HRP20040213A2 - Novel dihydropteridinones, method for producing the same and the use thereof as medicaments - Google Patents

Description

The proposed invention relates to new dihydropteridinones of the general formula (I)

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in which the radicals X, R1, R2, R3, R4, R5, R6 and R7 have the meanings given in the patent claims and in the description, on their isomers, the process for the preparation of these dihydropteridinones as well as on their use as medicine.

Background of the invention

Pteridinone derivatives are known from the state of the art as active substances with antiproliferative activity, WO 01/019825 describes the use of pteridinone derivatives for the treatment of tumors and viral diseases. The resistance of many types of tumors requires the development of new drugs to suppress tumors.

The task of the proposed invention is to provide new compounds with anti-inflammatory and antiproliferative activity.

Description of the invention in detail

It has surprisingly been found that compounds of the general formula (I), in which the radicals X and R1 to R7 have the following meanings, act as inhibitors of specific cellular kinases. Therefore, the compounds according to the invention can be used, for example, to treat diseases which are associated with the activity of specific cellular kinases and which are characterized by excessive or abnormal cell proliferation.

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

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where

R1 represents a residue selected from the group consisting of hydrogen, NH2, XH, halogen and a C1-C3-alkyl group which is optionally substituted with one or more halogen atoms,

R2 is a residue selected from the group consisting of hydrogen, CHO, XH, -X-C1-C2-alkyl and optionally substituted C1-C3-alkyl group,

R3 and R4 are the same or different and represent a residue selected from the group consisting of optionally substituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, -X-aryl, -X-heteroaryl, -X-cycloalkyl, -X-heterocycloalkyl, -NR8-aryl, -NR8-heteroaryl, -NR8-cycloalkyl and -NR8-hetero-cycloalkyl, or

a residue selected from the group consisting of hydrogen, halogen, COXR8, GON (R9)2, COR8 and XR8, or

R3 and R4 together form an alkyl bridge having 2 to 5 members and which may contain 1 to 2 heteroatoms,

R5 is hydrogen or a residue selected from the group consisting of optionally substituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl and -C3-C6-cycloalkyl, or

R3 and R5 or R4 and R5 together form a saturated or unsaturated bridge, which can have 1 to 2 heteroatoms,

R6 is optionally substituted aryl or heteroaryl,

R7 is hydrogen or -CO-X-C1-C4-alkyl, and

X is, in each case independently of each other, O or S,

R8 is, in each case mutually independent, hydrogen or a residue selected from the group consisting of optionally substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and phenyl,

as appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also as appropriate their pharmacologically unambiguous acid addition salts.

Preference is given to compounds of formula (I), in which

X and R 6 have the indicated meaning, i

R1 is hydrogen,

R2 is a residue selected from the group consisting of CHO, OH, and the group -CH3,

R3 and R4, the same or different, represent a residue selected from the group consisting of hydrogen, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, or

R3 and R4 together form a C2-C5-alkyl bridge,

R5 is a residue selected from the group consisting of optionally substituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl and C3-C6-cycloalkyl, or

R3 and R5 or R4 and R5 together form a saturated or unsaturated C3-C4-alkyl bridge, which may have 1 to 2 heteroatoms, and

R7 is hydrogen,

as appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also as appropriate their pharmacologically unambiguous acid addition salts.

Particular preference is given to compounds of formula (I) in which

R 1 -R 5 , R 7 , R 8 and X have the indicated meaning, i

R6 is the remainder of the general formula

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where

n is 1, 2, 3 or 4,

R9 is a residue selected from the group consisting of optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -CONH-C1-C10-alkylene, -O-aryl, -O-heteroaryl, -O -cycloalkyl, -O-heterocycloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl or

a residue selected from the group consisting of -O-C1-C6-alkyl-Q1, -CONR8-C1-C10-alkyl-Q1, -CONR8-C2-C10-alkenyl-Q1, -CONR8-Q2, halogen, OH, -SO2R9 , -SO2N(R8)2-COR8, -COOR8, -N(R8)2, -NHCOR8, CONR8OC1-C10-alkyl-Q1 and CONR8OQ2,

Q1 is hydrogen, -NHCOR8, or a residue selected from the group consisting of optionally substituted -NH-aryl-, -NH-heteroaryl, aryl-, heteroaryl-, C3-C8-cycloalkyl- and heterocycloalkyl groups,

Q2 is hydrogen or a residue selected from the group consisting of an optionally substituted aryl-, heteroaryl-, C3-C8-heterocycloalkyl, C3-C8-cycloalkyl and C1-C4-alkyl-C3-C8-cycloalkyl group,

R1 are the same or different and represent a residue selected from the group consisting of optionally substituted C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, -O-C1-C6-alkyl, -O-C2-C6- alkenyl, -O-C2-C6-alkynyl, C3-C6-heterocycloalkyl and C3-C6-cycloalkyl, or

a residue selected from the group consisting of hydrogen, -CONH2, -COOR3, -OCON(R8)2, -N(R8)2, -NHCOR8, -NHCON(R8)2, -NO2 and halogen, or

adjacent radicals R9 and R10 together form a bridge of general formulas

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Y is O, S or NR11,

m is 0, 1 or 2,

R 11 is hydrogen or C 1 -C 2 -alkyl, and

R13 is hydrogen or a residue selected from the group consisting of optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, -C1-C3-alkyl-phenyl, -C1-C3-alkyl-pyridyl, -C1-C3-alkyl-pyrazinyl, -C1-C3-alkyl-pyrimidinyl and -C1-C3-alkyl-pyridazinyl,

R13 is C1-C6-alkyl,

as appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also as appropriate their pharmacologically unambiguous acid addition salts.

Particular preference is given to compounds of formula (I), in which

R3-R6, R8 and X have the meanings indicated, i

R1 is hydrogen,

R 2 is CH 3 , and

R7 is hydrogen,

as appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also as appropriate their pharmacologically unambiguous acid addition salts.

A further object of the invention is the use of compounds of formula (I), in which X and R1-R7 have the indicated meanings, as a medicine.

Particular preference is given to the use of compounds of formula (I), in which X and R1-R7 have the indicated meanings, as a drug with antiproliferative activity.

A further object of the invention is the use of compounds of formula (I), in which X and R1-R7 have the indicated meanings, for the production of a drug for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases.

A further object of the invention is a method for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases, which is characterized by administering to patients an effective amount of a compound of formula (I), in which X and R1-R7 have the indicated meanings.

A further subject of the invention are pharmaceutical preparations which as an active substance contain one or more compounds of the general formula (I), in which X and R1-R7 have the given meanings, or their physiologically tolerable salts as necessary in combination with usual auxiliary substances and carriers.

A further object of the invention is a process for the preparation of a compound of the general formula (I),

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where

R1-R7 and X have the aforementioned meanings, which is indicated by the fact that the compound of the general formula (II)

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where

R1-R5 and X have the previously mentioned meanings and

L is the output group,

reacts with an optionally substituted compound of the general formula (III)

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where

R6 and R7 have the previously mentioned meanings. A further object of the invention is the compound of formula (II),

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in which R 1 -R 5 and X have the aforementioned meanings.

Compounds of formula (II) represent important intermediate products for the preparation of compounds of formula (I) according to the invention.

A further object of the invention is a process for the preparation of a compound of the general formula (I),

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where

R5 represents the remainder of the general formula

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R9 is an optionally substituted residue -CONH-C1-C10-alkylene or a residue selected from the group consisting of -CONR8-C1-C10-alkyl-Q1, -CONR8-C1-C10-alkenyl-Q1, -CONR8-Q3 and -COOR8, and R1-R5, R7, R10, n and X have the aforementioned meanings, which is indicated by the fact that the compound of the general formula (IA)

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where

R1 to R5, R7, R10 and n have the previously mentioned meanings, i

L is the output group,

reacts with a primary or secondary amine to the corresponding amide, or with an alcohol to the corresponding ester.

As an alkyl group, those alkyl groups, which are an integral part of other radicals. they can be branched or they can be unbranched and they can have 1 to 10 carbon atoms, preferably 1-6, especially preferably 1-4 carbon atoms, and they can be listed, for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl , octyl, nonyl and decyl. Unless otherwise stated, the above names propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl also include their possible isomeric forms. Thus, for example, the name propyl includes both isomeric radicals, n-propyl and iso-propyl, the name butyl includes n-butyl, iso-butyl, sec. butyl and tert-butyl, the name pentyl includes iso-pentyl, neopentyl, etc.

In the aforementioned alkyl groups, one or more hydrogen atoms can be replaced with other residues as needed. For example, these alkyl groups can be substituted with halogen atoms of fluorine, chlorine, bromine or iodine. Substituents are primarily fluorine and chlorine. A particularly favorable substituent is chlorine. If necessary, all hydrogen atoms of the alkyl group can also be replaced.

