New pyridyl alkane acid amides as cytostatics and immunosuppressives

Compounds of formula (I)

• 367
• wherein
• R1 is a hydrogen, halogen, cyano, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, trifluoromethyl, C3-C8-cycloalkyl, C1-C6-hydroxyalkyl, hydroxy, C1-C6-alkoxy, C3-C6-alkenyloxy, C3-C6-alkinyloxy, benzyloxy, C1-C7-alkanoyloxy, C2-C7-alkoxycarbonyloxy, C1-C6-alkylthio, C3-C6-alkenylthio, C3-C6-alkinylthio, C3-C8-cycloalkyloxy, C3-C8-cycloalkylthio, C2-C7-alkoxycarbonyl, aminocarbonyl, C2-C7-alkylaminocarbonyl, C3-C13-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, or NR5R6, wherein
• R5 and
• R6 are selected independently from each other from hydrogen, C1-C6-alkyl, C3-C6-alkenyl and C3-C6-alkinyl,
• R2 is hydrogen, halogen, cyano, C1-C6-alkyl, trifluoromethyl, hydroxy, C1-C6-alkoxy, benzyloxy or C1-C7-alkanoyloxy,
• wherein R1 and R2, in case they are adjacent, optionally form a bridge which is selected from the bridge members —(CH2)4— and —(CH═CH)2— and —CH2O—CR7R8—O—, wherein
• R7 and
• R8 are, independently from each other, hydrogen or C1-C6-alkyl,
• R3 is hydrogen, halogen, C1-C6-alkyl, trifluoromethyl or C1-C6-hydroxyalkyl and
• R4 is hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C6-cycloalkyl, hydroxy, C1-C6-alkoxy or benzyloxy,
• k is 0 or 1,
• A is C1-C6-alkylene, which is optionally substituted once to three-fold by C1-C3-alkyl, hydroxy, C1-C3-alkoxy, fluorine-or phenyl, or
• 1,2-cyclopropylene or
• C2-C6-alkylene, wherein a methylene unit can be isosterically replaced O, S, NR9, CO, SO or SO2, wherein the isosteric substitution, with the exception of ═CO, cannot be adjacent to the amide group, and wherein
• R9 is selected from hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C1-C6-acyl or C1-C6-alkylsulfonyl,
• D is selected from C1-C10-alkylene, optionally substituted once or twice by C1-C6-alkyl, hydroxy, or C1-C6-alkoxy,
• C2-C10-alkenylene, which is optionally substituted once or twich by C1-C6-alkyl, hydroxy, or C1-C6-alkoxy, wherein the double bond can also be to ring E,
• C3-C10-alkinylene, optionally substituted once or twice by C1-C6-alkyl, hydroxy, or C1-C6-alkoxy, and wherein
• C1-C10-alkylene, C2-C10-alkenylene or C3-C10-alkinylene, wherein one to three methylene units are each isosterically replaced by O, S, NR10, CO, SO or SO2, wherein
• R10 has the same meaning as R9, but is selected independently therefrom,
• E is selected from
• 368
• wherein the heterocyclic ring can optionally have a double bond and
• n and
• p can be, independently of each other, 0, 1, 2 or 3, with the proviso that n+p≦4 and
• q is 2 or 3,
• R11 is hydrogen, C1-C6-alkyl, hydroxy, hydroxymethyl, carboxy or C2-C7-alkoxycarbonyl and
• R12 hydrogen, C1-C6-alkyl or an oxo group adjacent to the nitrogen atom, wherein
• R11 and R12 optionally together form a C1-C3-alkylene bridge under formation of a bi-cyclic ring system,
• G is selected from hydrogen,
• G1, G2, G3, G4 and G5, wherein
• G1 represents the residue
• —(CH2)r—(CR14R15)s—R13 (G1)
• wherein
• r is an integer from 1 to 3 or 0 and
• s is 0 or 1,
• R13 is selected from hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C8-cycloalkyl,
• saturated, five- to seven-membered heterocycles, which can contain one or two hetero-atoms from the group N and/or S and/or O,
• benzyl or phenyl,
• monocyclic aromatic five or six-membered heterocycles, which can contain one to three hetero-atoms from the group N and/or S and/or O and are either bound directly or over a methylene group,
• anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
• anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic ring or a hydrated ring and either directly or over a methylene group,
• R14 has the same meaning as R13, but is selected independently thereof,
• R15 is selected from hydrogen, hydroxy, methyl, benzyl, phenyl,
