 mM luciferin. The reaction is started by adding purified PolC to a final concentration of ~ 2 nM and incubated at 30 ° C. for 30 min. The amount of pyrophosphate formed is then converted into ATP by adding ATP sulfurylase (Sigma, USA) in a final concentration of 5 nM and incubation at 30 ° C. for 15 min. To

The addition of 0.2 nM Firefly luciferase is used to measure the luminescence 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 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 tested in a concentration range from 0.5 to 256 μg / ml. After serial dilution of the test substances, the microtiter 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.

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:

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% Mucinsuspension. 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 infection. Female CFW1 mice are used for the infection attempt. The survival of the animals is recorded over 6 days.

B. Examples

Abbreviations

aq. water

DBU 1,8-diazabicyclo (5.4.0) undec-7-ene

DMSO dimethyl sulfoxide

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

ESI electrospray ionization. (For MS) 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

RP-HPLC reverse phase HPLC

RT room temperature

Rt retention time (with HPLC)

LC-MS methods

Method 1 Instrument: Micromass Quattro LCZ, HPllOO; Column: Symmetry C18, 50 mm x

2.1 mm, 3.5 µm; Eluent B: water + 0.1% formic acid, eluent A: acetonitrile + 0.1% formic acid; Gradient: 0.0min 10% A -_ 4.0min 90% A -> 6.0min 90% A; Oven: 40 ° C, flow: 0.5ml / min, UV detection: 208-400 nm Method 2

Instrument: Micromass Platform LCZ, HPllOO; Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Eluent B: water + 0.1% formic acid, eluent A: acetonitrile + 0.1% formic acid; Gradient: 0.0min 10% A -> 4.0min 90% A - 6.0min 90% A; Oven: 40 ° C, flow: 0.5ml / min, UV detection: 208-400 nm

Method 3

Instrument: Finnigan MAT 900S, TSP: P4000, AS3000, UV30000HR; Column: Symmetry C 18, 150 mm x 2.1 mm, 5.0 μm; Eluent C: water, eluent B: water + 0.6 g 35% HC1, eluent A: acetonitrile; Gradient: 0.0min 2% A, 49% B,

49% C - »2.5min 95% A, 2.5% B, 2.5% C -> 5.5min 2% A, 49% B, 49% C; Oven: 70 ° C, flow: 1.2 ml / min, UV detection: 210 nm

starting compounds

Example I

7-Amino-2,3-dihydro-5H- [1, 3] thiazolo [3, 2-a] pyrimidin-5-one

27.22 g (144.9 mmol) of 1,2-dibromoethane and 85.84 g (263.46 mmol) of cesium carbonate are suspended in 125 ml of dimethylformamide under argon. Then 18.86 g (131.73 mmol) of 6-amino-4-hydroxy-2-mercaptopyrimidine are added within 30 minutes. The mixture is stirred for 4 hours at room temperature and then warmed to 60 ° C. overnight. The reaction solution is cooled and concentrated in vacuo. The

100 ml of water are added to the residue. The mixture is stirred for 10 minutes and then left to stand for another 10 minutes. The precipitate is filtered off, twice with 25 ml Washed water and dried in a high vacuum. 15.8 g (71% of theory) of product are obtained.

LC-MS (Method 2): R _t = 0.53 min MS (ESIpos): m / z = 170 (M + H) ⁺

Example II

8-amino-3, 4-dihydro-2H, 6H-pyrimido [2, 1-b] [1, 3] thiazin-6-one

The preparation is as for example I from 11.26 g (69.85 mmol) of 6-amino-4-hydroxy-2-mercaptopyrimidine, 16.22 g (80.32 mmol) of 1,3-dibromopropane and 45.52 g (136.69 mmol) cesium carbonate. 12 g (93% of theory) of product are obtained. LC-MS (Method 1): R _t = 0.64 min MS (ESIpos): mz = 184 (M + H) ⁺

Example III

6-Amino-3- (2-sulfanylethyl) -2,4 (lH, 3H) -pyrimidinedione

15.5 g (91.6 mmol) of the compound from Example I and 14.66 g (366.42 mmol)

Sodium hydroxide are suspended together in 100 ml of water and brought to reflux

Heated for 2 hours. A clear solution is created. The reaction solution is cooled to 0 ° C. and neutralized with concentrated hydrochloric acid. It gets an hour at 0 ° C stirred. Then the precipitate is filtered off, washed twice with 20 ml each

Add water and diethyl ether and dry overnight in a vacuum drying cabinet at 60 ° C. 13.93 g (81% of theory) of product are obtained.