Also, unless otherwise described, in the above alkyl groups, one or more hydrogen atoms may be optionally substituted, for example, with an optionally substituted residue selected from the group consisting of CN, OCOCH3, aryl, preferably phenyl, heteroaryl, preferably thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl or pyrazinyl, saturated or unsaturated heterocycloalkyl, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, amine residue, preferably methylamine, benzylamine, phenylamine or hetero-arylamine, saturated or unsaturated bicyclic ring system, preferably benzimidazolyl and cycloalkyl, preferably cyclohexyl or cyclopropyl.

Unless otherwise stated, all alkyl bridges may be branched or unbranched alkyl groups with 2 to 5 carbon atoms, for example propylene-, isopropylene-, n-butylene, iso-butyl, sec. butyl and tert-butyl, etc. Particularly advantageous bridges are propylene and butylene bridges. In the mentioned alkyl bridges, 1 to 2 C-atoms can be, if necessary, replaced by one or more heteroatoms selected from oxygen, nitrogen and sulfur.

Branched and unbranched alkylene groups with 2 to 10 carbon atoms, preferably 2-6 carbon atoms, especially preferably 2-3 carbon atoms, if they have at least one double bond, come into consideration as alkenyl groups (also if they are constituent parts of other residues). Examples include: ethenyl, propenyl, butenyl, pentenyl, etc. Unless otherwise stated, the above names propenyl, butenyl, etc. also include possible isomeric forms. For example, the name butylene also includes n-butenyl, 1-methylpropenyl, 2-methylpropenyl, 1,1-dimethylethenyl, 1,2-dimethylethenyl, etc.

If not stated otherwise, in the aforementioned alkenyl groups, one or more hydrogen atoms may be replaced by other residues as necessary. For example, these alkyl groups can be substituted with halogen atoms by fluorine, chlorine, bromine or iodine. Favorable substituents are fluorine and chlorine. A particularly favorable substituent is chlorine. Also, if necessary, all hydrogen atoms of the alkenyl group may also be substituted.

All alkynyl groups (even if they are part of other groups) are branched or unbranched alkynyl groups with 2 to 10 carbon atoms if they have at least one triple bond, such as ethynyl, propargyl, butynyl, pentynyl, hexynyl, etc., preferably ethynyl or propynyl.

If not stated otherwise, in the aforementioned alkenyl groups, one or more hydrogen atoms may be replaced by other residues as necessary. For example, these alkyl groups can be substituted with halogen atoms by fluorine, chlorine, bromine or iodine. Favorable substituents are fluorine and chlorine. A particularly favorable substituent is chlorine. Also, if necessary, all hydrogen atoms of the alkynyl group can also be replaced.

The term aryl denotes an aromatic ring system with 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, preferably phenyl, which, if not stated otherwise, may carry, for example, one or more of the following substituents: OH, NO2, CN, -OCHF2, -OCF3, -NH2, halogen, for example fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, C1-C10-alkyl, preferably C1-C5-alkyl, preferably C1-C3-alkyl, particularly preferably methyl or ethyl, - O-C1-C3-alkyl, preferably -O-methyl or -O-ethyl, -N-methyl-tetrahydro-oxazinyl, -COOH, -COO-C1-C4-alkyl, preferably -COOCH2CH3, -COO-C(CH3 )3 or -COOCH3, -CONH2, -CONH-C1-C10-alkyl, whereby this alkyl can be further substituted if necessary, substituted -CONH-C3-C6-cycloalkyl if necessary, preferably -CONH-cyclopentyl substituted if necessary, optionally substituted -CONH-hetero-cycloalkyl, preferably piperidinyl, pyrrolidinyl or piperazinyl, optionally substituted -CONH-heteroaryl, preferably optionally substituted -CONH-pyridyl, pre optionally substituted -CONH-aryl, preferably optionally substituted -CONH-phenyl, -CONMeC1-C3-alkyl, whereby this alkyl can be further substituted as necessary, preferably -CONMeCH2-pyridyl, benzimidazole or the rest of the formula

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As 5-10-membered mono- or bicyclic heteroaryl rings in which up to three C-atoms are replaced by one or more heteroatoms selected from oxygen, nitrogen or sulfur, examples can be given of furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, wherein each of these heterocycles can be fused to a benzene ring, preferably benzimidazole, if necessary, and wherein these heterocycles, if not described otherwise, they can carry, for example, one or more of the following substituents: OH, NO2, CN, -OCHF2, -OCF3, -NH2, halogen, preferably fluorine or chlorine, C1-C10-alkyl, preferably C1-C5-alkyl, preferably C1- C3-alkyl, especially preferably methyl or ethyl, -O-C1-C3-alkyl, preferably -O-methyl or -O-ethyl, -methyl-N-tetrahydro-oxazinyl, -COOH, -COO-C1-C4-alkyl , preferably -COO-C(CH3)3 or -COOCH3, -CONH2,

optionally substituted phenyl, optionally substituted heteroaryl, preferably optionally substituted pyridyl or pyrazinyl,

-CONH-C1-C10-alkyl, whereby this alkyl can be optionally substituted, optionally substituted -CONH-C3-C6-cycloalkyl, preferably optionally substituted -CONH-cyclopentyl, optionally substituted -CONH-heteroaryl , preferably optionally substituted -OONH-pyridyl, optionally substituted -CONH-aryl, preferably optionally substituted -CONH-phenyl, -CONMeC1-C3-alkyl, whereby this alkyl can be substituted as required, preferably -CONMeCH2 -pyridyl, benzimidazole or the rest of the formula

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Cycloalkyl residues are defined as saturated or unsaturated cycloalkyl residues with 3 - 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, whereby the aforementioned cycloalkyl residues can if necessary, carry one or more substituents, preferably =O, or they can be condensed on the benzene ring.

"=O" means an oxygen atom connected through a double bond.

Heterocycloalkyl residues, if not stated otherwise, are understood as 5-, 6- or 7-membered saturated or unsaturated heterocycles, which can contain nitrogen, oxygen or sulfur as a heteroatom, for example tetrahydrofuran, tetrahydrofuranone, γ-butyrolactone, α-pyran, γ-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepane, oxazine, tetrahydro-oxazinyl, isothiazole, pyrazolidine, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, whereby these heterocycles can be substituted as necessary.

Halogens generally mean fluorine, chlorine, bromine or iodine.

Leaving groups L are understood to be the same or different leaving groups, such as chlorine, bromine, iodine, methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl, preferably chlorine.

The compounds according to the invention can exist in the form of individual optical isomers, mixtures of individual enantiomers, diastereomers or racemates, in the form of tautomers as well as in the form of free bases or corresponding acid addition salts with pharmacologically unmistakable acids, such as for example acid addition salts with hydrohalic acids, on for example with hydrochloric or hydrobromic acid, or with organic acids, such as for example oxalic, fumaric, diglycolic or methanesulfonic acid.

Substituent R1 can be a residue selected from the group consisting of hydrogen, NH2, XH, preferably OH, halogen, preferably fluorine or chlorine and a C1-C3-alkyl group which is optionally substituted with one or more, preferably with one, two or three halogens atoms, preferably fluorine or chlorine, preferably methyl or ethyl. A particularly advantageous substituent R1 is hydrogen.

Substituent R2 can be a residue selected from the group consisting of hydrogen, CHO, XH, preferably OH, -X-C1-C2-alkyl, preferably -O-CH3 or -O-CH2CH3, and optionally substituted C1-C3-alkyl group, wherein the alkyl group preferably has 1 to 2 carbon atoms, especially preferably one carbon atom and can be substituted if necessary, preferably with a halogen atom, especially preferably with a fluorine atom. A particularly advantageous substituent R 2 is methyl.

Substituents R3 and R4 can be the same or different and they represent a residue selected from the group consisting of optionally substituted C1-C10-alkyl, preferably C1-C6-alkyl, preferably C1-C4-alkyl, especially preferably methyl, ethyl or propyl, especially preferably methyl or ethyl, C2-C10-alkenyl, preferably ethenyl or propenyl, preferably ethenyl, C2-C10-alkynyl, preferably ethynyl or propynyl, aryl, preferably optionally substituted phenyl, heteroaryl, C3-C8-cycloalkyl, preferably cyclopropyl and cyclobutyl , C3-C8-heterocycloalkyl, -X-aryl, -X-heteroaryl, -X-cycloalkyl, -X-heterocycloalkyl, -NR8-aryl, -NR8-heteroaryl, -NR8-cycloalkyl and -NR8-heterocycloalkyl, or

a residue selected from the group consisting of hydrogen, halogen, COXR8, CON(R8)2, COR8 and XR8, preferably hydrogen, or

the residues R3 and R4 can together form a 2- to 5-membered alkyl bridge, preferably an ethylene, propylene or butylene bridge, wherein the propylene or butylene bridge can contain 1 to 2 heteroatoms, preferably oxygen, nitrogen or sulfur, especially preferably an ethylene bridge.

A particularly advantageous substituent R3 is methyl or ethyl.

Substituent R4 is particularly preferably hydrogen or methyl.

Compounds in which R3 and R4 are methyl are particularly preferred. All radicals mentioned for R3 and R4 can be substituted as needed.

