| abstract |
Compounds of the formula (1) possessing enzymatic activity of histone deacetylase inhibition; its preparation process, compositions containing them, as well as the use of the compound for the manufacture of a medicament. These compounds possess therapeutic properties to inhibit proliferative conditions such as cancer and psoriasis. Claim 1: A compound of formula (1), the N-oxide forms, pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, in which t is 0, 1, 2, 3 or 4 and when t is 0 then you want to mean a direct link; each Q is nitrogen or carbon; each X is nitrogen or carbon; each Y is nitrogen or carbon; each Z is -NH-, -O- or -CH2-; R1 is -C (O) NR3R4, -NHC (O) R7, -C (O) - C1-6SR7 alkanediyl, -NR8C (O) N (OH) R7, -NR8C (O) C1-6SR7 alkanediyl, -NR8C (O) C = N (OH) R7 or other zinc chelating group wherein R3 and R4 are each independently selected from hydrogen, hydroxyl, C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 aminoalkyl or aminoaryl; R 7 is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 arylalkyl, C 1-6 pyrazinyl alkyl, pyridinone, pyrrolidinone or methylimidazolyl; R8 is hydrogen or C1-6 alkyl; R 2 is hydrogen, hydroxy, amino, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkyloxy, C 1-6 arylalkyl, aminocarbonyl, hydroxycarbonyl, C 1-6 aminoalkyl, C 1-6 aminocarbonylalkyl, C 1-6 hydroxycarbonylalkyl, hydroxyaminocarbonyl, alkyloxy C1-6carbonyl, C1-6 alkyl C1-6 aminoalkyl or di (C1-6 alkyl) C1-6alkyl; -L- is a direct bond or a bivalent radical selected from -NR9C (O) -, -NR9SO2-, or -NR9CH2-, where R9 is hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C1-6 hydroxyalkyl, C 1-6 alkyloxy-C 1-6 alkyl or di (C 1-6 alkyl) aminoC 1-6 alkyl; the cyclic part A is a radical selected from (a-1), a (a-51) in which each s is independently 0.1, 2.3, 4 or 5; each R5 and R6 are independently selected from hydrogen; halo; hydroxyl; Not me; nitro; C1-6 trihaloalkyl; C1-6 trihaloalkyloxy; C1-6 alkyl; C1-6 alkyl substituted with aryl and C3-10 cycloalkyl; C1-6 alkyloxy; C 1-6 alkyloxyC 1-6 alkyloxy; C1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; C1-6 alkyl sulfonyl; C1-6 cyanoalkyl; C1-6 hydroxyalkyl; C1-6 hydroxyalkyloxy; C 1-6 hydroxyalkyl; C1-6 aminoalkyloxy; di (C1-6 alkyl) aminocarbonyl; di (hydroxyC 1-6 alkyl) amino; (aryl) (C1-6 alkyl) amino; di (C1-6 alkyl) C1-6 aminoalkyloxy; di (C 1-6 alkyl) C 1-6 aminoalkyl; di (C1-6 alkyl) aminoC 1-6 alkylC 1-6 aminoalkyl; arylsulfonyl; arylsulfonylamino; aryloxy; C 1-6 aryloxyalkyl; C2-6 arylalkenyl; di (C1-6 alkyl) amino; di (C1-6 alkyl) C1-6 aminoalkyl; di (C1-6 alkyl) amino (C1-6 alkyl) amino; di (C1-6 alkyl) amino (C1-6 alkyl) amino C1-6 alkyl; di (C 1-6 alkyl) C 1-6 aminoalkyl (C 1-6 alkyl) amino; di (C1-6 alkyl) aminoC 1-6 alkyl (C1-6 alkyl) aminoC 1-6 alkyl; aminosulfonylamino (C1-6 alkyl) amino; aminosulfonylamino (C 1-6 alkyl) C 1-6 aminoalkyl; di (C1-6 alkyl) aminosulfonylamino (C1-6 alkyl) amino; di (C1-6 alkyl) aminosulfonylamino (C1-6 alkyl) C1-6 aminoalkyl; cyano; thiophenyl; thiophenyl substituted with di (C1-6 alkyl) amino C1-6 alkyl (C1-6 alkyl) amino C1-6 alkyl, di (C1-6 alkyl) amino C1-6 alkyl, C1-6 alkylpiperazinylalkyl C1-6 hydroxyalkyl C1-6piperazinylalkyl C1 -6, C 1-6 hydroxyalkyloxyC 1-6 alkylpiperazinylalkylC 1-6 alkyl, di (C 1-6 alkyl) aminosulfonylpiperazinylalkylC 1-6 alkyl, C 1-6 alkyloxypiperidinyl, C 1-6 alkyloxypiperidinylalkylC 1-6 alkyl, morpholinylC 1-6 alkyl, hydroxyalkyl C 1-6) C 1-6 aminoalkyl, or di (C 1-6 hydroxyalkyl) C 1-6 aminoalkyl; furanyl; furanyl substituted with C1-6 hydroxyalkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and C1-6 alkyl; C1-6triazolyl alkyl; tetrazolyl; pyrrolidinyl; pyrrolyl; piperidinylalkylC 1-6 alkyloxy; morpholinyl; C1-6morpholinyl alkyl; C1-6 morpholinyl-alkyloxy; C1-6 morpholinyl alkyl; morpholinyl C1-6 alkyl; morpholinylCl-6-C 1-6 alkylaminoalkyl; piperazinyl; C 1-6 alkylpiperazinyl; C 1-6 alkylpiperazinylalkylC 1-6 alkyloxy; piperazinylalkylC 1-6 alkyl; naphthalenylsulfonylpiperazinyl; naphthalenylsulfonylpiperidinyl; naphthalenylsulfonyl; C 1-6 alkylpiperazinylalkylC 1-6 alkyl; C1-6 alkylpiperazinylalkylC 1-6 amino; C 1-6 alkylpiperazinylalkylC 1-6 aminoC 1-6 alkyl; C 1-6 alkylpiperazinylsulfonyl; aminosulfonylpiperazinylalkylC 1-6 alkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylalkylC 1-6 alkyl; di (C1-6 alkyl) aminosulfonylpiperazinyl; di (C 1-6 alkyl) aminosulfonylpiperazinylalkylC 1-6 alkyl; hydroxy C1-6piperazinyl; C 1-6 hydroxyalkylpiperazinylalkylC 1-6 alkyl; C 1-6 alkyloxypiperidinyl; C1-6 alkyloxypiperidinylalkylC 1-6 alkyl; piperidinylaminoC 1-6 amino alkyl; piperdylaminoC 1-6 alkylC 1-6 aminoalkyl; (C1-6 alkylpiperdinyl) (hydroxyC 1-6 alkyl) aminoC 1-6 alkyl; (C1-6 alkylpiperidinyl) (hydroxyC 1-6 alkyl) aminoC 1-6 alkylC 1-6 aminoalkyl; C 1-6 hydroxyalkyloxyC 1-6piperazinyl; C 1-6 hydroxyalkyloxyC 1-6 alkylpiperazinylalkylC 1-6 alkyl; (C1-6 hydroxyalkyl) (C1-6 alkyl) amino; (C 1-6 hydroxyalkyl) (C 1-6 alkyl) C 1-6 aminoalkyl; hydroxyC 1-6 alkylC 1-6 aminoalkyl; di (hydroxyC 1-6 alkyl) aminoC 1-6 alkyl; C1-6 pyrrolidinylalkyl; C1-6 pyrrolidinylalkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from C 1-6 alkyl or C 1-6 trihaloalkyl; pyridinyl; pyridinyl substituted with C1-6 alkyloxy, aryloxy or aryl; pyrimidinyl; tetrahydropyrimidinylpiperazinyl; tetrahydropyrimidinylpiperazinylalkylC 1-6 alkyl; quinolinyl; indole; phenyl; or phenyl substituted