EP1339699A1

EP1339699A1 - Substituted amidoalkyl uracils and the use thereof

Info

Publication number: EP1339699A1
Application number: EP01994632A
Authority: EP
Inventors: Barbara Albrecht; Michael Gerisch; Gabriele Handke; Axel Jensen; Thomas Krahn; Werner Nickl; Felix Oehme; Karl-Heinz Schlemmer; Henning Steinhagen
Original assignee: Bayer AG; Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2000-11-14
Filing date: 2001-11-02
Publication date: 2003-09-03
Also published as: WO2002040455A1; US20050075347A1; CA2428335A1; WO2002040455A8; AU2002224825A1; US7125995B2; DE10056312A1

Abstract

The invention relates to novel amidoalkyl uracil derivatives of formula (I), to a method for the production thereof, and to their use as medicament active substances for the prophylaxis and/or treatment of medical disorders.

Description

SUBSTITUTED AMIDOALKYLURACILE AND THEIR USE AS INHIBITORS OF POLY (ADP-RIBOSE) SYNTHETASE (PARS)

The present invention relates to new chemical compounds, a process for their preparation and their use as medicaments, in particular for the prevention and / or therapy of ischemia and repercussion damage.

The elucidation of the molecular mechanism of cell death is the subject of intensive biomedical research. The aim is to find specific active compounds that intervene in this process. In the

Investigation of the individual biochemical steps leading to cell death became attentive to poly (ADP-ribose) synthetase (PARS), a protein which is strongly expressed in the cell nucleus and which is involved in the repair of deoxyribonucleic acid (DNA) damage [Szabo and Dawson, Trends in Pharmacological Sciences, 19, 287-298 (1998)].

Activation of PARS plays an important role in N-methyl-D-aspartate (NMDA) and NO-induced neurotoxicity [Zhang et al., Science, 263, 687-689 (1994); Wallis et al., NeuroReport, 5, 245-248 (1993)], cerebral ischemia [Endres et al., J. Cereb. Blood Flow Metabol., 17, 1143-1151 (1997)], traumatic brain injuries [Wallis et al., Brain Res., 710, 169-177 (1996)] and ischemia / re-perfusion damage in the heart and skeletal muscle [Thiemermann et al ., Proc. Nat. Acad. Sci., 94, 679-683 (1997)]. In addition, the inhibition of PARS appears to have a positive effect on the therapy of arthritis [Szabo et al., Japanese J. Pharm., 75, Supp. 1:10 (1997)], Diabetes [Shimabukuro et al., J. Clin. Invest, 100,

290-295 (1997)] and endotoxic or septic shock [Zingarelli et al., Shock, 5, 258-264 (1996)], radiosensitization of hypoxic tumor cells [Weltin et al., Oncol. Res., 6, 399-403 (1994)], chronic colitis [Jijon et al., Am. J. Physiol. Gastrointest. Liver Physiol., 279, G641-51 (2000)], hearing loss [Tabuchi et al., Ann. Otol. Rhinol. Laryngol., 110 (2), 118-21 (2001)], inflammatory diseases of the Lungs such as asthma and chronic bronchitis [Cuzzocrea et al., Eur. J. Pharm., 342, 67-76 (1998)] and cancer.

If DNA is damaged by single or double-strand breaks, PARS is activated, an enzyme that produces polymeric ADP-ribose units from nicotinamide

Adenosine dinucleotide (NAD ⁺ ) builds up as a substrate. The polymeric ADP-ribose units formed are linked both to PARS itself and to other proteins, for example histones, topoisomerases and polymerases.

Increased activation of PARS leads to massive NAD ⁺ consumption.

The sharp decrease in the NAD ⁺ concentration and the associated impediment to ATP synthesis (decrease in the ATP concentration) causes a deterioration in the energetic state of the cell, which can lead to premature cell death (necrosis).

In the heart, reperfusion of ischemic myocardium leads to the generation of radicals, neutrophil infiltration, destruction of the myocardial tissue structure, contraction dysfunction and necrosis. The H ₂ O ₂ generated during the reperfusion phase reacts very quickly with NO to form peroxynitrite. NO, peroxynitrite and H ₂ O ₂ cause DNA strand breaks and thus lead to over-stimulation of the

PARS.

Another important point in reperfusion damage is the accumulation of neutrophils in the reperfected myocardium. Activation of PARS enhances neutrophil infiltration by stimulating the expression of P-selectin and ICAM-1.

PARS knock-out mice that are healthy and capable of reproduction are essentially protected against reperfusion damage. The infiltration of neutrophils is reduced by 50% and the structure of the myocardial tissue is preserved during the reperfusion phase. Low-molecular PARS inhibitors such as 3-aminobenzamide and 1,5-dihydroxyisoquinoline protect the tissue against necrotic cell death (reduction of the infarct size by 30 to 48%) and delay the myocardial damage in ischemia and reperfusion damage in the heart and brain and neuronal dysfunction.

However, the PARS inhibitors tested in animal experiments so far have several disadvantages. For example, 3-aminobenzamide is a non-specific PARS inhibitor which also inhibits cytochrome P ₄₅ o (Eriksson et al., Toxicology and applied Pharmacology, 136, 324-331 (1996)); 5-Iodo-6-amino-1,2-benzopyrone, on the other hand, shows strong side effects (Szabo and Dawson, Trends in Pharmacol. Sciences, 19, 287-298 (1998)). In addition, most inhibitors are not very potent and therefore only show an effect in animals at a relatively high dosage (Thiemermann et al., Proc. Natl. Acad. Sei., 94, 679-683 (1997)).

JP-A-03264579 and Chem. Pharm. Bull. 38 (10), 2726-2732 (1990) describe bicyclic 2,4- (1H, 3H) -pyrimidinediones as 5-ΗT ₂ antagonists for the treatment of cardiovascular diseases, depression and other mental illnesses. US 5,859,014 discloses tetrahydroquinazolinedione derivatives as αi-adrenergic

Receptor antagonists used to treat prostate hypertrophy. WO-A-00/42025 describes dihydropyrimidinones as PARS inhibitors. DE-A-1959705 and DE-A-2126148 list uracil derivatives for the production of crop protection agents. DE-A-2142317 names uracil derivatives with hypnotic properties. Furthermore, various bridged uracils are used as nucleoside

Analogs with potential antiviral activity are described (for example Nucleosides Nucleotides 13 (1-3), 177-196; 13 (4), 891-902 (1994) and J. Med. Chem. 39 (3), 789-795 (1996) ). The object of the present invention is now to provide new substances for the prevention and / or therapy of diseases, in particular ischemia and reperfusion damage.

Here, the compounds according to the invention presumably act as inhibitors of

Poly (ADP-Ribose) Synthetase (PARS).

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

wherein

a ring member means that is selected from the group of:

-D-,

-CH ₂ -D-, -D-CH ₂ -, -CH = CH-CH -, -CH -CH ⁼ CH-, -CH ₂ -CH ₂ -D-,

-D-CH ₂ -CH ₂ - and -CH ₂ -D-CH ₂ -, wherein

D means -CH ₂ -, -O- or -S-,

E denotes (CC ^ -alkylene or (C ₃ -C ₈ ) -cycloalkylene, which are optionally substituted one or more times, independently of one another, by substituents selected from the group consisting of (CrC ₄ ) -alkoxy, hydroxy and amino,

G is (C ₁ -C ₆ ) alkylene or (C ₃ -C ₈ ) cycloalkylene which is optionally substituted one or more times, independently of one another, by substituents selected from the group of (dC ^ alkoxy, hydroxy and amino are,

T represents a methylene group,

t means 0 or 1,

U (C ₆ -C! O) arylene, 5- to 7-membered heterocycle with up to three heteroatoms from the series N, O and / or S or ethindiyl, the ring systems being up to triple, independently of one another, by substituents selected from the group of nitro, cyano, halogen, (dC ^ alkyl,

(C ₃ -C ₈ ) cycloalkyl, (-C ₆ ) alkoxy, trifluoromethyl, di- and trifluoromethoxy, hydroxy, amino, mono- and di- (-C-C ₆ ) alkylamino, (-C ₆ ) Alkoxycarbonyl, aminosulfonyl, (dC ^ -alkylsulfonyl, mono- and di- (Cr C ₆ ) -alkylaminosulfonyl and (-C ^ -alkanoyloxy) may be substituted,

u means 0 or 1,

V (C ₆ -C ₁ o) -arylene, 5- to 7-membered heterocycles having up to three hetero atoms from the series N, O and / or S or ethynediyl group wherein the ring systems up to three times, independently of each other, by substituents selected from the group of nitro, cyano, halogen, (dC ^ -alkyl, (C ₃ - C ₈ ) -cycloalkyl, (CrC ₆ ) -alkoxy, trifluoromethyl, di- and trifluoromethoxy, hydroxy, amino, mono- and di- (-C-C ₆ ) -alkylamino, (C ₁ -C ₆ ) -alkoxy-carbonyl, Aminosulfonyl, (dC ₆ ) -alkylsulfonyl, mono- and di- (dC ₆ ) -alkylaminosulfonyl and (-C-C ₆ ) -alkanoyloxy may be substituted,

v means 0 or 1,

W -O-, -S-, -CO-O-, -O-CO- or -NR ⁴ - means

wherein

R ^{4 is} hydrogen or (-CC ₆ ) alkyl,

w means 0 or 1,

XO, S or NR ⁵ means

wherein

R ⁵ denotes hydrogen, (dC ₆ ) alkyl or benzyl,

Y ^{1 is} hydrogen,

Y ^{2 is} hydroxy

or

Y ¹ and Y ² together represent O, S or NR ⁶ ,

wherein R ^{6 is} hydrogen, (-CC ₆ ) -alkyl or benzyl,

R ^{1 is} hydrogen, (-CC ₆ ) -alkyl, which can be substituted one or more times by halogen, or (C ₃ -C ₈ ) -cycloalkyl,