• monocyclic aromatic five- or six-membered heterocycles, which can contain one to three hetero-atoms selected from the group N and/or S and/or O and are either bound directly or over a methylene group,
• anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
• anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic ring or a hydrated ring and either directly or over a methylene group,
• G2 is the residue
• 369
• wherein the substituents R13 and R15 can have the above meaning or the grouping
• —NR13R15
• can also be a nitrogen heterocycle bound over the nitrogen atom, selected from
• saturated or unsaturated monocyclic, four- to eight-membered heterocycles, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from the group N and/or S and/or O, or
• saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from the group N and/or S and/or O,
• G3 is the residue
• —SO2—(CH2)rR13 (G3)
• and
• G4 is the residue
• 370
• wherein
• Ar1 and Ar2 are selected independently from one another from phenyl, pyridyl or naphthyl and
• G5 is the residue
• —COR16 (G5)
• wherein
• R16 is selected from trifluoromethyl, C1-C6-alkoxy, C3-C6-alkenyloxy, or benzyloxy, and wherein
• aromatic ring systems in the substituents R1, R2, R4, R13, R14, R15, R16, Ar1 and Ar2 and/or in the ring system —NR13R15 can be substituted independently from each other by one to three of the same or different residues which are selected from halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-Cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-alkoxy, which can optionally be entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino or di-(C1-C6-alkyl)-amino and methylenedioxy for two adjacent groups on the aromatic ring or ring system,
• stereoisomers thereof and/or their mixtures thereof and pharmacologically acceptable acid addition salts.

Compounds according to one of the claims 1 or 2, characterized in that the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15 and R16 as well as A and D indicated therein have the following meaning in connection with the substitutions according to formula (I) given in the above claims

• 371
• wherein
• halogen is fluorine, chlorine, bromine or iodine,
• C1-C6-alkyl can be straight chain or branched and is preferably a methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl-, tert-butyl-, cyclopropylmethyl-, pentyl-, isopentyl-, tert-pentyl-, neopentyl-, cyclopropylethyl-, cyclobutylmethyl- or a hexyl group,
• alkylene is for example methylene, ethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene or decamethylene,
• C3-C6-alkenyl can be straight chain or branched and is preferably an allyl-, 2-butenyl-, 3-butenyl-, 2-methyl-2-propenyl-, 2-pentenyl-, 4-pentenyl-, 2-methyl-2-butenyl-, 3-methyl-2-butenyl-, 2-hexenyl-, 5-hexenyl-, 4-methyl-3-pentenyl- or 2,2-dimethyl-3-butenyl group,
• alkenylene is for example ethenylene, propenylene, butenylene, pentenylene, hexenylene, hexathenylene, heptenylene, octenylene, nonenylene or decenylene,
• C3-C6-alkinyl can be straight chain or branched and is preferably a propargyl-, 2-butinyl-, 3-butinyl-, 4-pentinyl-, 5-hexinyl- or 4-methyl-2-pentinyl group,
• alkinylene is for example propinylene, butinylene, pentinylene, hexinylene, heptinylene, octinylene, noninylene or decinylene,
• C3-C8-cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
• C1-C6-hydroxyalkyl contains a hydroxyl group in one of the above-named C1-C6-alkyl residues, especially in the form of the hydroxymethyl- and hydroxyethyl group, wherein
• C1-C6-alkoxy, C3-C6-alkenyloxy, C3-C6-alkinyloxy each contain, aside from the oxygen atom, one of the C1-C6-alkyl-, C3-C6-alkenyl- and/or C3-C6-alkinyl groups named above and the methoxy-, ethoxy-, isopropoxy-, tert-butoxy-, allyloxy- and propargyloxy group are preferred and is to be understood as among C1-C6-alkoxy entirely or partially substituted with fluorine, for example difluormethoxy, trifluormethox or 2,2,2-trifluorethoxy,