The residue R5 can be hydrogen or a residue selected from the group consisting of optionally substituted C1-C10-alkyl, for example C1-C6-alkyl-aryl or C1-C6-alkyl-heteroaryl, preferably C1-C6-alkyl, particularly preferably C1- C5-alkyl, especially preferably propyl, butyl, pentyl, hexyl, -CH2-cyclohexyl, (CH2)1-2-cyclopropyl or (CH2)2-4-OCOCH3, C2-C10-alkenyl, preferably propenyl, butenyl, pentenyl or hexenyl, preferably propenyl or hexenyl,

C2-C10-alkynyl, preferably propynyl, butynyl or pentynyl, preferably propynyl, aryl, preferably phenyl, heteroaryl, -C3-C6-cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and -C3-C6-cycloalkenyl, preferably cyclohexenyl or cyclopentenyl, or the substituents R 3 and R 5 or R 4 and R 5 may form together a saturated or unsaturated C 3 -C 4 -alkyl bridge which may contain 1 to 2 heteroatoms, preferably oxygen, sulfur or nitrogen.

All radicals listed with the meaning of R can be substituted as necessary.

Substituent R6 can be optionally substituted aryl, or heteroaryl, preferably aryl, preferably phenyl.

A particularly favorable substituent R6 is a phenyl residue that can be substituted with one of the residues R9 and R10 described below, whereby the phenyl ring of the residue R9 can preferably carry one, two, three or four, preferably one or two R10 residues, preferably in the para position in the ortho or meta position.

The substituent R7 can be hydrogen or -CO-X-C1-C4-alkyl, preferably hydrogen.

X in each case independently represents O or S, preferably O.

The residues R8 which are mentioned in the definitions of the substituents R3 and R4 represent in each case, independently of each other, hydrogen or a residue selected from the group consisting of optionally substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and phenyl, preferably hydrogen or C1-C2-alkyl.

Substituent R9 can be a residue selected from the group consisting of optionally substituted C1-C6-alkyl, preferably C2-C4-alkyl, preferably methyl, ethyl or propyl, especially preferably methyl, C2-C6-alkenyl, C2-C6-alkynyl, - CONH-C1-C10-alkylene, preferably -CONH-C1-C3-alkylene, preferably -COHH-C1-C2-alkylene, -O-aryl, preferably O-C6-C10-aryl, particularly preferably O-phenyl, -O -heteroaryl, -O-cycloalkyl, preferably O-C3-C6-cycloalkyl, particularly preferably O-cyclopropyl, -O-heterocycloalkyl, aryl, preferably C6-C10-aryl, particularly preferably phenyl, heteroaryl, cycloalkyl, preferably C3- C6-cycloalkyl, especially preferably cyclopropyl, and hetero-cycloalkyl, or a residue selected from the group consisting of -O-C1-C6-alkyl-Q1, -CONR8-C1-C10-alkyl-Q1, -CONR8-C1-C10-alkenyl -Q1, -CONR8-Q2, halogen, for example fluorine, chlorine, bromine or iodine, OH, -SO2R8, -SO2N(R8)2, -COR8, -COOR8-N(R8)2, -HHCOR8, CONR8OC1-C10 -alkyl-Q 1 and CONR 8 OQ 2 , wherein O 1 and Q 2 have the aforementioned meanings.

R9 is preferably one of the following residues: -CONH-C1-C10-alkyl, preferably -CQNH-C1-C3-alkyl, especially preferably -CONH-C1-C2-alkyl, whereby this alkyl can be substituted by CN, optionally substituted aryl, preferably optionally substituted phenyl, heteroaryl, preferably thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl or pyrazinyl, saturated or unsaturated heterocycloalkyl, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxaazinyl, amine residue, preferably methylamine, benzylamine, phenylamine or heteroarylamine, saturated or unsaturated bicyclic ring system, preferably benzimidazolyl and cycloalkyl, preferably cyclohexyl.

Furthermore, R9 is preferably -CONH-heteroaryl, preferably -CONH-pyridyl, -CONH-C3-C10-cycloalkyl, preferably -CONH-cyclopropyl, CONH-cyclobutyl or -CONH-cyclopentyl, particularly preferably -CONH-cyclopropyl, -CONH- cyclo-heterocycloalkyl, -CONH-C6-C10-aryl, preferably -CONH-phenyl, COO-C1-C3-alkyl, particularly preferably COOCH3, COOH, halogen, preferably F or chlorine, OH or the rest of the formula

[image]

All residues specified in the definition for R9 can be substituted as needed, preferably with one or more residues selected from the group consisting of OH, OCH3, Cl, F, CH3, COOH, CONHCH2Ph and CONHCH2-pyrazinyl-CH3.

Substituents R10 can in any case be the same or different and they represent a residue selected from the group consisting of optionally substituted C1-C6-alkyl, preferably C1-C3-alkyl, C2-C6-alkenyl, preferably C2-C3-alkenyl and C2- C6-alkynyl, preferably C2-C3-alkynyl, -O-C1-C3-alkyl, preferably -O-C2-C6-alkyl, -O-C2-C6-alkenyl, -O-C2-C6-alkynyl, C3- C6-heterocycloalkyl and C3-C6-cycloalkyl, or a residue selected from the group consisting of hydrogen, -CONH2, -COOR8, -OCON(R8)2, -N(R8)2, -NHCOR8, -NHCON(R8)2, -NO2 and a halogen, for example fluorine, chlorine, bromine or iodine.

Substituent R10 is preferably hydrogen, methyl, methoxy, fluorine or chlorine, particularly preferably hydrogen or methoxy, particularly preferably methoxy.

Adjacent residues R9 and R10 can together form a bridge of the general formula

[image]

whereby

Y is O, S or NR11, preferably NR11,

m is 0, 1 or 2, preferably 1,

R11 is hydrogen or C1-C2-alkyl, preferably hydrogen or methyl, particularly preferably hydrogen.

R12 is hydrogen or a residue selected from the group consisting of optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, -C1-C3-alkyl-phenyl, -C1-C3-alkyl-pyridyl, -C1-C3-alkyl-pyrazinyl, -C1-C3-alkyl-pyrimidinyl and -C1-C3-alkyl-pyridazinyl, preferably phenyl, pyridyl and pyrazinyl, and

R3 is C1-C6-alkyl, preferably methyl or ethyl.

The preparation of the compounds according to the invention can be carried out by the synthesis procedures A and B, which are described below, whereby the substituents of the general formulas (A1) to (A6) have the previously mentioned meanings. These procedures are intended to be illustrative of the invention without the intent to limit the invention to their content.

Procedure A

Grade 1A

The compound of formula (A1) reacts with the compound of formula (A2) to form the compound of formula (A3) (Scheme 1A). This reaction can be carried out according to WO 0043369 or WO 0043372. Compound (A1) can be obtained as a commercial product, for example from City Chemical LLC, 139 Allings Crossing Road, West Haven, CT, 06516, USA. Compound (A2) can be produced by methods known from the literature: (a) F. Effenberger, U. Burkhart, J. Willfahrt, Liebigs Ann. Chem. 1986, 314-333; b) T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36, 6373-6374; c) R. K. Olsen, J. Org. Chem. 1970, 35, 1912-1915; d) F.E. Dutton, B.H. Byung, Tetrahedron Lett. 1998, 30, 5313-5316; e) J. M. Rana juhi, M. M. Joullie, Synth. Commun. 1996, 26, 1379-1384).

Scheme 1A

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In step 1A, 1 equivalent of compound (A1) and 1 to 1.5 equivalents, preferably 1.1 equivalents of base, preferably potassium carbonate, potassium hydrogen carbonate, sodium carbonate or sodium hydrogen carbonate, calcium carbonate, especially preferably potassium carbonate, are mixed in a diluent, such as for example acetone, aqueous acetone, tetrahydrofuran, diethyl ether or dioxane, preferably acetone or diethyl ether, particularly preferably acetone.

At a temperature of 0 to 15°C, preferably 5 to 10°C, 1 equivalent of an amino acid of formula (A2) dissolved in an organic solvent, for example acetone, tetrahydrofuran, diethyl ether or dioxane, preferably in acetone, is added dropwise. The reaction mixture is heated with stirring to a temperature of 18°C to 30°C, preferably approx. 22°C, and then further stirring for another 10 to 24 hours, preferably approx. 12 o'clock. After that, the diluent is distilled off, the residue is mixed with water and the mixture is extracted two to three times with an organic solvent such as diethyl ether or ethyl acetate, preferably with ethyl acetate. The combined organic extracts are dried and the solvent is distilled off. The residue (compound A3) can be used in step 2 without further purification.

Grade 2A

The compound (A3) obtained in step 1A is reduced to three groups and is cyclized into the compound of formula (A4) (Scheme 2A).

Scheme 2A

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In step 2A, 1 equivalent of the nitro compound (A3) is dissolved in an acid, preferably in acetic, formic or hydrochloric acid, preferably in acetic acid, and heated to 50 to 70°C, preferably to approx. 60°C. Then a reducing agent, for example zinc, tin or iron, preferably iron powder is added until the end of the exothermic reaction and stirred for 0.2 to 2 hours, preferably 0.5 hours at 100 to 125°C, preferably at approx. 117°C. When cooled to room temperature, the iron salt is filtered off and the solvent is distilled off. The residue is taken up in a solvent or a mixture of solvents, for example ethyl acetate or dichloromethane/methanol 9/1 and half-saturated NaCl solution, and is filtered, for example through diatomaceous earth. The organic phase is dried and concentrated. The residue (compound A4) can be purified by chromatography or crystallization or used as a crude product in step 3A of the synthesis.