R> 2 is hydrogen or (dC ₆ ) alkoxycarbonyl,

and

R ³ (C ₆ -do) aryl or a 5- to 13-membered heterocycle with up to four

Heteroatoms from the series N, O and / or S means, the ring systems being selected up to three times, independently of one another, by substituents from the group of nitro, cyano, halogen, (dC ₆ ) -alkyl, (C ₃ -C ₈ ) - Cycloalkyl, (-CC ₆ ) alkoxy, trifluoromethyl, di- and trifluoromethoxy, hydroxy, oxo, amino, mono- and di- (-C-C ₆ ) alkylamino, mono- and di-

(-C-C ₆ ) -alkylaminomethyl, (dC ₆ ) -alkoxycarbonyl, aminosulfonyl, (-C-C ₆ ) -alkylsulfonyl, mono- and di- (-C-C ₆ ) -alkylaminosulfonyl, (Cι-C ₆ ) - alkanoyl, (-CC ₆ ) alkanoyloxy and -CH ₂ -R ⁷ can be substituted,

wherein

R ⁷ denotes a 5- to 7-membered heterocycle with up to three heteroatoms from the series N, O and / or S,

and their salts, hydrates, hydrates of the salts and solvates.

Depending on the substitution pattern, the compounds of the formula (I) according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates to both the enantiomers or

Diastereomers as well as their respective mixtures. The racemic forms can be as well as the diastereomers in a known manner in the stereoisomerically uniform constituents.

Furthermore, certain compounds of formula (I) 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 invention also includes prodrugs of the compounds according to the invention. According to the invention, prodrugs are those forms of the compounds of the formula (I) which can themselves be biologically active or active, but which can be converted into the corresponding biologically active form under physiological conditions (for example metabolically or solvolytically).

“Salts” of the compounds according to the invention are physiologically acceptable salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.

For example, particular preference is given to Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Salts can also be physiologically acceptable metal or ammonium salts of the compounds according to the invention. Alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts) and ammonium salts which are derived from ammonia or organic amines, for example ethylamine, di- or triethylamine, di- or triethanol, are particularly preferred - amine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.

According to the invention, “hydrates” or “solvates” refer to those forms of the compounds of the formula (I) which are in the solid or liquid state

Hydration with water or coordination with solvent molecules a molecule cool-Nerbinding or form a complex. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Equally, the hydrates and / or solvates of salts of the compounds according to the invention are also suitable.

Halogen stands for fluorine, chlorine, bromine and iodine. Chlorine and fluorine are preferred.

(dC ₆ ) alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. The corresponding alkyl groups with fewer carbon atoms, such as (C 1 -C ₄ ) -alkyl and (dC ₃ ) -alkyl, are derived analogously from this definition. In general, (C ₁ -C ₃ ) alkyl is preferred.

The meaning of the corresponding constituent of other more complex substituents, e.g. in the case of alkylene in which an alkyl radical as defined above is linked via two positions, alkylsulfonyl, mono- and di-alkylaminosulfonyl, mono- and di-alkylamino or mono- and di-alkylamino-methyl.

Mono- or di- (-CC ₆ ) -alkylaminocarbonyl stands for an amino group linked via a carbonyl group with one or with two identical or different straight-chain or branched alkyl substituents, each having 1 to 6 carbon atoms. The corresponding mono- or di-alkylaminocarbonyl groups with fewer carbon atoms, such as mono- or di- (C ₁ -C ₄ ) -alkylaminocarbonyl, which are preferred, are derived analogously from this definition. Examples include: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, t-butylaminocarbonyl, NN-D-unethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-memyl-iminocarbonyl, N-methyl-Nn- propylamino-carbonyl, N-isopropyl-Nn-propylaminocarbonyl and Nt-buryl-N-methyl-iminocarbonyl. (C ₃ -C ₈ ) Cycloalkyl stands for a cyclic alkyl radical with 3 to 8 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The corresponding cycloalkyl groups with fewer carbon atoms, such as (C ₃ -C ₆ ) cycloalkyl, are derived analogously from this definition. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.

The meaning of the corresponding constituent of other more complex substituents, e.g. for cycloalkylene in which a cycloalkyl radical as defined above is linked via two positions.

(-C-C ₆ ) alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy and n-hexoxy. The corresponding alkoxy groups with fewer carbon atoms, such as (dC ₄ ) alkoxy and (C ₁ -C ₃ ) alkoxy, are derived analogously from this definition. In general, (dC ₃ ) alkoxy is preferred.

The meaning of the corresponding constituent of other more complex substituents, e.g. Alkoxycarbonyl, in which an alkoxy radical as defined above is linked via a carbonyl group.

(-CC ₆ ) alkanoyl stands for a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, which carries a double bonded oxygen atom in the 1 position and is linked via the 1 position. Examples include: formyl, acetyl,

Propionyl, n-butyryl, i-butyryl, pivaloyl and n-hexanoyl. The corresponding alkanoyl groups with fewer carbon atoms, such as (dC ₄ ) -alkanoyl, are derived analogously from this definition. In general, (dC ₄ ) alkanoyl is preferred. (Cy-C ^ -alkanoyloxy stands for a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, which carries a double bonded oxygen atom in the 1 position and is linked via a further oxygen atom in the 1 position. Examples include: acetoxy, Propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy and n-hexanoyloxy.

(Cg-doVAryl stands for an aromatic radical with 6 to 10 carbon atoms. Examples include: phenyl and naphthyl.

The meaning of the corresponding constituent of other more complex substituents, e.g. Arylene in which an aryl radical as defined above is linked via two positions.

A 5- to 13-membered heterocycle with up to 4 heteroatoms from the series N, O and / or S represents a mono- or bicyclic, saturated, partially unsaturated or aromatic heterocycle which is linked via a ring carbon atom or a ring nitrogen atom. Examples include: thienyl, furyl, pyridyl, pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinoline, isoquinolinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, imidazopyridinyl, isoxazolyl, finidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl,

Thienopyrimidinyl, dihydroindolinyl, indolinyl, 1,3-benzodioxolyl, pyrrolidinyl, tetrahydrofuryl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, 1,4-di-azepinyl.

The corresponding heterocycles with others are derived analogously from this definition

Ring size such as 5- to 10-membered, 5- to 7-membered or 6-membered heterocycles.

The meaning of the corresponding component of other more complex substituents, such as, for example, heterocycles, is derived from this definition, in which a heterocyclyl radical as defined above is linked via two positions. Preferred compounds of the formula (I) are

wherein

A is a ring member -CH ₂ -D- or -D-CH ₂ -,

embedded image in which

D means -CH ₂ -, -O- or -S-,

E (dC ₆ ) -alkylene means that optionally one or more, independently of one another, by substituents selected from the group of (-C-C ₄ ) -

Alkoxy, hydroxy and amino is substituted,

G (-CC) alkylene means that optionally one or more times, independently of one another, by substituents selected from the group of (-C-C ₄ ) -

Alkoxy, hydroxy and amino is substituted,

t 0 means

U phenylene, 6-membered heterocycle with up to three heteroatoms from the

Row denotes N, O and or S, the ring systems being up to three times, independently of one another, selected by substituents from the group of nitro, cyano, fluorine, chlorine, (dC ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl , (dC ₆ ) -

Alkoxy, trifluoromethyl, di- and trifluoromethoxy can be substituted,

u means 0 or 1,

V phenylene, 6-membered heterocycle with up to three heteroatoms from the

Row N, O and / or S means, where the ring systems up to three times, dependent on one another, substituted by substituents selected from the group of nitro, cyano, fluorine, chlorine, (dC ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (dC ₆ ) alkoxy, trifluoromethyl, di- and trifluoromethoxy can,

v means 0 or 1,

W -O-, -S-, -CO-O-, -O-CO- or -NR ⁴ - means

embedded image in which

R ^{4 represents} hydrogen or (dC ₆ ) alkyl,

w means 0 or 1,

X O means

Y ^{1 is} hydrogen,

Y ^{2 is} hydroxy

or

Y ¹ and Y ² together represent O,

R ^{1 is} hydrogen or (dC ₆ ) -alkyl, which can be substituted one or more times by halogen,

R ^{2 represents} hydrogen,

and R ^{3 is} phenyl, naphthyl or a 5- to 10-membered heterocycle having up to four heteroatoms from the series N, O and / or S, the ring systems being up to three times, independently of one another, selected by substituents from the group of nitro, Cyano, halogen, (dC ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (dC ₆ ) alkoxy, trifluoromethyl, di- and trifluoromethoxy,

Hydroxy, oxo, amino, mono- and di- (-CC ₆ ) alkylamino can be substituted,

and their salts, hydrates, hydrates of the salts and solvates.