• C1-C6-alkylthio, C3-C6-alkenylthio, C3-C6-alkinylthio each contain, aside from the sulfur atom, one of the C1-C6-alkyl-, C3-C6-alkenyl- or C3-C6-alkinyl group named above, especially the methylthio-, ethylthio-, isopropylthio- and tert-butylthio group,
• C3-C8-cycloalkyloxy and C3-C8-cycloalkylthio are preferred as cyclopentyloxy- and cyclopentylthio- and/or cylohexyloxy,- and cyclohexylthio groups,
• C1-C7-alkanoyloxy groups contain, aside from the oxygen atom, an aliphatic acyl residue with 1 to 7 carbon atoms, especially the acetoxy-, propionyloxy- and pivaloyloxy group,
• C2-C7-alkoxycarbonyl groups contain, aside from the carbonyl group, one of the C1-C6-alkoxy groups mentioned above, especially the methoxycarbonyl-, ethoxycarbonyl-, isopropoxycarbonyl-, isobutoxycarbonyl-and tert-butoxycarbonyl group,
• C2-C7-alkoxycarbonyloxy groups contain, aside from the oxygen atom, one of the C2-C7-alkoxycarbonyl residues mentioned above, especially the methoxycarbonyloxy-, ethoxycarbonyloxy-, isopropoxycarbonyloxy-, isobutoxycarbonyloxy-and tert-butoxycarbonyl group as well as the allyloxycarbonyloxy group,
• C2-C7-alkylaminocarbonly and C3-C13-dialkylaminocarbonyl groups contain, beside the carbonyl group, an alkylamino- and/or dialkylamino residue, whose C1-C6-alkyl groups have the above meanings, wherein the dimethylaminocarbonyl-, dimethylaminocarbonyl- and the diisopropylaminocarbonyl groups are preferred, and
• aside from the unsubstituted amino group, one of the following C1-C6-alkylamino groups and/or di-(C1-C6-alkyl)amino groups are to be understood under the amino groups of the formula NR5R6,
• C1-C6-alkylamino contains one of the C1-C6-alkyl groups mentioned above, especially in form of the methylamino-, ethylamino-, propylamino-, isopropylamino-, butylamino- and the tert-butylamino group,
• di-(C1-C6-alkyl)amino carries two of the same or different of the above named C1-C6-alkyl groups on the nitrogen atom, especially in form of the dimethylamino-, diethylamino-, dipropylamino-, diisopropylamino-, isopropylmethylamino-, dibutylamino- or tert-butylmethylamino group,
• C1-C6-acyl is the residue of an aliphatic saturated or unsaturated, straight chain, branched or cyclic carboxylic acid, especially in form of the formyl-, acetyl-, propionyl-, acryloyl-, butyryl-, isobutyryl-, methacryloyl-, cyclopropylcarbonyl-, pentanoyl-, pivaloyl-, cyclobutylcarbonyl-, hexanoyl- and the dimethylacryloyl group,
• C1-C6-alkansulfonyl is preferably the methanesulfonyl-, ethanesulfonyl-, propanesulfonyl-, butanesulfonyl-, pentanesulfonyl- and the hexanesulfonyl group,
• saturated five- to seven-membered heterocycles with one or two hetero-atoms are especially tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, Piperidinyl, hexahydroazepinyl, piperazinyl, hexahydrodiazepinyl or morpholinyl,
• monocyclic aromatic five- or six-membered heterocycles with one to three hetero-atoms are especially furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl or triazinyl,
• anellated bi- and tricyclic aromatic or partially hydrated carbocycic ring systems with 8 to 16 ring atoms and at least one aromatic ring are preferably benzocyclobutyl, indanyl, indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl, fluorenyl, anthryl, dihydroanthryl, phenanthryl, dihydrophenanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl or tetrahydrodibenzocyclooctenyl, wherein mono- or dioxo-derivates, wherein, the residues of indanone, tetralone, anthrone, anthraquinone, fluorenone, phenanthrone, dibenzocycloheptenone, dihydrodibenzocycloheptenone or tetrahydrodibenzocyclooctenone are, for example, also to be understood as partially hydrated carbocyclic ring systems, anellated bi- and tricyclische aromatic or partially hydrated heterocyclic ring systems with 8 to 1 6 ring atoms and at least one aromatic ring are, for example, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, thiazolopyridyl, isothiazolopyridyl, imidazopyridyl, pyrazolopyridyl, thienopyrimidinyl, chromanyl, benzopyranyl, quinolyl, isoquinolyl, dihydroquinolyl, tetrahydroquinolyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, pyridoindolyl, acridinyl, phenothiazinyl, dihydrodibenzoxepinyl, benzocycloheptathienyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, octahydrodibenzothiepinyl, dihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, dihydropyridobenzodiazepinyl, dihydrodibenzoxazepinyl, dihydropyrildobenzoxepinyl, dihydropyridobenzoxazepinyl, dihydrodibenzothiazepinyl or dihydropyridobenzothiazepinyl, wherein their mono- or dioxo-derivates and/or optionally their possible tautomeres are also to be understood as partially hydrated heterocyclic ring systems, for example, the residues of indolinone, isatin, benzoxazol one and/or their tautomeres hydroxybenzoxazol, of benzisoxazolone, benzothiazolone, benzoisothiazolone and benzimidazolone and/or their tautomeres, hydroxybenzisoxazol, hydroxybenzothiazol, hydroxybenzoisothiazol and hydroxybenzimidazol, of indazolinone, of oxazolopyridinone, thiazolopyridinones, pyrazolopyridinones and imidazopyridinones and/or their tautomeres hydroxyoxazolopyridine, hydroxythiazolopyridines, hydroxypyrazolopyridines and hydroxyimidazopyridines, the residues of chromanone, chromone, quinolinone, dihydroquinolinone, tetrahydrocarbazolone, acridone, of dihydrodibenzoxepinones, benzocycloheptathiophenones, dihydrothienobenzothiepinones, dihydrodibenzothiepinones, dihydrodibenzoazepinones, benzocycloheptapyridinones, dihydropyridobenzoxazepinones, dihydrodibenzothiazepinones and of dihydropyridobenzothiazepinones,
• saturated and unsaturated monocyclic, four- to eight-membered heterocycles are —NR13R15 as a grouping which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from N and/or S and/or O, for example azetidine, pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine, (1H)tetrahydroazepine, octahydroazocine, pyrazolidine, piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine or thiomorpholine-1,1-dioxide,
• saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms, represent —NR13R15 as a grouping which, aside from the essential nitrogen atom optionally contain one or two further hetero-atoms, selected from N and/or S and/or O, for example 5-aza-bicyclo[2.1.1]hexane, 2-aza-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]heptane, 2-aza-bicyclo[2.2.2]octane, 8-aza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.2]octane, 9-aza-bicyclo[3.3.1]nonane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline, (4H)-dihydrobenzoxazine, (4H)-dihydrobenothiazine, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol, (10H)-dihydroacridine, 1,2,3,4-tetrahydroacridanone, (10H)-phenoxazine, (10H)-phenothiazine, (5H)-dibenzazepine, (5H)-dihydrodibenzazepine, (5H)-octahydrodibenzazepine, (5H)-dihydrodibenzodiazepine, (11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine, (10H)-dihydro-dibenzo[b,f]oxazepine, (10H)-dihydrodibenzo[b,f]thiazepine or (5H)-tetrahydrodibenzazocine, as well as optionally possible
• tautomeres in the case of substitution of the heterocycle as such or in an anellated ring system by free hydroxy-, mercapto- and/or amino groups, and
• stereoisomers such as, if applicable, cis/trans-isomers, endo/exo-isomers, optic isomers such as enantiomers, diastereomers as pure isomers or mixtures and/or racemic mixtures as well as the pharmacologically acceptable acid addition salts with inorganic or organic acids, wherein the hydrochlorides, hydrobromides, hydroiodides, sulfates and phosphates, are preferred as addition salts with suitable inorganic acids and acetates, benzoates, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, ascorbate, salicylate, formiate, glutarate, tricarballylate, citrates, fumarates, gluconates, malates, maleates, methanesulfonates, lactates, oxalates, succinates, tartrates and toluolsulfonates, for example p-toluolsulfonate are preferred as addition salts of organic acids.