Grade 3A

Compound (A4) obtained in step 2A can be converted into compound of formula (A5) by electrophilic substitution according to scheme 3A.

Scheme 3A

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In step 3A, 1 equivalent of the amide of formula (A4) is dissolved in an organic solvent, for example dimethylformamide or dimethylacetamide, preferably dimethylacetamide, and cooled to approx. -5 to 5°C, preferably 0°C.

Then 0.9 to 1.3 equivalents of sodium hydride and 0.9 to 1.3 equivalents of an alkyl halide, for example methyl iodide, are added. The reaction mixture is stirred for 0.1 - 3 hours, preferably approx. 1 hour at approx. 0 to 10°C, preferably at approx. 5°C and then, if necessary, it is mixed for another 12 hours in that temperature range. The reaction mixture is concentrated and extracted with water and an organic solvent, preferably dichloromethane, ethyl acetate. The organic phases are concentrated. The residue (compound A5) can be purified by chromatography, preferably over silica gel.

Grade 4A

The amination of the compound (A5) obtained in step 3A to the compound of the formula (A7) (Scheme 4A) can be carried out by versions of the procedure that are known from the literature: version 4.1 A (a) M.P.V. Boarland, J.F.W. McOmie, J. Chem. Soc. 1951, 1218-1221; (b) F.H.S. Curd, F.C. Rose, J. Chem. Soc. 1946, 343-348, version 4.2 A (a) Banks, J. Am. Chem. Soc. 1944, 66, 1131, (b) Ghosh and Dolly, J. Incian Chem. Soc. 1981, 58, 512-513.

Scheme 4A

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For example, in version 4.1 A1, an equivalent of compound (A5) and 1 to 3 equivalents, preferably approx. 2 equivalents of the compound (A6) are heated without solvent or in an organic solvent, such as for example sulfolane, dimethylformamide, dimethylacetamide, toluene, N-methylpyrrolidone, dimethylsulfoxide or dioxane, preferably sulfolane, for 0.1 to 4 hours, preferably for 1 hour at 100 up to 220°C, preferably at approx. 160°C. When cooled, an organic solvent or a mixture of organic solvents is added, for example diethyl ether/methanol, ethyl acetate, methylene chloride, or diethyl ether, preferably diethyl ether/methanol 9/1, whereby the product (A7) is crystallized or purified by chromatography .

For example, in version 4.2 A, 1 equivalent of compound (A5) and 1 to 3 equivalents of compound (A6) are mixed with an acid, for example 1-10 equivalents of 10-38% hydrochloric acid and/or an alcohol, for example ethanol , propanol/butanol, preferably ethanol, under reflux for 1 to 48 hours, preferably approx. 5 hours.

The secreted product (A7) is filtered off and, if necessary, washed with water, dried and crystallized from a suitable org. solvents.

In the event that R6 represents an optionally substituted benzimidazole, compounds (A6) can be obtained by a procedure known from the literature, for example according to the following scheme:

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Accordingly, for example, 33 mmol of compound (Z1), 49 mmol of compound (22) and 49 mmol of 1-ethoxycarbonyl-2-ethoxy-dihydroquinoline (EEDQ) in 50 ml of an organic solvent, preferably dimethylformamide for 1 to 4 hours, preferably approx. 3 hours stirring at approx. 100 to 130°C, preferably at approx. 115°C. Then the cooled reaction solution is added to 50 to 400 ml, preferably approx. 200 ml of a mixture of water and ethyl acetate (mixture ratio approx. 1:1). The formed crystals (23) are sucked off and washed. Then 4.2 mmol of the compound (Z3) is mixed with 12.5 mmol of tin(II) chloride and 30 mmol of potassium carbonate in approx. 50 ml of organic diluent, preferably ethyl acetate at approx. 22°C, 4 to 48 hours, preferably approx. 24 hours. After the addition of 22 g of diatomaceous earth, it is extracted with an organic diluent or a mixture of organic diluents, preferably with a mixture of dichloromethane and methanol (9:1). The combined extracts are concentrated and the resulting precipitate (7.4) or the resulting crystals (Z4) are isolated.

Grade 5A

In the event that R9 represents -CONR8-C1-C10-alkyl-Q1, -CONH-C1-C5-alkylene or -CONR8-Q2, wherein the substituents have the previously mentioned meanings, the compounds according to the invention can be obtained by methods known from the literature , for example according to scheme 5A.

The compound (A7') obtained in step 4A can be converted to the amide of general formula (A10) by saponification and final amination (Scheme (5A), version 5.1A), or by saponification and final conversion to the acid chloride (A9) and then amination (Scheme ( 5A), version 5.2A.

Scheme 5A

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Version 5.1 A:

According to version 5.1A, 20 mmol ester (A7) is heated in approx. 100 ml base, preferably 1N sodium hydroxide solution or lithium hydroxide solution and approx. 500 ml of alcohol, for example ethanol, dioxane or methanol, preferably methanol, until complete ester conversion. Then the alcohol is distilled. The rest is picked up in approx. 200 ml of water and, after cooling, acidify with acid, for example with hydrochloric acid, preferably with 2 N hydrochloric acid. The product (A8) is filtered off and dried.

For example, dissolve approx. 0.5 mmol of compound (A8) with approx. 0.5 mmol of O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and approx. 1.4 mmol of diisopropylethylamine (DIPEA) in approx. 5 ml of an organic diluent, for example tetrahydrofuran, dimethylformamide, N-methylpyrrolidione, dimethylacetamide, preferably dimethylforniamide. Then add approx. 0.75 mmol of the amine that forms the substituents R9 and the reaction mixture is stirred for 0.1 to 24 hours, preferably approx. 12 hours at 20°C to 100°C. After purification, for example by crystallization or chromatography, the product of formula (A10) is obtained.

Version 5.2 A:

According to version 5.2 A suspends for example approx. 1 mmol of compound (A8) in approx. 2.7 ml, thionyl chloride. The mixture is heated to 40°C to 80°C, preferably approx. 50°C and at a constant temperature, 2 to 10 drops are added to the reaction mixture with stirring, preferably approx. 3 drops of dimethylformamide. It is then stirred at 90°C until the end of the reaction. Excess thionyl chloride is distilled off.

Approx. 1 mmol of the resulting acid chloride (A9) is dissolved in approx. 30 ml of an organic diluent, for example dichloromethane. After the addition of the amine that forms the R9 substituents, it is mixed at approx. 22°C. The resulting precipitate is filtered off and washed with water. The resulting residue is washed with an organic diluent, for example methanol. The mother liquor is purified, for example by chromatography, and concentrated. The product (A10) is behind.

Procedure B

As an alternative to the process described above, as shown in scheme 8, in accordance with the procedure known from the literature, in the continuation of stage 1A, first the amination of the compound (A3) and then the cyclization of the product (B1) into the compound (B2) can be carried out, Further substitution of the compound ( B2) to compound (A7) can be carried out, for example, analogously to step 3A.

Scheme B

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New compounds of the general formula (I) can be synthesized analogously to the following synthesis examples. However, these examples are in any case only examples of procedures and serve to further explain the invention, which is not limited to their content.

Example 63 and Example 109:

For the synthesis of compounds 63 and 109, intermediate compound 4 should first be produced as described below.

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38.9 ml (0.263 mol) of 2-bromobutyric acid ethyl ester and 36.4 g (0.263 mol) of potassium carbonate are placed in 350 ml of ethyl acetate and then 46.7 ml (0.402 mol) of isoamylamine dissolved in 70 ml of ethyl acetate. It is boiled for 20 h under reflux. The resulting salt is filtered off, the filter is evaporated, mixed with 50 ml of toluene and evaporated again to dryness.

Yield: 54.3 g of compound 1 (red oil)

54.3 g of compound 1, dissolved in 400 ml of acetone and 30.7 g (0.222 mol) of potassium carbonate were cooled with cooling to 8°C, mixed with a solution of 43.1 g (0.222 mol) of 2,4-dichloro -5-nitropyrimidine in 250 ml of acetone and then stirred for 24 h at room temperature.

The resulting suspension is evaporated, the residue is extracted with water and ethyl acetate, the organic phase is washed with water and NaCl solution, dried over MgSO4 and evaporated to dryness.

Yield: 87.3 g of compound 2 (brown oil).

44.1 g of compound 2 is dissolved in 800 ml of glacial acetic acid, heated to 65°C and mixed with 36 g of iron powder in portions. After that, it is stirred for 3 h at 70°C, the precipitate is filtered off and the filtrate is evaporated.

The residue is chromatographed with dichloromethane/methanol 90:10 on silica gel, evaporated and purified on a chromatography column (eluent: ethyl acetate/cyclohexane 1:1).