Compounds of the formula (I) according to the invention are particularly preferred

wherein

A is a ring member -CH ₂ -D- or -D-CH ₂ -,

wherein

D means -CH ₂ - or -S-,

E represents a methylene or 1,2-ethylene group,

G represents a methylene or 1,2-ethylene group,

t 0 means

U denotes phenylene, pyridinediyl or piperazin-1,4-diyl,

u means 0 or 1,

V means pyrimidinyl, v means 0 or 1,

W denotes -O-, -CO-O- or -O-CO-,

w means 0 or 1,

X O means

Y ¹ and Y ² together represent O,

R ^{1 represents} hydrogen,

R ^{2 represents} hydrogen,

and

R ^{3 is} phenyl, naphthyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, thienopyrimidinyl, isoxazolyl, 1,3-benzodioxolyl or pyrrolidinyl, the ring systems in each case up to two, independently of one another, being selected by substituents from the group of nitro, cyano , Bromine, chlorine, fluorine, hydroxy, (-C-C ₃ ) alkoxy, (dC ₃ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, trifluoromethyl, amino and di- (dC ₃ ) -alkylamino can be substituted .

and their salts, hydrates, hydrates of the salts and solvates.

The compounds of Examples 4, 5, 7, 15, 16, 19, 23, 31 and 138 and their salts, hydrates, hydrates of the salts and solvates are very particularly preferred.

The present invention also relates to a process for the preparation of the compounds of the formula (I) according to the invention, wherein Compounds of formula (II)

in which

A has the meaning given above,

with compounds of the formula (III)

in which

Z represents an alkyl or benzyl radical and E and X the above

Have meaning

to compounds of the formula (IV)

in which

Z represents an alkyl or benzyl radical and A, E and X are those given above

Have meaning

implements, then with chlorocarbonyl isocyanate to give compounds of the formula (N)

in which

represents an alkyl or benzyl radical and A, E and X have the meaning given above,

implements,

the reaction product obtained in a next step into the Nerbindungen of formula (VT),

in which

A, E and X have the meaning given above,

convicted this optionally activated, in particular by conversion into a suitable carboxylic acid derivative such as, for example, carboxylic acid halide, carboxylic acid anhydride, carboxylic acid amide or carboxylic acid ester,

subsequently

either

[A] with compounds of the formula (VII),

in which G, R ¹ , R ³ , T, U, V, W, Y ¹ , Y ² , t, u, v and w have the meaning given above and which are optionally used in the form of their salts,

to compounds of the formula (VIII)

in which A, E, G, R ¹ , R ³ , T, U, N, W, X, Y ¹ , Y ² , t, u, v and w have the meaning given above,

implements

or

[B] with compounds of the formula (IIIa),

Y ^/ ^ τ _r u _u -v _v -w _w

in which G, R ¹ , T, U, V, Y ¹ , Y ² , t and u have the meaning given above, v is 1, w is 0 and V additionally as a substituent is a suitable leaving group such as halogen, preferably bromine or iodine, or contains triflate and which are optionally used in the form of their salts,

on the level of compounds of the formula (Villa),

(Vffla)

in which A, E, G, R ^! , T, U, V, X, Y ¹ , Y ² , t and u have the meaning given above, v is 1, w is 0 and V additionally has a suitable leaving group as a substituent, such as halogen, preferably bromine or iodine, or Triflat contains

and subsequent aryl coupling reaction in the presence of a catalyst

Compounds of formula (IX)

in which

R ^{3 has} the meaning given above and M represents an optionally substituted metallic or semi-metallic element such as zinc, magnesium, boron, lithium, copper or tin,

converts to compounds of formula (VIII)

and optionally compounds of the formula (VIII) with compounds of the formula (X)

R ² -Q (X),

in which

R ^{2 has} the meaning given above but is not hydrogen and Q represents a leaving group,

converted to compounds of formula (I) in which R ^{2 is} not hydrogen. The compounds of the formula (I) obtained in this way can then optionally be converted into the corresponding salts by reaction, for example with an acid.

The process according to the invention for the preparation of compounds of the formula (I) can be illustrated by way of example using the following formula schemes:

Suitable solvents for the process described above are organic solvents which are inert under the reaction conditions or water. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, or other solvents such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, pyridine or hexamethylphosphoric acid triamide or mixtures thereof.

The reactions generally take place in a temperature range from -78 ° C. to 150 ° C., preferably in the range from 0 ° C. to 130 ° C.

The reactions can be carried out at normal, elevated or reduced pressure (for example in the range from 0.5 to 5 bar). Generally one works at

Normal pressure.

The usual inorganic or organic bases are suitable as bases. These preferably include alkali and alkaline earth metal hydroxides such as lithium, sodium or potassium hydroxide or alkali and alkaline earth metal carbonates such as sodium or potassium carbonate or sodium or potassium methoxide or sodium or potassium ethoxide or potassium tert-butoxide or amides such as sodium amide, lithium bis - (Trimethylsilyl) amide or lithium diisopropylamide or amines such as triethylamine, diisopropylethylamine, diisopropylamine, N-methylmorpholine, 4-dimethylamino-pyridine or pyridine.

The preferred solvent for the reaction of compounds (II) with compounds (EI) to compounds (IV) is toluene. The temperature range for this reaction is in particular between 80 ° C and 120 ° C. In addition, the reaction can optionally be carried out by adding catalytic amounts of acid, preferably organic

Sulfonic acid, especially camphorsulfonic acid, can be accelerated.

The reaction of compounds (IV) with chlorocarbonyl isocyanate to give compounds (V) is preferably carried out in toluene as the solvent. The addition of chlorocarbonyl isocyanate is preferably carried out at room temperature, the other The reaction then takes place in particular in a temperature range between 80 ° C and 120 ° C.

The hydrolysis of Nerbindungen (V) to compounds (VI) is carried out according to customary methods, for example by treating the esters in inert solvents with acids or with bases, in which case the salts formed initially are converted into the free carboxylic acids by treatment with acid , In the case of t-butyl esters, the hydrolysis is preferably carried out using acids. In the case of methyl or ethyl esters, the hydrolysis is preferably carried out with bases.

Suitable acids are generally trifluoroacetic acid, sulfuric acid, hydrogen chloride, hydrogen bromide and acetic acid or a mixture thereof, optionally with the addition of water. Trifluoroacetic acid is particularly preferably used.

The usual inorganic bases are suitable as bases for the hydrolysis. These preferably include alkali hydroxides or alkaline earth hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, or alkali carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate. Sodium hydroxide or lithium hydroxide are particularly preferably used.

Suitable solvents for the hydrolysis are water or the usual organic solvents. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, dimethylformamide, dichloromethane or dimethyl sulfoxide. It is also possible to use mixtures of the solvents mentioned. Water / ethanol and, in the case of reaction with trifluoroacetic acid, dichloromethane are preferred.

When carrying out the hydrolysis, the base or the acid is generally used in an amount of from 1 to 100 mol, preferably from 1.5 to 40 mol, based on 1 mol of the ester. The hydrolysis is generally carried out in a temperature range from 0 ° C. to + 100 ° C.

Preferred solvents for the reaction of compounds (VI) with compounds (VII) or (VIIa) are dichloromethane or dimethylformamide. The reaction takes place in particular at room temperature. Conventional condensing agents such as carbodiimides, e.g. N, N-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), or carbonyl - Compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-

Ethyl 5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydro quinoline, or propanephosphonic anhydride, or isobutylchlorofor at, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-l-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), 2- (2-oxo-l- (2H) -pyridyl) -l, 1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7 -Azabenzotriazol-l-yl) - N, N, N ^ N'-tetramethyl uronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole. Alkali carbonates e.g. Sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines e.g. triethylamine,

N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine are used. The combination of EDC, N-methylmorpholine, 4-dimethylaminopyridine and 1-hydroxybenzotriazole is particularly preferred.

The aryl coupling reaction of compounds (Villa) with Nerbindungen (IX) takes place under customary reaction conditions in the presence of a catalyst, preferably in the presence of a transition metal catalyst, in particular in the presence of a palladium catalyst (see, for example, J. Tsuji, Palladium Reagents and Catalysts, J. Wiley & Sons, 1995) preferred in dimethylformamide as solvent. Palladium (O) - or are preferably used as transition metal catalysts

Palladium (π) compounds, especially bis (triphenylphosphine) palladium (II) - chloride or tetrakis (triphenylphosphine) palladium (0), use. Boron or tin derivatives, for example B (OH) ₂ or trialkyltin, are preferably used as the metallic or semi-metallic group M in the compounds of the formula (IX). If organic boron compounds are used (Suzuki coupling, review: N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483), the reaction takes place in particular at a temperature of 90 ° C. to 110 ° C in the presence of a base, preferably aqueous sodium carbonate solution. When using organic tin compounds (Stille coupling, review: V. Farina, V. Krishnamurthy, WJ Scott in: The Stille Reaction, 1998, J. Wiley and Sons, New York), the reaction takes place in particular at a temperature of 110 ° C to 130 ° C.

Examples of suitable leaving groups Q for compounds of the formula (X) are: halogen or 1-imidazolyl. Chlorine is preferred.

The compounds of the formulas (II), (III), (VII), (VIIa), (IX) and (X) are known to the person skilled in the art or can be prepared by customary methods or analogously to the reaction steps described in the examples.

The compounds of the formula (I) according to the invention surprisingly show an unforeseeable, valuable pharmacological spectrum of action and are therefore particularly suitable for the prophylaxis and / or treatment of diseases.