1H-NMR (200MHz, DMSO-d ₆ ) δ = 3.79 (t, 2H), 4.54 (d, 1H), 6.23 (s, 2H), 10.42 (s,

1H)

LC-MS (method 2): R _t = 0.66 min

MS (ESIpos): m / z = 188 (M + H) ⁺

Example IV

6-amino-3- (3-sulfanylpropyl) -2,4 (lH, 3H) -pyrimidinedione

The preparation is carried out as for example III from 4.3 g (23.47 mmol) of the compound from example II and 3.75 g (93.87 mmol) of sodium hydroxide. 1.52 g (32% of theory) of product are obtained.

LC-MS (method 1): R _t = 0.94 min MS (ESIpos): m / z = 218 (M + H) ⁺

Example V

6- (2,3-Dmydro-lH-inden-5-ylamino) -3- (2-sulfanylethyl) -2,4 (lH, 3H) -pyrimidinedione 3 g (16.02 mmol) of the compound from Example HI, 3.2 g (24.04 mmol) of 5-aminoindane and 4.08 g (24.04 mmol) of 5-aminoindane hydrochloride are together at 160 ° C. for 6 hours heated. After cooling to room temperature, the reaction solution is stirred with 50% ethanol and the precipitate is filtered off with suction. It is washed again with 20 ml of 50% ethanol and twice with 20 ml of diethyl ether and dried in a high vacuum. 4.71 g (97% of theory) of product are obtained. 1H-NMR (300MHz, DMSO-d ₆ ) δ = 2.02 (quintet, 2H), 2.59 (q, 2H), 2.84 (q, 4H), 3.83 (t, 2H), 4.71 (s, 1H), 6.95 ( d, 1H), 7.06 (s, 1H), 7.22 (d, 1H), 8.17 (s, 1H), 10.43 (s, 1H)

LC-MS (Method 2): R _t = 3.53 min MS (ESIpos): m / z = 304 (M + H) ⁺

Example VI

6 - [(3-ethyl-4-methylphenyl) amino] -3- (2-sulfanylethyl) -2,4 (lH, 3H) -pyrimidinedione

The preparation is carried out as for example V from 3 g (16.02 mmol) of the compound from example III, 5.78 g (33.65 mmol) of 3-ethyl-4-methylaniline hydrochloride and 2.93 ml (16.82 mmol) N, N-diisopropylethylamine. 4.83 g (98% of theory) of product are obtained. 1H-NMR (300MHz, DMSO-d ₆ ) δ = 1.14 (t, 3H), 2.24 (s, 3H), 2.53-2.63 (m, 4H), 3.83 (t, 2H), 4.71 (s, 1H), 6.91-6.98 (m, 2H), 7.14 (d, 1H), 8.1 (s, 1H), 10.41 (s, 1H) LC-MS (method 3): R _t = 2.39 min MS (ESIpos): m / z = 306 (M + H) ⁺ Example VII

6 - [(3-Ethyl-4-methylphenyl) amino] -3- (3-sulfanylpropyl) -2.4 (1H, 3H-pyrimidinedione

The preparation is carried out as for example V from 2.98 g (14.81 mmol) of the compound from example IV, 7.63 g (44.42 mmol) of 3-ethyl-4-methylaniline hydrochloride and 3.87 ml (22, 21 mmol) N, N-diisopropylethylamine. 4.25 g (90% of theory) of product are obtained.

1H-NMR (200MHz, DMSO-d ₆ ) δ = 1.13 (t, 3H), 1.7-1.83 (m, 2H), 2.23 (s, 3H), 3.77 (t, 2H), 4.72 (s, IH), 6.97 (s, IH), 7.05 (dd, 2H), 8.15 (s, IH), 10.48 (s, IH), 4H are still below the DMSO peak LC-MS (method 1): R _t = 3.7 min MS (ESIpos): m / z = 320 (M + H) ⁺

Preparation Examples

example 1

6- (2,3-Dihydro-lH-inden-5-ylamino) -3- (2 - {[(5-phenyl-l, 3,4-oxadiazol-2-yl) methyl] sulfanyl} ethyl) -2 , 4 (lH, 3H) -pyrimidinedione

40 mg (0.13 mmol) of the compound from Example V and 28.23 mg (0.15 mmol) of 2- (chloromethyl) -5-phenyl-l, 3,4-oxadiazole are placed in 3 ml of dimethylformamide. Then 40.14 mg (0.26 mmol) of l, 8-diazabicyclo (5.4.0) undec-7.-ene are added and the mixture is stirred for 3 hours at room temperature. The reaction solution is concentrated in vacuo. The residue is taken up in dichloromethane and washed once with 1N hydrochloric acid and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. After this

Drying in a high vacuum gives 5.6.8 mg (84% of theory) of product. LC-MS (method 2): R _t = 3.97 min MS (ESIpos): m / z * = 462 (M + H) ⁺ The examples listed in the following table can be prepared from the corresponding starting compounds analogously to the instructions described above.