The residue was precipitated from ethyl acetate/petroleum ether. Yield: 16.1 g of compound 3 (beige powder).

16.1 g of compound 3 was dissolved in 75 ml of dimethylacetamide and in a nitrogen atmosphere and cooled to 5°C with stirring. Then 2.51 g (0.063 mol) of NaH (60% dispersion in mineral oil) is added, the temperature rising to 16°C. After 30 minutes, add 3.94 ml (0.083 mol) of methyl iodide, dissolved in 75 ml of dimethylacetamide, and stir for 24 h at 22°C.

The solvent is evaporated, mixed with 200 ml of water and the resulting precipitate is filtered off with suction and then mixed with petroleum ether.

Yield: 15.1 g of compound 4 (yellow powder).

1H-NMR (250 MHz): 7.80 (1H, s), 4.35 (m, 1H), 3.92 (m, 1H), 3.22 (s, 3H), 3.14 (m, 1H), 1.81 (m, 2H), 1.60-1.40 (m, 3H), 0.90 (m, 6H), 0.70 (t, 3H).

Synthesis of example 63

2.5 g of compound 4, 1.43 g of 4-amino-3-methoxybenzoic acid, 1.25 ml conc. hydrochloric acid, 150 ml dest. of water and 37.5 ml of ethanol and boiled for 10 h under reflux. The precipitate is filtered off, washed with water and stirred in methanol. Then the precipitate is recrystallized using petroleum ether and ether. Yield: 1.6 g of compound 5 (white powder).

0.2 g of the compound, 5.5 ml of benzylamine, 0.16 g of TETU and 0.17 g of DIPEA were dissolved in 2 ml of dimethylformamide (DMF) and stirred for 48 hours at room temperature. The reaction mixture is then taken up in methylene chloride, washed with water and the organic phase is concentrated. The product is extracted with the addition of petroleum ether/ethyl acetate 9:1 as light beige crystals. Yield: 0.18 g, melting point: 178°C.

Synthesis of example 109

5 g of 2-amino-5-nitroaniline, 6.03 g of 4-pyridylcarboxylic acid and 12.1 g of EEDQ were dissolved in 50 ml of DMF and stirred for 1.75 h at 115°C. DMF is then distilled off under vacuum and the reaction mixture is then heated for 1 h at 130°C. The residue is taken up in 30 ml of DMF and mixed with 200 ml of water and 100 ml of ethyl acetate. The resulting slurry of crystals is filtered off and washed with water, ethyl acetate and ether.

Yield: 5.8 g of compound 6.

2 g of compound 6 was mixed with 0.2 g of 5% Pd/C in 30 ral of ethanol and hydrogenated in the presence of hydrogen. It is then concentrated and recrystallized from ethanol and toluene.

Yield: 1.75 g of compound 7 in the form of a white powder.

0.2 g of compound 5, 0.28 g of compound 7, 0.001 g of sodium tert-butylate, 2.5 ml of ethylene glycol dimethyl ether, 0.006 g of palladium(II) acetate and 0.22 g of 2-(di-tert-butylphosphino)- of bi-phenyl is dissolved in 1.5 ml of N-methylpyrrolidone (NMP). Then it is heated for 5 hours at 160°C. The reaction mixture is then purified over 20 g of silica gel and the product is recrystallized from ether, ethyl acetate and petroleum ether.

Yield: 0.04 g of yellow crystals. Melting point: 180°C.

Examples 218, 58 and 4

For the synthesis of compounds 218, 58 and 4, intermediate compound 11 is first produced as described below.

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55.8 g of DL-alanine methyl ester × HCl is dissolved in 500 ml of methanol and then 76.1 ml of 30% sodium methylate solution is added and the salt is filtered off. 37.8 g of trimethylacetaldehyde was added to the filtrate and then allowed to stand for 22 h. Then 9.5 g of 10% Pd/C is added and hydrogenated for 3.1 h under 0.5 bar and at 20°C. The reaction mixture is sucked off over diatomaceous earth and evaporated. The residue is taken up in diethyl ether, the salt is filtered off over diatomaceous earth and the filtrate is evaporated.

Yield: 55.8 g of compound 8 (clear liquid).

48.5 g of 2,4-dichloro-5-nitropyrimidine is placed in 400 ml of diethyl ether and 41.0 g of potassium hydrogen carbonate in 400 ml of water is added. Cool down to -5°C. At -5°C, 43.3 g of compound 8 dissolved in 400 ml of diethyl ether is added dropwise. Stir for 1 h at -5°C and 2 h at 0°C, then warm to room temperature and let the reaction mixture stand for 24 h. The organic phase is separated, dried over MgSO4 and concentrated to dryness.

Yield: 79.2 g of compound 9 (yellow resin).

79.0 g of compound 9 is dissolved in 1000 ml of glacial acetic acid and heated to 70°C. Then the heat source is removed and 52 g of iron is added in meals. The temperature rises to approx. 110°C and stirred for 1 h at that temperature. The hot suspension is filtered and the filtrate is evaporated.

The residue is taken up in ethyl acetate and mixed with 150 ml conc. HCl, the organic phase is separated and the aqueous phase is repeatedly extracted with dichloromethane. The combined organic phases are evaporated, passed over silica gel and purified by column chromatography (eluent: petroleum ether/ethyl acetate 1:1).

Since the isolated substance is still heavily contaminated, it is cleaned once more through silica gel. The desired compound is recrystallized and the crystals are suctioned off. The mother liquor is evaporated and recrystallized from ethyl acetate/diethyl ether.

Yield: 17.63 g of compound 10,

7.6 g of compound 10 and 6.4 ml of methyl iodide were placed in 75 ml of dimethylacetamide (DMA) and cooled to -15°C. 1.25 g of NaH (60% dispersion in mineral oil) is added in portions and stirred for 30 minutes at -10° to -0°C. Then 150 ml of ice water is added, the crystals are sucked off and washed with water and petroleum ether. The crystals are taken up in dichloromethane, filtered through diatomaceous earth and the filtrate is evaporated to dryness.

It is recrystallized from petroleum ether.

Yield: 6.3 g of compound 11 (beige crystals).

1H-NMR (250 MHz): 7.73 (1H, s), 4.35 (d, 1H), 4.25 (m, 1H), 3.35 (s, 3H), 2.55 (d, 1H), 1.31 (d, 3H), 0.95 (s, 9H).

Synthesis of example 218

0/2 g of compound 11, 3,5-difluoro-4-hydroxyaniline and 0.75 ml of sulfolane are heated for 15 min at 130°C, 15 min at 140°C and 10 min at 170°C. It is then mixed with ether, the excess solution is decanted and the residue is recrystallized from methanol/ether and recrystallized from methanol.

Yield: 0.15 g of white crystals. Melting point: >250°C.

Synthesis of example 4

6.3 g of compound 11 is dissolved in 25 ml of sulfolane at 100°C, then mixed with 4.0 g of ethyl ester of 4-aminobenzoic acid and heated for 1 h at 170°C. The reaction mixture is then mixed with 50 ml of ether. When crystallization occurs, add another 50 ml of ether and 50 ml of methanol. Crystals are crystallized from methanol.

Yield: 6.6 g of compound 12 (yellowish crystals), m.p. : above 85°C decomposition occurs.

3.55 g of compound 12 are suspended in 250 ml of methanol and 25 ml of 4N sodium hydroxide solution are mixed at 60°C. After 6 h, 15 ml of glacial acetic acid is added, the resulting crystals are filtered off and washed with methanol/ether.

Yield: 1.2 g of compound 13 (white crystals).

1.5 g of compound 13 is dissolved in 7.5 ml of thionyl chloride and heated for 1 h at 80°C. Then the thionyl chloride is distilled off, the residue is mixed with ether, the crystals are suctioned off and washed with ether.

Yield: 1.7 g of compound 14 (yellow crystals).

0.18 g of 3-aminopyridine was dissolved in 10 ml of tetrahydrofuran (THF) and mixed with 0.4 ml of triethylamine. Then 0.22 g of compound 14 was added and stirred for 16 h at room temperature. The reaction mixture is evaporated to dryness, taken up in ethyl acetate, extracted with water, evaporated again and the product recrystallized from ethyl acetate.

Yield: 0.07 g (beige crystals), mp: 215-216°C.

Synthesis of example 58

0.05 g of compound 13 was suspended in 10 ml of dichloromethane, then mixed with 0.15 ml of DIPEA and 0.05 g of TBTU. The solution is then stirred for 30 minutes and mixed with 0.01 ml of 4-picolylamine. After 18 h, the reaction mixture is mixed with 20 ml of water, the organic phase is separated and the product is purified by chromatography on silica gel and then recrystallized from ethyl acetate/petroleum ether. Yield: 0.044 g (white crystals), mp: 238-240°C.

Example 65 and 125

For the synthesis of compounds 65 and 125 , intermediate compound 18 should first be produced as described below.

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28.3 g of isobutylamine, 36 g of ethyl ester of R,S-2-bromo-propionic acid and 28 g of potassium carbonate are boiled in 150 ml of ethyl acetate for 6 h under reflux. When it cools down, the salt is sucked off and the royal jelly is evaporated. The residue is mixed with 100 ml of toluene and evaporated to dryness.