with one, two or three substituents independently selected from halo, amino, nitro, C1-6 alkyl, C1-6 alkyloxy, C1-4 hydroxyalkyl, trifluoromethyl, trifluoromethyloxy, C1-4 hydroxyalkyloxy, C1-4 alkyl sulfonyl, C1 alkyloxy -4- C1-4alkyloxy, C1-4alkyloxycarbonyl, C1-4 aminoalkyloxy, di (C1-4alkyl) C1-4alkyloxyxyl, di (C1-4alkyl) amino, di (C1-4alkyl) aminocarbonyl, di (C1alkyl -4) C 1-4 aminoalkyl, di (C 1-4 alkyl) C 1-4 aminoalkylC 1-4 alkyl, di (C 1-4 alkyl) aminoC 1-4 alkyl (C 1-4 alkyl) amino, di (C 1-4 alkyl) aminoalkyl C 1-4 (C 1-4 alkyl) aminoC 1-4 alkyl, aminosulfonylamino (C 1-4 alkyl) amino, aminosulfonylamino (C 1-4 alkyl) aminoC 1-4 alkyl, di (C 1-4 alkyl) aminosulfonylamino (C 1-4 alkyl) amino , di (C1-4 alkyl) aminosulfonylamino (C1-4 alkyl) C1-6 aminoalkyl, cyano, piperidinylalkyl C1-4, pyrrolidinylalkyl C1-4, aminosulfonylpiperazinyl, aminosulfonylpiperazinylalkyl C1-4 alkyl, di (C1-4 alkyl) aminosulfonylpi zinyl, di (C1-4 alkyl) aminosulfonylpiperazinylalkyl C1-4, hydroxyalkyl C1-4piperazinyl, hydroxyalkyl C1-4piperazinylalkyl C1-4, alkyloxy C1-4piperidinyl, C1-4 alkyloxypiperidinylalkyl C1-4, hydroxyalkyloxy C1-4alkyl C1-4pipentylalkyl -4C 1-4 alkylpiperazinylC 1-4 alkyl, (hydroxyC 1-4 alkyl) (C 1-4 alkyl) amino, (hydroxyC 1-4 alkyl) (C 1-4 alkyl) aminoC 1-4 alkyl, di (hydroxyC 1-4 alkyl) arnino, di (C1-4 hydroxyalkyl) C1-4 aminoalkyl, furanyl, furanyl substituted with -CH = CH-CH = CH-, pyrrolidinylalkyl C1-4, pyrrolidinylalkyloxy C1-4, morpholinyl, morphinylalkyl C1-4, morpholinyl C1-4 alkyl, morpholinylC1 alkyl -4amino, morpholinylC1-4alkylC1-4alkyl, piperazinyl, C1-4alkylperazinyl, C1-4alkylpiperazinylC1-4alkyl, C1-4 piperazinylC1-4alkyl, C1-4piperazinylC1-4alkyl, C1-4alkyl 4piperazinylalkyl C1-4aminoalkyl C1-6, pyrimidinylpiperazinyl, piperidinylaminoalkyl C1-4ami no, piperidinylaminoC 1-4 alkylC 1-4 alkyl, (C 1-4 alkylpiperidinyl) (hydroxyC 1-4 alkyl) aminoC 1-4 alkyl, (C 1-4 alkylpiperidinyl) (hydroxyC 1-4 alkyl) C 1-4 aminoalkylC 1-4 alkyl, pyridinylalkylC 1-4 , hydroxyC 1-4 alkyl, di (hydroxyC 1-4 alkyl) amino, di (C 1-4 alkyl) aminoC 1-4 alkyl, aminothiadiazolyl, aminosulfonylpiperazinylalkyl C 1-4 alkyloxy, or thiophenylC 1-4 alkyl; each R5 and R6 being able to be located on the nitrogen in replacement of the hydrogen; aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, C1-6 alkyl, C1-6 alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl. Claim 11: A process for the preparation of a compound according to claim 1, characterized in that an intermediate of the formula (2) is reacted with an appropriate acid, such as, for example, trifluoroacetic acid, producing a hydroxamic acid of the formula (1-a), in which R1 is -C (O) NH (OH). |