C. Design Examples for 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. After drying, the granules are mixed with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (tablet format see above). A pressing force of 15 kN is used as a guideline for the pressing.

Oral suspension:

Composition: 1000 mg of the compound from Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel

(Xanthan gu 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 injection purposes.

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

claims

1. Compounds of the formula in which

R represents hydroxy, alkoxy, alkenyl, cycloalkyl, aryl, heterocyclyl or heteroaryl,

where R ¹ may be aryl optionally substituted with 1 to 3 substituents independently selected from the group halogen, cyano, nitro, alkyl, alkoxy, alkanoyl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, aminosulfonyl and alkylaminosulfonyl,

and

and where R ¹ is heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group halogen, alkyl, alkoxy, alkylthio, cycloalkyl, aryl, oxo, alkanoyl, alkanoylamino, alkoxycarbonyl, amino, alkylamino, aminocarbonyl and alkylaminocarbonyl,

R2 is a substituent of the following formula

wherein

R ^ -l and R2-2 are independently selected from the group -Ce-alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ - cycloalkyl and halogen, or

R ^ -l and R2-2 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,

and .

A is a C3-C6-alkanediyl chain in which a carbon atom is replaced by a sulfur atom, where there must be at least 2 carbon atoms between the sulfur atom in A and the nitrogen atom in the uracil ring, and where R ¹ is hydroxy or Alkoxy between the sulfur atom in A and the Oxygen atom in R ¹ must have at least 2 carbon atoms, and which is optionally substituted with up to 2 substituents selected from the group consisting of hydroxyl, alkoxy, oxo or amino.

Compounds of formula (I) according to claim 1, in which

R ^{1 represents} aryl, heterocyclyl or heteroaryl,

where R ¹ may be optionally substituted aryl with 1 to 2 substituents independently selected from the group halogen,

Cyano, nitro, alkyl, alkoxy, alkanoyl and amino,

and

wherein aryl can be optionally substituted with 1 to 2 substituents independently selected from the group halogen, nitro,

- alkyl and alkoxy,

and

where R ¹ may be optionally substituted with 1 to 2 substituents independently selected from the group halogen, alkyl, alkoxy, alkylthio, cycloalkyl, aryl, oxo, alkanoyl, alkanoylamino, alkoxycarbonyl, amino, alkylamino, aminocarbonyl and alkylaminocarbonyl,

R2. a substituent of the following formula

wherein

R2-1 and R2-2 are independently selected from the group C _r C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl and halogen, or

R -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 can optionally be substituted by up to 3 halogen,

and

A is a Cs-Cg-alkanediyl chain in which a carbon atom is replaced by a sulfur atom, where there must be at least 2 carbon atoms between the sulfur atom in A and the nitrogen atom in the uracil ring, and where R ¹ is hydroxy or Alkoxy must be at least 2 carbon atoms between the sulfur atom in A and the oxygen atom in R ¹ , and which is optionally substituted with up to 2 substituents selected from the group consisting of hydroxy or oxo.

Compounds of formula (I) according to claim 1 or 2, in which R ^{1 represents} heteroaryl,

where R ¹ may be heteroaryl optionally substituted with 1 to 2 substituents independently selected from the group halogen,

Alkyl, alkoxy, alkylthio, cycloalkyl, aryl, oxo, alkanoyl, alkanoylamino, alkoxycarbonyl, amino, alkylamino, aminocarbonyl and alkylaminocarbonyl.

Compounds of formula (I) according to any one of claims 1 to 3, in which

R ^{2 is} selected from the group

Compounds of formula (I) according to any one of claims 1 to 4, in which

R ^J -A is the same.

Compounds of formula (I) according to any one of claims 1 to 4, in which

R ^J -A equal is.

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

in which

R has the meaning given in claim 1, and

A ^{1 represents} the part of A which is located between the sulfur atom and the uracil ring,

with compounds of the general formula (HI) in which

R ^{1 has} the meaning given in claim 1, A represents the part of A which is between the sulfur atom and the radical R ¹ ,

and

X ^{1 represents} halogen, preferably chlorine, bromine or iodine.

Compounds according to one of claims 1 to 6 for the treatment and / or prophylaxis of diseases.

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 according to one of claims 1 to 6 for the manufacture of a medicament for the treatment and or prophylaxis of bacterial infections.

11. Medicament according to claim 9 for the treatment and / or prophylaxis of bacterial infections.

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