Yield: 37.2 g of compound 15 (yellow oil).

38.4 g of 2,4-dichloro-5-nitropyrimidine is placed in 300 ml of diethyl ether, 30 g of potassium hydrogen carbonate in 300 ml of water is added and cooled to 0°C. 37.0 g of compound 15 is dissolved in 300 ml of diethyl ether and added dropwise at 0°-3°C. After 3 h, the phases are separated, the organic phase is dried and evaporated to dryness.

Yield: 71.6 g of compound 16.

40.0 g of compound 16 is dissolved in 300 ml of glacial acetic acid and heated to 70°C. The heat source is removed and then 30 g of iron is added in portions. The temperature rises to 110°C. The reaction mixture was cooled to 90°C and stirred for 20 minutes at that temperature. It is then filtered hot and the filtrate is evaporated. The residue is mixed with 300 ml of water and 300 ml of dichloromethane and filtered through diatomaceous earth. Phases separate. The organic phase is washed with water, dried over MgSO4 and evaporated to dryness. It is isolated after mixing in petroleum ether.

Yield: 26.7 g of compound 17.

15.0 g of compound 17 was placed in 100 ml of DMA, 4.13 ml of methyl iodide was added and cooled to 5°C. In portions, 2.60 g of NaH is added as a 60% dispersion in mineral oil. The temperature rises to 13°C. After 30 minutes, 300 ml of ice water is added, the separated crystals are sucked off and washed with petroleum ether.

Yield: 13.9 g of compound 18.

1H-NMR (250 MHz): = 7.95 (1H, s), 4.30 (m, 1H), 3.95 (m, 1H), 3.24 (s, 3H), 2.95 (m , 1H), 2.05 (m, 1H), 1.30 (d, 3H), 0.96 (d, 3H), 0.92 (d, 3H).

Synthesis of example 65

2.1 g of compound 18 in 10 ml of sulfolane was mixed with ethyl ester of 4-aminobenzoic acid and stirred for 2 h at 160°C. Then it was mixed with ether and the precipitated crystals were washed with ether.

Yield: 3.0 g of compound 19.

3 g of compound 19 was mixed with 200 ml of methanol and 25 ml of 4N NaOH and stirred for 4 h at 60°C. It is then mixed with glacial acetic acid, the separated crystals are filtered off and washed with ether.

Yield: 2.3 g of compound 20 (white crystals).

0.1 g of compound 20 was suspended in 3 ml of dichloromethane and 3 ml of DMF and then mixed with 0.13 g of DIPEA, 0.095 g of TBTU and 0.045 g of hydroxybenzotriazole (HOBt). The solution was then stirred for 30 minutes and mixed with 0.035 g of N-methyl-3-picolylamine. After 0.5 h, the reaction mixture is mixed with water and 1 g of potassium carbonate, the aqueous phase is extracted twice with 50 ml of ethyl acetate, and the product is purified by chromatography on silica gel and then recrystallized from ethanol/acetone.

Yield: 0.08 g

Synthesis of example 125

3.7 g of compound 20, 3.8 g of TBTU, 1.6 g of HOBt and 5 ml of DIPEA were dissolved in 40 ml of DMF and stirred for 4 h at room temperature. The reaction mixture is concentrated, taken up in 200 ml of ethyl acetate and extracted twice with 5 ml of 5% potassium carbonate solution each. The organic phase is concentrated, the separated crystals are filtered off and washed with ethyl acetate and ether.

Yield: 1.65 g of compound 21 (yellowish crystals).

0.486 g of compound 21 was refluxed for 0.5 h with 0.33 g of 1,2-phenylenediamine in 10 ml of toluene for 0.5 h and then the reaction mixture was concentrated. The residue is mixed with 100 ml of ethyl acetate and the organic phase is extracted twice with water. The organic phase is concentrated, the separated crystals are sucked off and washed with a little ethyl acetate.

Yield: 0.25 g of compound 22 (white crystals).

0.22 g of compound 22 in 20 g of polyphosphoric acid was stirred for 0.5 h at 150°C, then poured onto ice and mixed with ammonia. It is then extracted twice with 100 ml each of ethyl acetate, org. phase is washed with water and concentrated. The secreted product (crystals) is suctioned off and washed with ethyl acetate and ether.

Yield: 0.115 g of yellowish crystals, melting point: 287°C (decomposition).

Example 171

For the synthesis of compound 171, intermediate compound 27 must first be produced.

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34.4 g of N-isopentyl-benzylamine, 36.2 g of ethyl ester of 2-bromo-propionic acid and 42.0 g of potassium carbonate are placed in 250 ml of DMF and stirred for 3 h at 110°C. When it cools down, the inorganic salt is filtered off, the filtrate is poured out. The residue is extracted with water and diethyl ether, the organic phase is washed with water, dried and evaporated to dryness.

Yield: 55.5 g of compound 23.

55.5 g of compound 23 is placed in 600 ml of ethanol and hydrogenated for 20 minutes with 20 ml of 32% HCl and 6 g of 10% Pd/C at 20°C and under 5 bar. It is then filtered through diatomaceous earth and evaporated. The residue is mixed with 400 ml of diethyl ether, the precipitate is filtered off with suction and washed with diethyl ether.

Yield: 23.5 g of compound 24, m.p. 105°C.

23.5 g of compound 24 was dissolved in 200 ml of water and mixed with 20.0 g (0.103 mol) of 2,4-dichloro-5-nitropyrimidine in 400 ml of diethyl ether. The reaction mixture was cooled to -10°C and 50.0 g (0.499 mol) of potassium carbonate was added in portions. It is stirred for 1 h at -5°C and 1 h at 0°C and then warmed to room temperature. The aqueous phase is separated, the organic phase is washed with water, dried and evaporated to dryness.

Yield: 36.9 g of compound 25.

20.0 g of compound 25 is dissolved in 280 ml of glacial acetic acid and heated to 70°C. The heat source is removed and 17 g of iron is added. The temperature rises to 100°C and then it is stirred for 30 minutes at that temperature. It is then hot filtered and the filtrate is evaporated. The residue is mixed with 300 ml of dichloromethane and 30 ml of 32% HCl and the phases are separated. The aqueous phase is extracted with dichloromethane, the combined organic phases are washed with water and with an aqueous ammonia solution, dried and evaporated to dryness. The residue is stirred with diethyl ether.

Yield: 10.5 g of compound 26, melting point: 182°-185°C.

2.7 g of compound 26 and 2.5 ml of methyl iodide were placed in 27 ml of DMA and cooled to -10°C. Add 0.45 g of NaH (60% dispersion in mineral oil) and stir for 30 minutes at –5°C. Then 10 g of ice and 5 ml of 2N HCl are added and evaporated. The residue is extracted with ethyl acetate and water, the organic phase is dried, evaporated to dryness and filtered over silica gel.

Yield: 3.0 g of compound 27 (oil).

1H-NMR (250 MHz): = 7.67 (1H, s), 4.32-4.07 (m, 2H), 3.32 (s, 3H), 3.08 (m, 1H), 1 .70-1.50 (m, 3H), 1.42' (d, 3H), 0.95 (m, 6H).

Synthesis of example 171

0.28 g of compound 27, 0.9 ml of sulfolane and 0.22 g of p-amino-benzoic acid benzylamide were mixed for 0.5 h at 170°C. The reaction mixture is then mixed with ether and the crystals are filtered off. The product is recrystallized from ethanol.

Yield: 0.15 g, melting point: 228-240°C, (yellowish crystals).

Analogous to the previously described procedures, compounds of formula (I) listed in Table 1 were obtained, among others.

The abbreviations X2, X3, X4, X5 and X6, used in Table 1, represent in each case a bond with a position in the general formula instead of the corresponding residue R2, R3, R4, R5 and R6 listed in Table 1.

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The abbreviations X1 to X6 in the table above for the listed residues indicate the connection of the respective residue to the corresponding group R1 to R6.

As it was found, the compounds of the general formula (I) are characterized by multiple application possibilities in the field of therapy. Such application possibilities are highlighted, in which the inhibition of specific cell cycle kinases plays a role, especially the inhibitory effect on the proliferation of cultured human tumor cells, but also on the proliferation of other cells, such as, for example, endothein cells.

As it could be shown by FACS analysis, the inhibition of proliferation caused by the compounds according to the invention could be acted upon by arresting the cell primarily in the G2/M phase of the cell cycle.