They can preferably be used in drugs for the prevention and / or therapy of ischemia and reperfusion damage in the heart (after an acute infarction), in the brain

(after stroke) or skeletal muscle, cardiovascular diseases such as unstable angina and arteriosclerosis, neuronal and neurodegenerative diseases such as Epilepsy, chronic pain, Alzheimer's disease and Parkinson's disease, traumatic brain injuries, septic shock as well as arthritis, diabetes, chronic colitis, sudden hearing loss, inflammatory diseases of the

Lungs such as asthma and chronic bronchitis and cancer can be used. The present invention also relates to the use of the substances of the formula (I) for the production of medicaments and pharmaceutical compositions for the prophylaxis and / or treatment of the aforementioned clinical pictures.

The present invention further relates to a method for the prophylaxis and / or treatment of the aforementioned clinical pictures with the substances of the formula

(I) -

In addition, the compounds according to the invention can also be used in the treatment of acute myocardial infarction in combination with one or more of the following medicaments which belong to the standard therapy for acute myocardial infarction: calcium channel blockers (such as, for example, nifedipine, diltiazem, verapamil), nitrovasodilators (such as, for example, isosorbide dinitrate , Glycerol trinitrate, isosorbide-5-mono-nitrate, molsidomine), beta-blockers (such as metoprolol,

Atenolol, propranolol, solatol), platelet aggregation inhibitors (such as acetylsalicylic acid, triclopidine, clopidrogrel), thrombolytics (fibrinolytics) (such as streptokinase, alteplase, reteplase, urokinase, anistreplase), such as anticoagulantarfarin, eg anticoagulantarfarin, anticoagulant, warino ACE inhibitors (such as enalapril), glycoprotein Ilb / IIIa receptor antagonists (such as

Tirofiban, eptifibatide), antiarrhythmics (such as lidocaine, amiodarone) and beta-adrenergic agonists (such as dopamine, dobutamine).

Assessment of physiological effectiveness

1) Test description PARS inhibition test (in vitro)

The effectiveness of substances as PARS inhibitors is tested based on the method of Ushiro [Ushiro et al., J. Biol. Chem., 262, 2352-2357 (1987)]. Recombinantly expressed (Bac-To-Bac, Baculo virus expression system; mstruction manual; Life Technologies) human PARS enzyme is activated in a buffer that contains radioactively labeled [ ¹⁴ C] -NAD ⁺ . The synthesized poly (ADP-ribose) units are precipitated by trichloroacetic acid and the proportion of labeled protein is determined by scintillation measurements. Incubation of PARS with inhibitors leads to a decrease in the proportion of labeled protein and thus to a lower radioactivity.

Inhibition of PARS activity can be expressed as a% of PARS inhibition when incubated with various substances or as the concentration at which 50% of the enzyme is inhibited, i.e. H. are shown as ICso value.

Material buffer: 100 mM 2-amino-2-hydroxymethyl-1,3-propanediol (Tris) -HC1, pH 7.4 10 mM MgCl ₂

1 mM dithiothreitol (DTT)

Tris-HCl and MgCl ₂ are dissolved in water, DTT is added from a 100 mM aqueous starting solution (stored at -20 ° C) and the pH is adjusted to 7.4 with concentrated HC1. DNA: 1 mg / ml calf thymus DNA

1 mg / ml calf thymus DNA (Sigma) is dissolved in water and sonicated to induce strand breaks. 500 ul aliquots were stored at -20 ° C.

Histones: 10 mg / ml type HA histones, calf thymus

10 mg / ml lyophilized histones (from Sigma) are dissolved in water.

500 μl aliquots are stored at -20 ° C.

NAD ⁺ Mix: 2 mM NAD ⁺ in buffer

NAD ⁺ (Sigma) solutions are freshly prepared before each test. 3 μl of labeled [ ¹⁴ C] -NAD ⁺ (2.8 kBq, from Amersham) are added to 7 μl of cold NAD ⁺ solution.

Trichloroacetic acid (TCA): TCA is stored as a 10% by weight solution at 4 ° C.

PARS: Human PARS protein is expressed recombinantly in the Baculo virus system (Bac-To-Bac, Baculo virus expression system; Instruction Manual; Life Technologies) and purified. 500 μl aliquots are stored at -80 ° C.

methods

The compounds to be tested are dissolved in a concentration of 10 mM in DMSO (dimethyl sulfoxide). The assay is carried out in deep 96-hole plates. 70 μl buffer, 10 μl DNA, 10 μl histones, 10 μl NAD ⁺ / [ ¹⁴ C] -NAD ⁺ Mix and 0.5-5 μl PARS (approx. 10,000 cpm / test) with 1 μl of the compounds ( Final concentration 0.001-10 μM) combined in a total volume of approx. 110 μl. After 10 min. Incubation at room temperature, 1 ml of ice-cold TCA solution is added and the precipitated, labeled proteins are sucked onto a filter paper (Printed Filter Mat A; Wallac) using a harvester (Scatron). The filter is dried using a scintillation sheet (Multilex A; Fa. Wallac) melted together and in a ß counter for 1 min. measured per hole.

Results of the PARS inhibition test

In addition to the substances described in this application, the known PARS inhibitor 1,5-dihydroxyisoquinoline (DHCH) is also tested as a reference substance. The results of the test are given as IC ₅ o values for the inhibition of PARS.

The results are shown in Table 1:

Table 1: PARS inhibition (in vitro)

2) Test description cell protection assay (in vitro)

Based on a method described by Bowes [Bowes et al., Br. J. Pharmacol., 124, 1760-1766 (1998)], the ability of PARS inhibitors to examine cells prior to being incubated with H ₂ Protect O ₂ induced cell death. The incubation of endothelial cells with H ₂ O ₂ leads to the generation of DNA strand breaks, which in turn activate the PARS, which leads to a drastic decrease in energy in the cells and cell death. Living cells are separated by one in the electron transport system Mitochondria converted fluorimetric redox indicator (Alamar blue) quantified.

In detail, 7500 MHEC5-T cells / hole (DSM ACC 336; German coUection of microorganisms and cell cultures) are sown as a 4-fold determination on a 96-hole plate. After 24 hours, the cells are incubated with 3 mM aqueous H ₂ O ₂ solution and various concentrations of the substances in the presence of 6 vol.% Alamar blue solution in the medium for 5 hours at 37 ° C. 10 μM 1,5-dihydroxyisoquinoline (DHCH) solution is used as reference substance. After the incubation, the fluorescence is measured at 530-560 nm excitation wavelength and 590 nm emission wavelength. The% of cell protection is calculated as the difference between the living cells treated with H ₂ O ₂ only and the cells treated with HO ₂ and PARS inhibitor. 10 μM DHCH is used as the internal standard and 100% protection is set. The values obtained for the other substances are related to this value.

Cell Protection Assay Results:

Examples of the protection of endothelial cells by PARS inhibitors are listed in Table 2 below. The EC50 values indicate the concentration at which 50% of the maximum cell protection is reached, the maximum protection being set as 100% value by 10 μM DHCH. DHCH has an EC ₅₀ value of 2 μM.

Table 2: Cell protection (in vitro)

3) Test description "Working heart" model I (in vivo)

For studies on the isolated heart in the "working heart" mode [Bardenheuer and Schrader, Circulation Res., 51, 263 (1983)], isolated rat hearts are subjected to a 60-minute "low-flow" phase to generate global ischemia and the Effect of the substances on the restoration of the left ventricular pressure (LVPmax) and the contraction force (dP / dt) was examined during the reperfusion phase. 1,5-Dihydroxyisoquinoline is used as the control substance.

The present invention furthermore relates to medicaments and pharmaceutical compositions which comprise at least one compound of the formula (I), preferably together with one or more pharmacologically acceptable auxiliaries or excipients, and to their use for the purposes mentioned above.

The active substance can act systemically and / or locally. For this purpose, it can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonally, nasally, 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. enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions and solutions.

Parenteral administration can be done by bypassing a resection step (intravenously, intraarterially, intracardially, intraspinally or intralumbally) or by engaging absorption (intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration, application forms are a. 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 mixtures), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants.

The active compounds can be converted into the administration 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 or cyclodextrins), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) or taste and / or smell corrections.

The therapeutically active compounds should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight of the total mixture, ie. H. the active substance should be present in amounts sufficient to achieve the dosage range indicated.

In addition to the compounds of the formula (I) according to the invention, the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.

In general, both in human and in veterinary medicine, it has proven to be advantageous, if appropriate, for the active compound (s) according to the invention in total amounts of from about 0.01 to about 100, preferably 0.05 to 50 mg / kg of body weight per 24 hours in the form of several single doses to achieve the desired results. A single dose contains the active ingredient (s) according to the invention preferably in amounts of about 0.01 to 50, in particular 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the medication, on the type of formulation and on the time or interval at which the

Administration takes place. In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. Unless otherwise stated, all percentages in the examples below relate to the weight; volume ratios are given for solvent mixtures.

B Manufacturing examples

The following abbreviations are used in the description of the examples:

DMF = N, N-dimethylformamide

DMAP = 4-dimethylaminopyridine

EDC = N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride

Z = benzyloxycarbonyl

starting compounds

The heteroaryl-piperazines required as starting compound for some synthesis examples can be prepared by reacting corresponding chloro-heteroaromatics with piperazine.

Λ V-DiethyI-2- (l-piperazinyl) -4-pyrimidinamine

A solution of piperazine (5.8 g, 67.33 mmol) and N- (2-chloro-4-pyrimidinyl) -N, N-diethylamine (5.0 g, 26.93 mmol; preparation see: L. Strekowski, Pol. J. Chem. 1980 , 54, 1557-62) in ethanol (200 ml) is heated at 100 ° C for 16 hours. The mixture is then concentrated in vacuo and extracted with water / ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. To

Chromatography on silica gel (eluent: dichloromethane / methanol) gives 4.01 g of the product (63%) as a yellow oil.

