ME01444B - Substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase - Google Patents

Claims (12)

1. A compound of formula (I), its N-oxide form, its pharmaceutically acceptable addition salt and its stereochemical isomeric form, indicated that each is an integer with the value 0, 1 or 2 and when n is equal to 0 then a direct bond is possible ; each m is an integer with value 1 or 2; each X is independently N or CH; each Y is independently O, S, or NR 4 ; where each R4 is hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl, C3-6cycloalkyl, C3-6cycloalkylmethyl, phenylC1-6alkyl, -C(=O)-CHR5R1 or -S(=O)2-N(CH3)2 ; wherein each R 5 and R 1 is independently hydrogen, amino, C 1-6 alkyl or aminoC 1-6 alkyl; and when Y is equal to NR4 and R2 is in the 7-position of indolyl then R2 and R4 together can form the divalent radical -(CH2)2- (a-1), or -(CH2)3- (a-2); R1 is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkylsulfonyl C1-6alkylcarbonyl or mono- or di(C1-6alkyl)aminosulfonyl; R2 is hydrogen, hydroxy, amino, halo, C1-6alkyl, cyano, C2-6alkenyl, polyhaloC1-6alkyl, nitro, phenyl, C1-6alkylcarbonyl, hydroxycarbonyl, C1-6alkylcarbonylamino, C1-6alkyloxy, or mono- or di(C1- 6alkyl)amino; R 3 is hydrogen, C 1-6 alkyl, or C 1-6 alkyloxy; and when R2 and R3 are on adjacent carbon atoms, both can form the bivalent radical -O-CH2-O-. 2. A compound according to claim 1, characterized in that each n is an integer with a value of 0 or 1; each R4 is hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6cycloalkyl or phenylC1-6alkyl; R1 is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl or C1-6alkylsulfonyl; and R2 is hydrogen, halo, C1-6alkyl, cyano, nitro, polyhaloC1-6alkyl or C1-6alkyloxy. 3. A compound according to claim 1 and 2, characterized in that each n is an integer with a value of 1; each m is an integer with value 1; each X is independently N; each Y is independently NR4; each R 4 is C 1-6 alkyl; R 1 is hydrogen; R 2 is hydrogen or halo; and R 3 is hydrogen. 4. A compound as claimed in claims 1, 2 and 3, characterized in that said compound is compound no. la Compound no. 30 Compound no. 39 and compound no. 50 . 5. A pharmaceutical composition characterized by containing pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound according to claims 1 to 4. 6. A process for preparing a pharmaceutical composition according to claim 5, characterized in that the pharmaceutically acceptable carriers and the compound according to claim 1 to 4 are intimately mixed. 7. A compound according to any one of claims 1 to 4 for use as a medicament. 8. Use of the compound as stated in claims 1 to 4, characterized in that it relates to the production of medicaments for the treatment of proliferative diseases. 9. A combination of an anti-tumor agent and an HDAC inhibitor as set forth in any of claims 1 to 4. 10. A process for the production of a compound according to claim 1, characterized in that a) the reaction of an intermediate of formula (II), where Q is tetrahydropyranyloxyaminocarbonyl, which is referred to here as an intermediate of formula (Il-a), with a suitable acid, such as, for example, trifluoroacetic acid acid, gives a hydroxamic acid of formula (I). b) reaction of intermediates of formula (II), where Q is C1-2alkyloxycarbonyl, referred to herein as intermediates of formula (II-c), with hydroxylamine, in the presence of a base and in a suitable solvent, gives a hydroxamic acid of formula (I) 11. A compound of formula (II) of its N-oxide form, its pharmaceutically acceptable addition salt and its stereochemical isomeric form, wherein each n is an integer having a value of 0, 1 or 2 and when n equals 0 then a direct bond is possible ; each m is an integer with value 1 or 2; each X is independently N or CH; each Y is independently O, S, or NR 4 ; where each R4 is hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl, C3-6cycloalkyl, C3-6cycloalkylmethyl, phenylC1-6alkyl, -C(=O)-CHR5R6 or -S(=O)2-N(CH3)2 ; wherein each R 5 and R 6 is independently hydrogen, amino, C 1-6 alkyl or aminoC 1-6 alkyl; and when Y is equal to NR4 and R2 is in the 7-position of indolyl then R2 and R4 together can form the bivalent radical -(CH2)2- (a-1), or -(CH2)3- (a-2); R1 is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkylsulfonyl C1-6alkylcarbonyl or mono- or di(C1-6alkyl)aminosulfonyl; R2 is hydrogen, hydroxy, amino, halo, C1-6alkyl, cyano, C2-6alkenyl, polyhaloC1-6alkyl, nitro, phenyl, C1-6alkylcarbonyl, hydroxycarbonyl, C1-6alkylcarbonylamino, C1-6alkyloxy, or mono- or di(C1- 6alkyl)amino; R 3 is hydrogen, C 1-6 alkyl, or C 1-6 alkyloxy; when R2 and R3 are on adjacent carbon atoms, they can form the divalent radical -O-CH2-O-; and Q is C 1-6 alkyloxycarbonyl, hydroxycarbonyl or tetrahydropyranyloxyaminocarbonyl. 12. A process for the preparation of a compound as stated in claim 11, characterized in that a) the reaction of a compound of formula (II), where Q is hydroxycarbonyl, which is referred to here as a compound of formula (II-b), with an intermediate of formula (111) in the presence of a suitable reagent such as N-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine, monohydrochloride (EDC) and 1-hydroxy-1N-benzotriazole (HOBT) forms compounds of formula (II-a), b ) reaction of the intermediate of the formula (VI) with the corresponding carboxaldehyde of the formula (V), where t is an integer with a value of 0 or 1, and when t is equal to 0 then a direct connection is possible, in the presence of a suitable reagent, forms compounds of the formula (IIa ), c) reaction of compounds of formula (II), where Q is methyl- or ethyloxycarbonyl (C1-2alkyl), referred to herein as compounds of formula (II-c), with a suitable acidic solution or basic solution, forms compounds of formula (Il -b), d) reaction of ethyl ester of carboxylic acid of formula (IV) with corresponding carboxaldehyde of formula (V), in the presence of a suitable reagent, forms compounds of formula (II-c), e) reaction of intermediate of formula (XIV) with corresponding intermediate of formula ( XV), in the presence of a suitable reagent, in a suitable solvent, forms compounds of formula (II-c), f) reaction of an intermediate of formula (X) with an intermediate of formula (XI) where W is a suitable leaving group such as, for example, halo, for example fluoro, chloro, bromo or iodo, or a sulfonyloxy radical such as methylsulfonyloxy, forms compounds of formula (II-c), or the reaction of an intermediate of formula (XII) with an intermediate of formula (XIII), where W is the appropriate leaving group as above described, forms compounds of formula (II-c).