CARBONYLAMINO-DERIVATIVES AS NOVEL INHIBITORS OF HISTONE DEACETYLASE
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Abstract
This invention comprises the novel compounds of formula (I)
wherein n, m, t, R1, R2, R3, R4, R5, L, Q, X, Y and
have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.
100 Citations
25 Claims
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1-13. -13. (canceled)
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14. A compound of formula (I),
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended; -
m is 0 or 1 and when m is 0 then a direct bond is intended; t is 0, 1, 2, 3 or 4 and when t is 0 then a direct bond is intended; each Q is nitrogen or each X is nitrogen or each Y is nitrogen or R1 is —
C(O)NR8R9, —
NHC(O)R10, —
C(O)—
C1-6alkanediylSR10, —
NR11C(O)N(OH)R11, —
NR11C(O)C1-6alkanediylSR10, —
NR11C(O)C═
N(OH)R10 or another Zn-chelating-group wherein R8 and R9 are each independently selected from hydrogen, hydroxy, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl or aminoaryl;R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, arylC1-6alkyl, C1-6alkylpyrazinyl, pyridinone, pyrrolidinone or methylimidazolyl; R11 is hydrogen or C1-6alkyl; R2 is hydrogen, halo, hydroxy, amino, nitro, C1-6alkyl, C1-6alkyloxy, trifluoromethyl, di(C1-6alkyl)amino, hydroxyamino or naphthalenylsulfonylpyrazinyl; -L- is a direct bond or a bivalent radical selected from C1-6alkanediyl, C1-6alkanediyloxy, amino, carbonyl or aminocarbonyl; each R3 independently represents a hydrogen atom and one hydrogen atom can be replaced by a substituent selected from aryl; R4 is hydrogen, hydroxy, amino, hydroxyC1-6alkyl, C1-6alkyl, C1-6alkyloxy, arylC1-6alkyl, aminocarbonyl, hydroxycarbonyl, aminoC1-6alkyl, aminocarbonylC1-6alkyl, hydroxycarbonylC1-6alkyl, hydroxyaminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminoC1-6alkyl or di(C1-6alkyl)aminoC1-6alkyl; R5 is hydrogen, C1-6alkyl, C3-10cycloalkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl or aryl; is a radical selected from wherein each s is independently 0, 1, 2, 3, 4 or 5; each R6 and R7 are independently selected from hydrogen;
halo;
hydroxy;
amino;
nitro;
trihaloC1-6alkyl;
trihaloC1-6alkyloxy;
C1-6alkyl;
C1-6alkyl substituted with aryl andC3-10cycloalkyl;
C1-6alkyloxy;
C1-6alkyloxyC1-6alkyloxy;
C1-6alkylcarbonyl;
C1-6alkyloxycarbonyl;
C1-6alkylsulfonyl;
cyanoC1-6alkyl;
hydroxyC1-6alkyl;
hydroxyC1-6alkyloxy;
hydroxyC1-6alkylamino;
aminoC1-6alkyloxy;
di(C1-6alkyl)aminocarbonyl;
di(hydroxyC1-6alkyl)amino;
(aryl)(C1-6alkyl)amino;
di(C1-6alkyl)aminoC1-6alkyloxy;
di(C1-6alkyl)aminoC1-6alkylamino;
di(C1-6alkyl)aminoC1-6alkylaminoC1-6alkyl;
arylsulfonyl;
arylsulfonylamino;
aryloxy;
aryloxyC1-6alkyl;