1H NMR (200 MHz, DMSO-d ₆ , όVppm): 7.79 (1H, d); 5.87 (1H, d); 3.50-3.63 (4H, m); 3.31-3.50 (4H, m); 2.63-2.77 (4H, m); 1.08 (6H, t).

MS (ESI +): 236 (M + H).

The chloro-heteroaromatics required for the preparation of various heteroarylpiperazines can be prepared, for example, analogously to the following references:

2-chloro-5- (4-chlorophenyl) pyrimidine (DJ Brown, T.-C. Lee, J. Chem. Soc. C 1970, 214-19) 2-Ghloro-l, 3,5-triazine (from 2- (phenylsulfanyl) -l, 3,5-triazine, G. Porrozzi et al., Gazz. Chim. Ital. 1980, 110, 609-12)

6-Chloro-2-pyridinamine (JJ Kaminski et al., J. Med. Chem. 1987, 30, 2047-51) 2-Chloro-4-methoxyquinazoline (NA Lange, FE Sheibley J. Am. Chem. Soc. 1931 , 53, 3867-75)

2-chloroethylglycinate can be obtained from H. Kunz, M. Buchholz, Chem. Ber. 1979, 112, 2145-2157.

The 3- [4- (5-fluoro-2-pyrimidinyl) -l-piperazinyl] -3-oxo-l-propanamine required to prepare synthesis examples 138 and 166 is obtained from 5-fluoro-2- ( Synthesis of l-piperazinyl) pyrimidine by reaction with N - [(benzyloxy) carbonyl] - ß-alanine and subsequent removal of the protective group by catalytic hydrogenation.

synthesis Examples

example 1

3- (2,4-dioxo-3,4,5,6,7,8-hexahydro-l (2H) -quinazolinyl) -N- (2- [2-naphthyl] -2-oxo-ethyl) propancarbonsäureamid

a) Ethyl 3- (2,4-dioxo-3,4,5,6,7,8-hexahydro-l (2H) -quinazolinyl) propane carboxylic acid

The released amine of 15.36 g (100.0 mmol) of 3-methyl ester hydrochloride and 10.36 ml (100.0 mmol) of cyclohexanone are placed in 200 ml of toluene, a spatula seat of camphorsulfonic acid is added and the water separator for 1.5 hours heated under reflux. The reaction solution is then allowed to cool under argon and 8.05 ml (100.0 mmol) of chlorocarbonyl isocyanate are added at room temperature. After heating for one hour under reflux, the reaction mixture is mixed with saturated aqueous sodium dihydrogenphosphate solution after cooling and extracted several times with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After removing the solvent, the raw product is columnar purified by chromatography (silica gel, methylene chloride / methanol 500: 1-20: 1). The product fraction is concentrated and dried in vacuo. 14.44 g (54.2 mmol; 54% yield) of a pale yellow solid are obtained. Rr value: 0.31 (ethyl acetate). 1H-NMR (200 MHz, DMSO-de, δ / ppm): 11.20 (s, 1H), 4.07 (q, 2H), 3.95 (t, 2H),

2.65-2.53 (m, 4H), 2.19 (t, 2H), 1.68 (m, 2H), 1.55 (m, 2H), 1.18 (t, 3H). MS (ESI): 284.2 (M + NH ^, 267.2 (M + H).

b) 3- (2,4-Dioxo-3,4,5,6,7,8-hexahydro-l (2H) -quinazolinyl) propane carboxylic acid

A solution of 14.4 g (54.1 mmol) of 3- (2,4-dioxo-3,4,5,6,7,8-hexahydro-l (2H quinazolinyl) propane carboxylic acid ethyl ester and 6.47 g (270 , 4 mmol) of lithium hydroxide in 200 ml of a mixture of ethanol and water (4: 1) is stirred under reflux for one hour, then the cooled solution is mixed with 1M hydrochloric acid to a pH of 1 and then evaporated to dryness The received

The residue is dissolved in about 20 ml of water. When ether is added, the product is obtained as a precipitate, which is filtered off with suction and dried in vacuo. 10.2 g (42.8 mmol, 79% yield) of a pale yellow solid are obtained. 1H-NMR (200 MHz, DMSO-d ₆ , δ / ppm): 12.38 (s, 1H), 11.19 (s, 1H), 3.92 (t, 2H), 2.60-2, 53 (m, 4H), 2.19 (t, 2H), 1.69 (m, 2H), 1.55 (m, 2H).

MS (ESI): 256 (M + NH ^, 239 (M + H).

c) 3- (2,4-Dioxo-3,4,5,6,7,8-hexahydro-l (2H) -quinazolinyl) -N- (2- [2-naphthyl] -2-oxo- 1 - ethyl) propancarbonsäureamid

To a solution of 40 mg (0.17 mmol) of 3- (2,4-dioxo-3,4,5,6,7,8-hexahydro-l (2H) - quinazolinyl) propane carboxylic acid and 38 mg (0.17 mmol) of 2- (2-Νaphthyl) -2-oxo-l-ethanaminium chloride (from Bionet) in 5 ml of methylene chloride, add 70 μl (0.42 mmol) of N, N-diisopropylamine and a spatula tip of 4-dimethylaminopyridine. 47 mg (0.18 mmol) of 1,3-dicyclohexylcarbodiimide are added to this reaction solution at 0 ° C. and the mixture is stirred at room temperature for 18 hours. Subsequently the reaction mixture is partitioned between methylene chloride and an aqueous buffer solution with ρH = 2. The organic phase is dried over sodium sulfate and concentrated. The residue obtained is separated by means of preparative HPLC (column: Kromasil 100 C 18, 5 mm, 250 x 40 mm; eluent: acetonitrile / water; flow: 25 ml / min; UV detection at 210 nm). 33 mg (0.08 mmol,

48% yield) of the product as an amorphous solid. Rr value: 0.24 (methylene chloride / methanol 20: 1).

1H-NMR (200 MHz, DMSO-d ₆ , δ / ppm): 11.21 (s, 1H), 8.72 (s, 1H), 8.46 (t, 1H), 8.11-7, 95 (m, 3H), 7.72-7.60 (m, 3H), 4.76 (d, 2H), 3.95 (t, 2H), 2.64-2.54 (m, 4H) , 2.21 (t, 2H), 1.70 (m, 2H), 1.57 (m, 2H).

MS (ESI): 406.8 (M + H ⁺ ).

Example 2

3- (2,4-Dioxo-3,4,7,8-tetrahydro-2H-thiopyrano [4,3-d] pyrimidine-1 (5H) -yl) -N- (2-oxo {2-methylimidazo [l, 2-a] pyridin-3-yl} ethyl) propancarbonsäureamid

a) 3- (2,4-Dioxo-3,4,7,8-tefrahydro-2H-thiopyrano [4,3-d] pyrimidine-1 (5H) -yl) propane carboxylic acid tert-butyl ester

The released amine of 3.09 g (17.0 mmol) of 3-alanine t-butyl ester hydrochloride and 1.98 g (17.0 mmol) of tetrahydro-4-thiopyranone are placed in 60 ml of toluene, with a spatula seat of camphorsulfonic acid added and heated under reflux for an hour on a water separator. The reaction solution is then allowed to cool under argon and 1.37 ml (17.0 mmol) of chlorocarbonyl isocyanate are added at room temperature. After heating for one hour under reflux, after cooling, the reaction mixture is mixed with saturated aqueous sodium dihydrogenphosphate solution and extracted several times with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After removing the solvent, the product is dried in vacuo. 5.20 g (16.6 mmol; 98% yield) of a yellow solid are obtained. Rr value: 0.51 (ethyl acetate).

1H-NMR (200 MHz, DMSO-de, δ / ppm): 11.46 (s, 1H), 3.93 (t, 2H), 3.34 (s, 2H),

2.86 (s, 4H), 2.55 (t, 2H), 1.40 (s, 9H).

MS (ESI): 330.4 (M + NH ₄ ⁺ ), 313.3 (M + H ¹ .

b) 3- (2,4-Dioxo-3,4,7,8-tettahydro-2H-thiopyrano [4,3-d] pyrimidine-1 (5H) -yl) propane carboxylic acid

A solution of 5.2 g (16.6 mmol) of 3- (2,4-dioxo-3,4,7,8-tetrahydro-2H-thiopyrano [4,3-d] pyrimidine-1 (5H) -yl) propane carboxylic acid tert-butyl ester and 77 ml

(998.7 mmol) trifluoroacetic acid in 200 ml methylene chloride is stirred for two hours at room temperature. The solution is then evaporated to dryness and the residue obtained is dried in vacuo. 4.2 g (16.64 mmol, 99% yield) of a brown resin are obtained, which slowly crystallize out. 1H-NMR (200 MHz, DMSO-d ₆ , δ / ppm): 11.39 (s, 1H), 3.95 (t, 2H), 3.34 (s, 2H),

2.87 (s, 4H), 2.57 (t, 2H), COOH was not observed. MS (ESI): 274 (M + NΗ), 257 M + ϊ).

c) 2-Bromo-1- (2-methylimidazo [1,2-a] pyridin-3-yl) ethanone

1.75 g (10.1 mmol) of 1- (2-methylimidazo [1,2-a] pyridin-3-yl) ethanone (Maybridge) are placed in 20 ml of concentrated hydrobromic acid. A solution of 0.56 ml (11.0 mmol) of bromine in 10 ml of concentrated hydrobromic acid is added dropwise to this solution at 60 ° C. over an hour. The mixture is left to stand at 5 ° C. overnight, the product is filtered off and washed with aqueous sodium hydrogen carbonate solution and water. 1.1 g (4.3 mmol, 43% yield) are obtained. Rr value: 0.34 (methylene chloride methanol 20: 1).