At that stage of the cell cycle, depending on the cells used, they shut down at that stage of the cell cycle for a certain amount of time before inducing programmed cell death. The arrest in the G2/M phase of the cell cycle is caused, for example, by inhibition of specific cell cycle kinases. Studies on model organisms such as Schizosaccharomyces pombe or Xenopus, or research in human cells have shown that the transition from G2 phase to mitosis is regulated by CDK1/cyclin B kinase (Nurse, 1990). This kinase, which is also called "mitosis promoting factor" (MPF), phosphorylates and regulates in this way a large number of proteins, such as nuclear lamin, kinesin-like motor protein, condensin and Golgi matrix protein, which play an important role in the breakdown of the nuclear envelope, in the separation of the centrosome, in the construction of the mitotic spindle apparatus, in the condensation of chromosomes and the breakdown of the Golgi apparatus (Nigg, E., 2001). A mouse cell line with temperature-sensitive CDK1 kinase mutants shows rapid degradation of CDK1 kinase upon temperature elevation, followed by G2/M phase arrest (Th'ng et al., 1990). Treatment of human tumor cells with CDK1/cyclin B inhibitors such as butyrolactone also results in G2/M phase arrest and subsequent apoptosis (Nishio, et al. 1996). Another kinase, which has a role in the G2 phase and the phase of mitosis, is Polo-like kinase 1 (Plk1), which is responsible for the maturation of the centrosome, for the activation of the phosphatase Cdc25C, as well as for the activation of the Anaphase Promoting Complex (Glover et al., 1998, Qian et al., 2001). Injection of Plk1 antibody leads to G2 arrest in non-transformed cells, while tumor cells arrest in the mitosis phase (Lane and Nigg, 1996). In addition, protein kinase aurora B has also been attributed an essential function during entry into mitosis, Aurora B phosphorylates histone H3 at Ser11 and thereby induces chromosome condensation (Hsu, J.Y. at al., 2000). However, specific cell cycle arrest in the G2/M phase can also be caused, for example, by inhibition of a specific phosphatase such as Cdc25C (Russell and Nurse, 1986). Yeasts with a defective cdc25 gene arrest in the G2 phase, while overexpression of cdc25 leads to premature entry into the mitosis phase (Russell and Nurse, 1987). G2/M phase arrest can also be induced by inhibiting certain motor proteins, so-called kinesins such as Eg5 (Mayer et al., 1999), or with agents that stabilize or destabilize microtubules (e.g. colchicine, taxol, etoposide, vinblastine, vincristine) (Schrff and Horwitz, 1980).

On the basis of their biological properties, the compounds of the general formula I according to the invention, their isomers and their physiologically tolerable salts are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation.

Such diseases include, for example, viral infections (eg HIV and Kaposi's Sarcoma); inflammatory and autoimmune diseases (eg colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukemia, lymphoma and hard tumors; skin diseases (eg psoriasis); bone diseases; cardiovascular diseases (eg restenosis and hypertrophy). They are further useful as protection against proliferating cells (eg hair, gut, blood and progenitor cells), against DNA damage by radiation, UV-treatment and/or treatment with cytostatics (Davis et al., 2001).

The new compounds can be used for the prevention, short-term and long-term treatment of the above-mentioned diseases, also in combination with other active substances, which are used for the same indications, for example, with cytostatics.

The activity of the compounds according to the invention was determined by a cytotoxicity test on cultured human tumor cells and/or by FACS analysis, for example on HeLaS3 cells. In both test methods, the compounds show very good efficiency, i.e. for example an EC50 value in the HeLaS3 cytotoxicity test of less than 5 μmol, as a rule, less than 1 μmole.

Measurement of cytotoxicity on cultured human tumor cells

To measure cytotoxicity on cultured human tumor cells, cervical carcinoma cells of the HeLaS3 tumor cell line (obtained from the American Type Culture Collection (ATCC)) were cultured in Ham's F12 medium (Life Technologies) and 10% fetal bovine serum (Life Technologies) and harvested are in the log phase of growth. HeLaS3 cells were then plated in 96-well plates (Costar) at a density of 1000 cells per well and incubated overnight in an incubator (at 37°C and 5% CO2), with only 6 wells of each plate supplemented with medium ( 3 wells for media control, 3 wells for incubation with reduced Alamar Blue). Active substances were added to the cells at different concentrations (dissolved in DMSO; final concentration: 1%) (in each case as a triplicate determination). After 72 hours of incubation, 20 μl of Alamar Blue (AccuMed International) was added to each well and the cells were further incubated for 7 hours. For control, 20 μl of reduced Alamar Blue (Alamar Blue reagent that was kept for 30 min in an autoclave) was added to 3 wells. After 7 h of incubation, the color change of the Alamar Blue reagent was determined in individual wells in a Perkin Elmer fluorescence spectrophotometer (excitation 530 mm, emission 590 nm, intervals 15, total time 0.1). The amount of Alarnar Blue reagent changed represents the metabolic activity of the cells. The relative activity of the cells was calculated in percentages of the control (HeLa S3 cells without inhibitor) and the concentration of the active substance that inhibits the cell activity by 50% (IC50) was determined. For the cake, the values were calculated from the mean value of three individual determinations - with the correction of the value of the blank experiment (media control).

FACS analysis

Propidium iodide (PI) binds stoichiometrically to double-stranded DNA and is therefore suitable for determining the percentage of cells in G1, S, and G2/M phases of the cell cycle based on cellular DNA content. Cells in GO and G1 phase have diploid DNA content (2N), while cells in G2 or mitosis have 4N DNA content.

For PI staining, for example, 0.4 Mio HeLaS3 cells are seeded at the bottom of a 75 cm2 cell culture flask, after 24 hours 1% DMSO is added as a control or test substance at different concentrations (in 1% DMSO). The cells are incubated for 24 hours with the test substance, i.e. with DMSO, and then washed 2 times with PBS and separated with trypsin/EDTA. The cells are then centrifuged (1000 rpm, 5 min, 4°C), and the cell pellet is washed twice with PBS. The cells are then resuspended in 0.1 ml of PBS. Cells are then fixed with 80% ethanol for 16 hours at 4°C or alternatively for 2 hours at -20°C. Fixed cells (108 cells) are centrifuged (1000 rpm, 5 min, 4°C), washed with PBS and then centrifuged once more. The cell pellet was resuspended in 2 ml of Triton X-100 in 0.25% PBS and incubated for 5 min on ice. Then 5 ml of PBS is added and centrifuged again. The cell pellet is resuspended in 350 μl PI dye solution (0.1 mg/ml RNase A, 10 μg/ml prodium iodide in 1× PBS). Cells are incubated for 20 minutes in the dark with the dye buffer and then transferred to a FAGS Scan sample measurement dish. DNA measurement is performed in a Becton Dickinson FACS Analyzer, with an argon laser (500 mW, emission 488 nm), and the DNA Cell Quest program (BD). Logarithmic PI fluorescence is determined with a band-pass filter (BP 585/42). Numerical determination of the cell population in individual phases of the cell cycle is performed using the ModFit LT program of Becton Dickinson.

The compounds of the general formula (I) can be used alone or in combination with other active substances according to the invention, if necessary also in combination with other pharmacologically active substances.

Suitable administration forms are, for example, tablets, capsules, suppositories, solutions, especially solutions for injections (s, c., i.v., i.m.) and infusion, juices, emulsions or dispersion powders. In this case, the proportion of pharmaceutically effective compound(s) is in any case in the range of 0.1-90 wt.%, preferably 0.5-50 wt. % of the total composition, i.e. in quantities that are sufficient to obtain the specified dosage range. The above doses can be given several times a day, if necessary. Suitable tablets can be obtained, for example, by mixing one or more active substances with known excipients, for example with inert diluents such as calcium carbonate, calcium phosphate or milk sugar, with solubilizing agents such as corn starch or alginic acid , with binders such as starch or gelatin, with glidants such as magnesium stearate or talc, and/or with depot effect agents such as carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. Tablets can also consist of several layers.

Suitable dragees can be produced by coating cores produced analogously to tablets with agents commonly used for coating dragees, such as for example collidon or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, cores can also consist of multiple layers. Equally, the coating of the dragee can also consist of several layers, whereby the auxiliary materials mentioned above for tablets can be used.

Juices of the active substance according to the invention, or combinations of active substances, can additionally contain sweeteners such as saccharin, cyclamate, glycerin or sugar as a means of improving taste, for example fragrances such as vanillin or orange extract. In addition, they may contain suspending or thickening aids such as sodium carboxymethylcellulose, leavening agents, for example condensation products of fatty alcohols and ethylene oxide, or preservatives such as p-hydroxybenzoate.

Injection and infusion solutions are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkaline salts of ethylenediamine-tetraacetic acid, if necessary with the use of emulsifiers and/or dispersing agents , whereby, for example, when water is used as a diluent, organic solvents can also be used as dissolution enhancers, i.e. as auxiliary solvents, and are filled into injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or a combination of active substances can be produced, for example, by mixing the active substance with an inert carrier such as milk sugar or sorbitol and filling them into gelatin capsules.

Suitable suppositories can be produced, for example, by mixing with a carrier intended for this purpose, such as neutral fats or polyethylene glycol, or their derivatives.