1H-NMR (200 MΗz, DMSO-de, δ / ppm): 9.76 (d, 1Η), 7.98 (, 2Η), 7.58 (m, 1H), 4.79 (m, 2H) , 2.80 (s, 3H). MS (ESI): 252.9 (M + H ⁴ ). d) 2-Amino-1 - (2-methylimidazo [1, 2-a] pyridin-3-yl) ethanone hydrochloride

A solution of 3.00 g (21.4 mmol) of hexamethylenetetramine is mixed with a filtered solution of 1.00 g (3.95 mmol) of 2-bromo-1- (2-methylimidazo [1,2-a] pyridine-3 -yl) - ethanone added in chloroform. After stirring for one hour, the solution is cooled to 0 ° C. and the precipitate obtained is filtered off. This is dissolved in 10 ml of concentrated hydrochloric acid and the mixture is stirred for one hour at room temperature. It is then diluted with 20 ml of ethanol, evaporated to dryness, and concentrated from i-propanol. Hydrochloric acid 100: 1 recrystallized. The product is filtered off and washed with a little i-propanol. 279 mg (1.23 mmol, 31.3% yield) of a white microcrystalline solid are obtained.

1H NMR (200 MHz, DMSO-d ₆ , δ / ppm): 9.70 (d, 1H), 8.7 (br.s., amine protons), 7.94 (m, 2H), 7, 53 (m, 1H), 4.51 (m, 2H), 2.85 (s, 3H); additional signals for ammonium chloride MS (ESI): 190.3 (M + H ⁺ ).

e) 3- (2,4-Dioxo-3,4,7,8-tetrahydro-2H-thiopyrano [4,3-d] pyrimidine-1 (5H) -yl) -N- (2-oxo- {2 -methylimidazo [l, 2-a] pyridin-3-yl} ethyl) propancarbonsäureamid

To a solution of 100 mg (0.39 mmol) of 3- (2,4-dioxo-3,4,7,8-tetrahydro-2H-thiopyrano [4,3-d] pyrimidin-l (5H) -yl) propanecarboxylic acid and 88 mg (0.39 mmol) 2-amino-1- (2-methylimidazo [1,2-a] pyridin-3-yl) ethanone hydrochloride in 5 ml dimethylformamide are successively added 58 mg (0.43 mmol ) 1-Hydroxy-1H-benzotriazole, 86 mg (0.45 mmol) EDC, 9 mg (0.08 mmol) 4-dimethylaminopyridine and 150 μl (1.37 mmol) 4-methyorphorpholine. The mixture is stirred at room temperature for 18 hours and then added to ice. The aqueous phase is extracted with diethyl ether and methylene chloride, and the combined organic phases are dried over sodium sulfate. The residue obtained after the concentration is prepared by means of preparative HPLC (column: Kromasil 100 C 18.5 mm, 250 x 40 mm; eluent: acetonitrile / water; flow: 25 ml / min; UV detection at 210 nm). separates. 16 mg (0.04 mmol, 9% yield) of the product are obtained as an amorphous white solid.

Rr value: 0.12 (methylene chloride / methanol 20: 1).

1H-NMR (200 MHz, DMSO-dg, δ / ppm): 11.43 (s, 1H), 9.62 (d, 1H), 8.44 (t, 1H), 7.74 (d, 1H) ), 7.62 (t, 1H), 7.24 (dt, 1H), 4.49 (d, 2H), 3.98 (t, 2H), 3.37 (s, 2H), 2.86

(m, 4H), 2.74 (s, 3H), 2.61 (t, 2H). MS (ESI): 428.2 (M + ϊ).

Example 3

3- (2,4-Dioxo-3,4,7,8-tetrahydro-2H-thiopyrano [4,3-d] pyrimidine-1 (5H) -yl) -N- (2- (3,4-dichlorophenyI ) -2-hydroxy-l-ethyl) propancarbonsäureamid

To a solution of 200 mg (0.78 mmol) of 3- (2,4-dioxo-3,4,7,8-tetrahydro-2H-thiopyrano [4,3-d] pyrimidin-l (5H) -yl) propane carboxylic acid and 189 mg (0.78 mmol) 2-amino-1- (3,4-dichlorophenyl) ethanol hydrochloride (H. Bercher et al., Pharmazie 1976, 31, 351-354) in 10 ml dimethylformamide are added in succession 116 mg (0.86 mmol) 1 -hydroxy-1H-benzotriazole, 172 mg (0.90 mmol) EDC, 18 mg

(0.16 mmol) 4-dimethylaminopyridine and 260 µl (2.34 mmol) 4-methylhnorpholine. The mixture is stirred at room temperature for 18 hours and the reaction mixture is added then on ice. The aqueous phase is subsequently extracted with diethyl ether and methylene chloride, and the combined organic phases are dried over sodium sulfate. The residue obtained after concentration is purified by column chromatography (silica gel, methylene chloride / methanol 50: 1-20: 1). The product fraction was concentrated and dried in vacuo. 68 mg (0.15 mmol,

20% yield) of the product as an amorphous white solid. Rr value: 0.02 (methylene chloride / methanol 20: 1).

1H NMR (200 MHz, DMSO-de, δ / ppm): 11.43 (s, IH), 8.09 (t, IH), 7.57 (m, 2H), 7.27 (d, IH ), 5.52 (m, 2H), 4.61 (q, IH), 3.89 (t, 2H), 3.22 (t, 2H), 2.86 (s, 4H), 2.41 (t, 2H), OH was not observed.

MS (ESI): 461.2 (M + NΗ), 444.1 (M + Η ⁺ ).

Example 4

3- (2,4-Dioxo-3,4,7,8-tetrahydro-2H-thiopyrano [4,3-d] pyrimidine-1 (5H) -yI) -N- (2-oxo-2- [4 - (2-pyrimidinyl) -l-piperazinyl] ethyl) propancarbonsäureamid

a) 2- [4- (Chloroacetyl) -1 -piperazinyl] pyrimidine

Chloroacetyl chloride (1.16 ml, 14.62 mmol) is added to an ice-cooled solution of 2- (l-piperazinyl) pyrimidine (2.0 g, 12.18 mmol) in dichloromethane (20 ml) and triethylamine (5.09 ml, 36.54 mmol) 5 minutes and the

Mixture warmed to RT. After 30 min at RT, water (50 ml) is then added, and the mixture is extracted twice with methylene chloride (50 ml). The organic phase is washed with saturated sodium chloride solution. After drying the organic phase over sodium sulfate, filtration, concentration in vacuo and chromatography on silica gel (eluent: cyclohexane ethyl acetate = 10: 1 to 1: 1), 2.05 g (70%) of product are obtained as a colorless solid.

MS (EI): 242 (M + H) ⁺

1H NMR (d ⁶ -DMSO): 3.45-3.65 (4 H, m); 3.65-3.85 (4H, m); 4.43 (2H, s); 6.79 (1H, t); 8.39 (2 H, d)

b) 2-Oxo-2- [4- (2-pyrimidinyl) -1 -piperazinyl] ethylamine hydrochloride

A solution of the compound from Example 4a) (0.9 g, 3.74 mmol) in chloroform becomes a solution of hexamethylenetetramine (0.58 g, 4.11 mmol) in ethanol (25 ml)

(4 ml) was added and the mixture was then stirred at RT for 10 min. Then will

Sodium iodide (0.56 g, 3.74 mmol) was added and the mixture was stirred at RT overnight.

Sodium iodide (0.62 g, 4.15 mmol) is then added and the mixture is stirred at RT overnight. The suspension obtained is cooled (ice cooling) and filtered. The residue is washed with ice-cold ethanol (10 ml), dried, dissolved in a mixture of ethanol (10 ml) and concentrated hydrochloric acid (2 ml) and

Stirred at 50 ° C for 3 hours. The suspension obtained is also cooled

(Ice cooling) and filtered. The filtrate is then concentrated in vacuo and recrystallized from a mixture of isopropanol-concentrated hydrochloric acid (ratio 100: 1). The product is obtained as a colorless solid (1.03 g, 79%). That so The product obtained contains traces of ammonium chloride as impurities, but these do not have to be separated off for the further reaction step.

MS (ESI): 222.1 (M-Cl) ⁺ 1H-NMR (d ⁶ -DMSO): 3.45-3.55 (2H, m); 3.56-3.62 (2H, m); 3.70-4.0 (6H, m); 6.69

(1 H, t); 8.18 (br.s, amine protons); 8.42 (2H, d); additional signals for ammonium chloride

c) 3- (2,4-Dioxo-3,4J, 8-tefr-uiydro-2H-tl-üopyrano [4,3-d] pyrimidm-l (5H) -yl) -N- (2-oxo- 2- [4- (2-pyrimidinyl) -l-piperazinyl] ethyl) propancarbonsäureamid

1-Hydroxybenzotriazole (293 mg, 2.17 mmol) and EDC (434 mg, 2.27 mmol) are added to a solution of the compound from Example 2b) (505 mg, 1.97 mmol) in dimethylformamide (20 ml) and the mixture is stirred at RT for 10 min. Then N-methylmorpholine (0.87 ml, 7.89 mmol), the compound from Example 4b) (1.03g,

2.96 mmol) and a spatula tip of DMAP are added and the mixture is stirred at room temperature overnight. After filtration, the solution is separated directly by means of preparative HPLC (column: Kromasil 100 C 18, 5 μm, 250 x 40 mm; eluent: acetonitrile water; flow: 25 ml / min; UV detection at 210 nm). After concentration in vacuo, 369 mg (40.7%) of the product are obtained as an amorphous solid.

MS (ESI +): 460.3 (M + H)

1H NMR (d ⁶ -DMSO): 2.45-2.60 (2 H, m); 2.80-2.95 (4H, m); 3.30-3.40 (2H, m); 3.45-3.60 (4H, m); 3.65-3.83 (4H, m); 3.86-4.05 (4H, m); 6.68 (1H, t); 8.20 (1H, t); 8.39 (2H, d); 11.41 (l H, s)

The free amine 2-oxo-2- [4- (2-pyrimidinyl) -l-piperazinyl] ethylamine [4b *] corresponding to the compound from Example 4b can also be prepared in an alternative way via the corresponding Z-protected compound [4a *] become. 4a *) NZ-2-oxo-2- [4- (2-pyrimidinyl) -l-piperazinyl] ethylamine

To a solution of l- (2-pyrimidinyl) piperazine dihydrochloride (1.0 g, 4.22 mmol) in DMF (10 ml) is added 1 -hydroxy-1H-benzotriazole (0.42 g, 3.09 mmol) and EDC (0.62 g, 3.23 mmol) added. Then N-Z-glycine (0.59 g, 2.81 mmol), N-methylmorpholine (1.85 ml, 16.87 mmol) and a catalytic amount of DMAP are added and the mixture is stirred overnight at room temperature. The reaction mixture is poured onto 50 ml of water and stirred for 1 hour at room temperature. The precipitate is filtered off, washed with 5 ml of water and 5 ml of diethyl ether and dried in vacuo. 852 mg (85%) of the product are obtained as a colorless solid.

1H NMR (200 MHz, DMSO-d _ό , δ / ppm): 8.39 (2H, d); 7.22-7.44 (5H, m); 6.67 (IH, t); 5.03 (2H, s); 3.92 (2H, d); 3.40-3.61 (4H, m), 3.62-3.84 (4H, m). MS (ESI +): 356 M + ϊt). 4b *) 2-Oxo-2- [4- (2-pyrimidinyl) -l-piperazinyl] ethylamine

To a solution of the compound from Example 4a *) (850 mg, 2.39 mmol) in methanol

(20 ml) palladium on carbon (85 mg, 10 wt .-% Pd) is added and hydrogenated for 3 hours under a 3 bar hydrogen atmosphere. It is then filtered off through Celite and concentrated in vacuo. After chromatography on silica gel (eluent: dichloromethane / methanol / triethylamine), 517 mg of the product are obtained as a colorless solid.

1H NMR (200 MHz, DMSO-d ₆ , δ / ppm): 8.39 (2H, d); 6.67 (IH, t); 2.80-3.85 (12H, m, signals heavily superimposed). MS (ESI +): 222.1 (M + H *).

Example 5

3- (2,4-Dioxo-3,4,7,8-tetrahydro-2H-thiopyrano [4,3-d] pyrimidine-1 (5H) -yl) -N- (2-oxo-2- [4 - (2-pyrazinyl) phenyl] ethyl) propancarbonsäureamid

a) 3- (2,4-Dioxo-3,4,7,8-tetrahydro-2H-thiopyrano [4,3-d] pyrimidine-1 (5H) -yl) -N- (2-oxo-2- [4-bromophenyl] ethyl) propancarbonsäureamid

is prepared analogously to the instructions for the compound from Example 4c) from 2-amino-1- (4-bromophenyl) ethanone and the compound from Example 2b).

MS (DCI): 469.1 (M + NEU 1H-NMR (d ⁶ -DMSO): 2.40-2.65 (4 H, m); 2.75-2.95 (4 H, m); 3.85-4.05 (2 H, m);

4.60 (2H, d); 7.74 (2H, d); 7.92 (2H, d); 8.41 (1H, br.t); 11.42 (1H, s) b) 3- (2,4-Dioxo-3,4,7,8-tetrahydro-2H-thioρyrano [4,3-d] ρyrimidin-l (5H) -yl) -N- (2-oxo-2- [4- (2-pyrazinyl) ρhenyl] ethyl) propancarbonsäureamid

Bis (triphenylphosphino) palladium (II) chloride (31 mg, 0.044 mmol) and 2-tributylstannylpyrazine (196 mg, 0.53 mmol) are added to a solution of the compound from Example 5a) (200 mg, 0.44 mmol) in DMF (5 ml). given. The reaction mixture is stirred at 120 ° C. overnight. After cooling and filtration, the reaction mixture is separated directly by means of preparative HPLC (column: Kromasil 100 C 18, 5 μm, 250 x 40 mm; eluent: acetonitrile water; flow: 25 ml / min; UV detection at 210 nm). After concentration in vacuo, 44 mg (22%) of the

Product as a colorless solid.

MS (DCI): 451.9 (M + H ^"1" )

1H NMR (d ⁶ -DMSO): 2.40-2.65 (4 H, m); 2.80-2.95 (4H, m); 3.90-4.05 (2H, m); 4.68 (2H, d); 8.12 (2H, d); 8.32 (2H, d); 8.49 (1H, br.t); 8.70 (1H, m); 8.80 (IH, m); 9.37 (1H, m); 11.43 (1H, br.s)

The compounds listed in the following table were prepared in an analogous manner:

HPLC Methods:

(A): Eluent A: 0.5% HClO ₄ in water; Eluent B: acetonitrile; Gradient: 0.5 min. 98% A, 2% B; 4.5 min. 10% A, 90% B; 6.7 min. 98% A, 2% B; Flow: 0.75 ml / min; Column temperature: 30 ° C; UV detection at 210 nm; Pillar: Kromasil

C18 (60x2 mm).

(B): Eluent A: 0.1% formic acid in water; Eluent B: 0.1% formic acid in acetonitrile; Gradient: 0 min. 90% A, 10% B; 4 min. 10% A, 90% B; 6.1 min. 90% A, 10% B; Flow: 0.5 ml / min; Column temperature: 40 ° C; UV detection at

210 nm; Column: Symmetry C18 (50x2.1 mm).

(C): Eluent A: 0.06% HCl in water; Eluent B: acetonitrile; Gradient: 1 min. 90% A, 10% B; Flow: 0.6 ml / min; 4 min. 10% A, 90% B; Flow: 0.8 ml / min; Column temperature: 50 ° C; UV detection at 210 nm; Column: Symmetry C18

(150x2.1 mm).

Claims

Patentansprttche

1. Compounds of formula (I)

wherein

A represents a ring member selected from the group of:

-D-,

-CH ₂ -D-, -D-CH ₂ -, -CH = CH-CH ₂ -, -CH ₂ -CH = H-,

-CH ₂ -CH ₂ -D-, -D-CH ₂ -CH ₂ - and -CH ₂ -D-CH ₂ -,

wherein

D means -CH ₂ -, -O- or -S-, E denotes (dC ^ -alkylene or (C ₃ -C ₈ ) cycloalkylene, which are optionally substituted one or more times, independently of one another, by substituents selected from the group consisting of (CrC ^ -alkoxy, hydroxy and amino,

G is (C ₁ -C ₆ ) alkylene or (C -C ₈ ) cycloalkylene, which optionally one or more times, independently of one another, by substituents selected from the group of (-C) alkoxy, hydroxy and amino are substituted,

T represents a methylene group,

t means 0 or 1,

U (C ₆ -Cιo) arylene, 5- to 7-membered heterocycles with up to three

Heteroatoms from the series N, O and / or S or ethindiyl means, the ring systems being selected up to three times, independently of one another, by substituents from the group of nitro, cyano, halogen, (dC ₆ ) alkyl, (C ₃ -C ₈ ) -cycloalkyl, (dC ₆ ) -alkoxy, trifluoromethyl, di- and trifluoromethoxy, hydroxy, amino, mono- and

Di- _(Cι-C6) alkylamino, _(Cι-C6) - alkoxycarbonyl, aminosulfonyl, (C ₁ -C ₆₎ alkylsulfonyl, mono- and di- (C ₁ -C ₆₎ alkylaminosulfonyl and (Cι- C ₆ ) -alkanoyloxy may be substituted,

u means 0 or 1,

V (C ₆ -Cιo) arylene, 5- to 7-membered heterocycles with up to three

Heteroatoms from the series N, O and / or S or ethindiyl means, the ring systems being selected up to three times, independently of one another, by substituents from the group of nitro, cyano,