Excipients can be mentioned, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerin), carriers such as e.g. natural stone flour (e.g. kaolin, loam, talc, chalk), synthetic stone flour (e.g. highly dispersed silicic acid and silicates), sugar (e.g. from sugar cane, milk sugar and grape sugar), emulsifiers (e.g. lignin, sulfite alkali, methylcellulose, starch and polyvinylpyrrolidone) and glidants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application is carried out in the usual way, preferably orally or transdermally, especially preferably orally. In the case of oral administration, apart from the mentioned carriers, the tablets can understandably also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, especially potato starch, gelatin and the like. Gliding agents such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions, in addition to the auxiliaries mentioned above, the active substances can be mixed with various flavor enhancers or dyes. For parenteral administration, solutions of the active substance can be used with the use of suitable liquid carriers.

Dosage for intravenous example is from 1 to 1000 mg per hour, preferably between 5 and 500 mg per hour.

Despite this, it may be necessary to deviate from the stated amounts depending on the body weight, i.e. the method of application, the individual reaction to the medicine, the formulation method and the time, i.e. the intervals between the administration of the medicine. Thus, in some cases smaller doses than above may be sufficient for the smallest amount of veins, while in other cases the upper limit must be exceeded. In the case of application of larger amounts, it may be advisable to divide the administration of the drug into several smaller individual doses during the day.

The following formulation examples illustrate the proposed invention, but they are not intended to limit its scope.

Examples of pharmaceutical formulations

A) Tablets

1 tablet contains:

active substance 100 mg

milk sugar 140 mg

corn starch 240 mg

polyvinylpyrrolidone 15 mg

magnesium stearate 5 mg

500 mg

Finely ground active substance, milk sugar and part of corn starch are mixed together. The mixture is sieved, then moistened with a solution of polyvinylpyrrolidone in water, crushed, wet granulated and dried. The granulate, the rest of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is pressed into tablets of a suitable shape and size.

B) Tablets

1 tablet contains:

active substance 80 mg

milk sugar 55 mg

corn starch 190 mg

microcrystalline cellulose 35 mg

polyvinylpyrrolidone 15 mg

sodium carboxymethyl starch 23 mg

magnesium stearate 2 mg

400 mg

Finely ground active substance, part of corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together. The mixture is sieved and with the rest of the cornstarch and water it is processed into a granulate that is dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added to this, mixed and the mixture is pressed into tablets of a suitable shape and size.

C) Solution for ampoules

active substance 50 mg

sodium chloride 50 mg

water for inj. 5 ml

The active substance is dissolved in water, at its own pH value or, if necessary, at pH 5.5-6.5 and mixed with sodium chloride as an isotonant. The resulting solution is filtered to free it from pyrogens and the filtrate is filled under aseptic conditions into ampoules, which are then sterilized and sealed. Ampoules contain 5 mg, 25 mg or 50 mg of active substance.

Claims (12)

1. Compounds of the general formula (I), [image] indicated by that R1 represents a residue selected from the group consisting of hydrogen, NH2, XH, halogen and a C1-C3-alkyl group which is optionally substituted with one or more halogen atoms, R2 is a residue selected from the group consisting of hydrogen, CHO, XH, -X-C1-C2-alkyl and optionally substituted C1-C3-alkyl group, R3 and R4 are the same or different and represent a residue selected from the group consisting of optionally substituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, C3-C8-cycloalkyl, C3-C8- heterocycloalkyl, -X-aryl, -X-heteroaryl, -X-cycloalkyl, -X-heterocycloalkyl, -NR8-aryl, -NR8-heteroaryl, -NR8-cycloalkyl and -NR8-hetero-cycloalkyl, or a residue selected from the group consisting of hydrogen, halogen, COXR8, CON(R8)2, COR8 and XR8, or R3 and R4 together form an alkyl bridge having 2 to 5 members and which may contain 1 to 2 heteroatoms, R5 is hydrogen or a residue selected from the group consisting of optionally substituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl and C3-C6-cycloalkyl, or R3 and R5 or R4 and R5 together form a saturated or unsaturated C3-C4-alkyl bridge, which can have 1 to 2 heteroatoms, R6 is optionally substituted aryl or heteroaryl, R7 is hydrogen or -CO-X-C1-C4-alkyl, and X is, in each case independently of each other, O or S, R8 is, in each case mutually independent, hydrogen or a residue selected from the group consisting of optionally substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and phenyl, as appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also as appropriate their pharmacologically unambiguous acid addition salts. 2. Compounds according to claim 1, characterized in that X and R 6 have the indicated meaning, i R1 is hydrogen, R 2 is a residue selected from the group consisting of CHO, OH, and the group -CH 3 R3 and R4, the same or different, represent a residue selected from the group consisting of hydrogen, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, or R3 and R4 together form a C2-C5-alkyl bridge, R5 is a residue selected from the group consisting of optionally substituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl and C3-C6-cycloalkyl, or R3 and R4 or R4 and R5 together form a saturated or unsaturated bridge, which may have 1 to 2 heteroatoms, and R7 is hydrogen, as appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also as appropriate their pharmacologically unambiguous acid addition salts. 3. Compounds according to claim 1 or 2, characterized in that R 1 -R 5 , R 7 , R 8 and X have the indicated meaning, i R6 is the remainder of the general formula [image] where n is 1, 2, 3 or 4, R9 is a residue selected from the group consisting of optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -CONH-C1-C10-alkylene, -O-aryl, -O-heteroaryl, -O- cycloalkyl, -O-heterocycloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl or a residue selected from the group consisting of -O-C1-C6-alkyl-Q1, -CONR8-C1-C10-alkyl-Q1, -CONR8-C2-C10-alkenyl-Q1, -CONR8-Q2, halogen, OH, -SO2R8 , -SO2N(R8)2, -COR8, -COOR8, -N(R8)2, -NHCOR8, CONR8OC1-C10-alkyl-Q1 and CONR8OQ2, Q1 is hydrogen, -NHCOR8, or a residue selected from the group consisting of optionally substituted -NH-aryl-, -NH-heteroaryl, aryl-, heteroaryl-, C3-C8-cycloalkyl- and heterocycloalkyl groups, Q2 is hydrogen or a residue selected from the group consisting of an optionally substituted aryl-, heteroaryl-, C3-C8-heterocycloalkyl, C3-C8-cycloalkyl and C1-C4-alkyl-C3-C8-cycloalkyl group, R10 are the same or different and represent a residue selected from the group consisting of optionally substituted C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, -O-C1-C6-alkyl, -O-C2-C6- alkenyl, -O-C2-C6-alkynyl, C3-C6-heterocycloalkyl and C3-C6-cycloalkyl, or a residue selected from the group consisting of hydrogen, -CONH2, -COOR8, -OCON(R8)2, -N (R8)2, -NHCOR8, -NHCON(R8)2, -NO2 and halogen, or adjacent radicals R9 and R10 together form a bridge of general formulas [image] Y is O, S or NR11, m is 0, 1 or 2, R 11 is hydrogen or C 1 -C 2 -alkyl, and R12 is hydrogen or a residue selected from the group consisting of optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, -C1-C3-alkyl-phenyl, -C1-C3-alkyl-pyridyl, -C1-C3-alkyl-pyrazinyl, - C1-C3-alkyl-pyrimidinyl and -C1-C3-alkyl-pyridazinyl, R13 is C1-C6-alkyl, as appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also as appropriate their pharmacologically unambiguous acid addition salts. 4. Compounds according to any of claims 1 to 3, characterized in that R3-R6, R8 and X have the meanings indicated, i R1 is hydrogen, R 2 is CH 3 , and R7 is hydrogen, as appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also as appropriate their pharmacologically unambiguous acid addition salts. 5. The compound of formula I according to any of claims 1 to 4, characterized in that it is used as a medicine. 6. The compound of formula I according to any one of claims 1 to 4, characterized in that it is used as a drug with an antiproliferative effect. 7. Use of the compound of formula I, characterized in that it is used for the production of a drug for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases. 8. Method for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases, characterized in that patients are given an effective amount of the compound of formula I according to claims 1 to 4. 9. Pharmaceutical preparations, characterized in that they contain as an active substance one or more compounds of the general formula (I) according to any claim 1 to 4 or its physiologically effective salts as necessary in combination with usual auxiliary substances and/or carriers. 10. Process for the production of the compound of the general formula (I), [image] where R1-R7 and X have the meanings given in claims 1 to 4, indicated that the compound of the general formula (II) [image] where R1-R5 and X have the meanings given in claims 1 to 4 and L is the output group, reacts with an optionally substituted compound of the general formula (III) [image] where R6 and R7 have the meanings given in claims 1 to 4. 11. Compound of formula (II), [image] characterized in that R1-R5 and X have the meanings given in claims 1 to 4. 12. Procedure for the preparation of the compound of the general formula (I), [image] where R6 represents the rest of the general formula [image] R9 is an optionally substituted residue -CONH-C1-C10-alkylene or a residue selected from the group consisting of -CONR8-C1-C10-alkyl-Q1, -CONR8-C1-C10-alkenyl-Q1, -CONR8-Q3 and -COOR8 , i R1-R5, R7, R10, n and X have the meanings given in claims 1 to 4, indicated that the compound of the general formula (IA) [image] where R1 to R5, R7, R10 and n have the meanings given in claims 1 to 4, i L is the output group, reacts with a primary or secondary amine to the corresponding amide, or with an alcohol to the corresponding ester.