Halogen, (dC ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (Cι-C ₆ ) alkoxy, tri- fluoromethyl, di- and trifluoromethoxy, hydroxy, amino, mono- and di- (dC _ö ) alkylamino, (-C-C ₆ ) - alkoxycarbonyl, aminosulfonyl, (dC ₆ ) -alkylsulfonyl, mono- and di- (dC ₆ ) Alkylamino sulfonyl and (dC ₆ ) alkanoyloxy may be substituted,

v means 0 or 1,

W -O-, -S-, -CO-O-, -O-CO- or -NR ⁴ - means

wherein

R ^{4 is} hydrogen or (-CC ₆ ) - alkyl,

w means 0 or 1,

XO, S or NR ⁵ means

wherein

R ⁵ denotes hydrogen, (dC ₆ ) alkyl or benzyl,

Y ^{1 is} hydrogen,

Y ^{2 is} hydroxy

or

Y ¹ and Y ² together represent O, S or NR ⁶ ,

wherein R ^{6 represents} hydrogen, (CC ₆ ) alkyl or benzyl,

R ^{1 is} hydrogen, (-CC ₆ ) - alkyl, which can be substituted one or more times by halogen, or (C ₃ -C ₈ ) cycloalkyl,

R ^{2 is} hydrogen or (-CC ₆ ) alkoxycarbonyl,

and

R ^{3 is} (C ₆ -Cιo) aryl or a 5- to 13-membered heterocycle having up to four heteroatoms from the series N, O and / or S, the ring systems being selected up to three times, independently of one another, by substituents the group of nitro, cyano, halogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₆ ) alkoxy, trifluoromethyl, di- and trifluoromethoxy, hydroxyl, oxo, amino, Mono- and Di- (Cι-C ₆ ) -

Alkylamino, mono- and di- (-CC ₆ ) -alkylaminomethyl, (-C-C ₆ ) -alkoxycarbonyl, aminosulfonyl, (-CC- ₆ ) alkylsulfonyl, mono- and di- (-C-C ₆ ) -alkylaminosulfonyl, (-C-C ₆ ) alkanoyl, (-C-C ₆ ) alkanoyl-oxy and -CH ₂ -R ⁷ can be substituted,

wherein

and their salts, hydrates, hydrates of the salts and solvates.

2. Compounds according to claim 1,

wherein A is a ring member -CH ₂ -D- or -D-CH ₂ -,

embedded image in which

D means -CH ₂ -, -O- or -S-,

E (dC ₆ ) alkylene, which is optionally substituted one or more times, independently of one another, by substituents selected from the group of (-C ₄ ) alkoxy, hydroxy and amino,

G denotes (C ₁ -C ₆ ) -alkylene which is optionally substituted one or more times, independently of one another, by substituents selected from the group of (C 1 -C ₄ ) alkoxy, hydroxy and amino,

t 0 means

U is phenylene, 6-membered heterocycle with up to three heteroatoms from the series N, O and / or S, the ring systems being up to three times, independently of one another, selected by substituents from the group of nitro, cyano, fluorine, chlorine, ( C ₁ -C ₆ -alkyl, (C ₃ -

C ₆ ) -cycloalkyl, (-C-C ₆ ) alkoxy, trifluoromethyl, di- and trifluoromethoxy may be substituted,

u means 0 or 1,

V is phenylene, 6-membered heterocycle with up to three heteroatoms from the series N, O and / or S, the ring systems being up to three times, independently of one another, selected by substituents from the group of nitro, cyano, fluorine, chlorine, ( C ₁ -C ₆ -alkyl, (C ₃ -C ₆ ) -cycloalkyl, (-C-C ₆ ) -alkoxy, trifluoromethyl, di- and trifluoromethoxy may be substituted, 0 or 1 means

W -O-, -S-, -CO-O-, -O-CO- or -NR ⁴ - means

wherein

R ⁴ denotes hydrogen or (dC ₆ ) alkyl,

w means 0 or 1,

X O means

Y ^{1 is} hydrogen,

Y ^{2 is} hydroxy

or

Y ¹ and Y ² together represent O,

R ^{1 is} hydrogen or (-CC ₆ ) - alkyl, which can be substituted one or more times by halogen,

R ^{2 represents} hydrogen,

and

R ^{3 is} phenyl, naphthyl or a 5- to 10-membered heterocycle having up to four heteroatoms from the series N, O and / or S, the ring systems being up to three times, independently of one another, by sub- substituents selected from the group consisting of nitro, cyano, halogen, (Ci- _C6) alkyl, (C ₃ -C ₆₎ -cycloalkyl, _(Cι-C6) alkoxy, trifluoromethyl, di- and trifluoromethoxy, hydroxy, oxo , Amino, mono- and di- (dC ₆ ) alkylamino can be substituted,

and their salts, hydrates, hydrates of the salts and solvates.

3. Compounds according to claim 1,

wherein

A is a ring member -CH ₂ -D- or -D-CH ₂ -,

wherein

D means -CH ₂ - or -S-,

E represents a methylene or 1,2-ethylene group,

G represents a methylene or 1,2-ethylene group,

t 0 means

U denotes phenylene, pyridinediyl or piperazin-1,4-diyl,

u means 0 or 1,

V means pyrimidinyl,

v means 0 or 1, W denotes -O-, -CO-O- or -O-CO-,

w means 0 or 1,

X O means

Y ¹ and Y ² together represent O,

R ^{1 represents} hydrogen,

R ^{2 represents} hydrogen,

and

R ^{3 is} phenyl, naphthyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, thienopyrimidinyl, isoxazolyl, 1,3-benzodioxolyl or pyrrolidinyl, the ring systems in each case up to two, independently of one another, being selected by substituents from the group of nitro, cyano , Bromine, chlorine, fluorine, hydroxy, (dC ₃ ) alkoxy, (dC ₃ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, trifluoromethyl, amino and di- (dC ₃ ) alkylamino can be substituted .

and their salts, hydrates, hydrates of the salts and solvates.

4. compounds of Examples 4, 5, 7, 15, 16, 19, 23, 31 and 138 and their salts,

Hydrates, hydrates of salts and solvates.

5. Nerbindungen of formula (T), as defined in claim 1, for the prevention and / or therapy of diseases. Nerfahren for the preparation of Nerbindungen of formula (I) as defined in claim 1, characterized in that

Compounds of the formula (IN)

in which

Z represents an alkyl or benzyl radical and A, E and X have the meaning given in claim 1,

with chlorocarbonyl isocyanate to give compounds of the formula (V)

in which

represents an alkyl or benzyl radical and A, E and X have the meaning given in claim 1,

implements,

the reaction product obtained in a next step into the Nerbindungen of formula (NI),

in which

A, E and X have the meaning given in claim 1,

convicted

subsequently

either

[A] with compounds of the formula (NU),

in which G, R ^l , R ³ , T, U, N, W, Y ¹ , Y ² , t, u, v and w the in

Have the meaning given,

to compounds of formula (VIII)

in which A, E, G, R ¹ , R ³ , T, U, N, W, X, Y ^l , Y ² , t, u, v and w have the meaning given in claim 1,

implements

or

[B] with Nerbindungen of the formula (Vlla),

in which G, R ¹ , T, U, N, Y ¹ , Y ² , t and u have the meaning given in claim 1, v is 1, w is 0 and N additionally contains a suitable leaving group as a substituent,

about the level of compounds of the formula (Villa),

in which A, E, G, R ¹ , T, U, N, X, Y ¹ , Y ² , t and u have the meaning given in claim 1, v is 1, w is 0 and N is additionally a substituent contains a suitable leaving group,

and subsequent aryl coupling reaction in the presence of a catalyst with Nerbindungen of formula (IX)

R ³ -M (IX),

in which

R has the meaning given in claim 1 and M represents an optionally substituted metallic or semi-metallic element such as zinc, magnesium, boron, lithium, copper or tin,

converted to Nerbindeln of formula (NIII)

and optionally compounds of the formula (VIII) with compounds of the formula (X) R ² -Q (X),

in which

R ^{2 has} the meaning given in claim 1 but is not hydrogen and Q represents a leaving group,

converted to Nerbindungen of formula (I) in which R ^{2 has} the meaning given in claim 1 but is not hydrogen.

7. Nerfahren for the production of Nerbindungen of formula (I) as defined in claim 1, characterized in that

Compounds of the formula (VT),

in which

A, E and X have the meaning given in claim 1,

either

[A] with compounds of the formula (VII),

in which G, R ¹ , R ³ , T, U, V, W, Y ¹ , Y ² , t, u, v and w have the meaning given in claim 1,

to compounds of the formula (VIII)

in which A, E, G, R ¹ , R ³ , T, U, V, W, X, Y ¹ , Y ² , t, u, v and w have the meaning given in claim 1,

implements

or

[B] with compounds of the formula (VIIa),

in which G, R ¹ , T, U, V, Y ¹ , Y ² , t and u have the meaning given in claim 1, v is 1, w is 0 and V additionally contains a suitable leaving group as a substituent,

about the level of compounds of the formula (Villa),

R ³ -M (IX),

in which R ^{3 has} the meaning given in claim and M denotes an optionally substituted metallic or semi-metallic element such as zinc, magnesium, boron, lithium, copper or tin,

converted to Nerbindeln of formula (NIII)

and optionally Nerbindungen of formula (NIII) with Nerbindungen of formula (X)

R ² -Q (X),

in which

R has the meaning given in claim 1 but is not hydrogen and Q represents a leaving group,

converted to Nerbindeln of formula (I), in which R ^{2 has} the meaning given in claim 1 but is not hydrogen.

8. A composition comprising at least one compound of formula (I) as defined in claim 1 and at least one further active ingredient.

9. A composition comprising at least one compound of the formula (I) as defined in claim 1 and at least one further auxiliary.

10. Use of compounds of the formula (I), as defined in claim 1, for the production of medicaments for the treatment of ischemia and reperfusion damage.