arylC2-6alkenediyl;
di(C1-6alkyl)amino;
di(C1-6alkyl)aminoC1-6alkyl;
di(C1-6alkyl)amino(C1-6alkyl)amino;
di(C1-6alkyl)amino(C1-6alkyl)aminoC1-6alkyl;
di(C1-6alkyl)aminoC1-6alkyl(C1-6alkyl)amino;
di(C1-6alkyl)aminoC1-6alkyl(C1-6alkyl)aminoC1-6alkyl;
aminosulfonylamino(C1-6alkyl)amino;
aminosulfonylamino(C1-6alkyl)aminoC1-6alkyl;
di(C1-6alkyl)aminosulfonylamino(C1-6alkyl)amino;
di(C1-6alkyl)aminosulfonylamino(C1-6alkyl)aminoC1-6alkyl;
cyano;
thiophenyl;
thiophenyl substituted with di(C1-6alkyl)aminoC1-6alkyl(C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylpiperazinylC1-6alkyl, hydroxyC1-6alkylpiperazinylC1-6alkyl, hydroxyC1-6alkyloxyC1-6alkylpiperazinylC1-6alkyl, di(C1-6alkyl)aminosulfonylpiperazinylC1-6alkyl, C1-6alkyloxypiperidinyl, C1-6alkyloxypiperidinylC1-6alkyl, morpholinylC1-6alkyl, hydroxyC1-6alkyl(C1-6alkyl)aminoC1-6alkyl, or di(hydroxyC1-6alkyl)aminoC1-6alkyl;
furanyl;
furanyl substituted with hydroxyC1-6alkyl;
benzofuranyl;
imidazolyl;
oxazolyl;
oxazolyl substituted with aryl and C1-6alkyl;
C1-6alkyltriazolyl;
tetrazolyl;
pyrrolidinyl;
pyrrolyl;
piperidinylC1-6alkyloxy;
morpholinyl;
C1-6alkylmorpholinyl;
morpholinylC1-6alkyloxy;
morpholinylC1-6alkyl;
morpholinylC1-6alkylamino;
morpholinylC1-6alkylaminoC1-6alkyl;
piperazinyl;
C1-6alkylpiperazinyl;
C1-6alkylpiperazinylC1-6alkyloxy;
piperazinylC1-6alkyl;
naphtalenylsulfonylpiperazinyl;
naphtalenylsulfonylpiperidinyl;
naphtalenylsulfonyl;
C1-6alkylpiperazinylC1-6alkyl;
C1-6alkylpiperazinylC1-6alkylamino;
C1-6alkylpiperazinylC1-6alkylaminoC1-6alkyl;
C1-6alkylpiperazinylsulfonyl;
aminosulfonylpiperazinylC1-6alkyloxy;
aminosulfonylpiperazinyl;
aminosulfonylpiperazinylC1-6alkyl;
di(C1-6alkyl)aminosulfonylpiperazinyl;
di(C1-6alkyl)aminosulfonylpiperazinylC1-6alkyl;
hydroxyC1-6alkylpiperazinyl;
hydroxyC1-6alkylpiperazinylC1-6alkyl;
C1-6alkyloxypiperidinyl;
C1-6alkyloxypiperidinylC1-6alkyl;
piperidinylaminoC1-6alkylamino;
piperidinylaminoC1-6alkylaminoC1-6alkyl;
(C1-6alkylpiperidinyl)(hydroxyC1-6alkyl)aminoC1-6alkylamino;
(C1-6alkylpiperidinyl)(hydroxyC1-6alkyl)aminoC1-6alkylaminoC1-6alkyl;
hydroxyC1-6alkyloxyC1-6alkylpiperazinyl;
hydroxyC1-6alkyloxyC1-6alkylpiperazinylC1-6alkyl;
(hydroxyC1-6alkyl)(C1-6alkyl)amino;
(hydroxyC1-6alkyl)(C1-6alkyl)aminoC1-6alkyl;
hydroxyC1-6alkylaminoC1-6alkyl;
di(hydroxyC1-6alkyl)aminoC1-6alkyl;
pyrrolidinylC1-6alkyl;
pyrrolidinylC1-6alkyloxy;
pyrazolyl;
thiopyrazolyl;
pyrazolyl substituted with two substituents selected from C1-6alkyl or trihaloC1-6alkyl;
pyridinyl;
pyridinyl substituted with C1-6alkyloxy, aryloxy or aryl;
pyrimidinyl;
tetrahydropyrimidinylpiperazinyl;
tetrahydropyrimidinylpiperazinylC1-6alkyl;
quinolinyl;
indole;
phenyl;
phenyl substituted with one, two or three substituents independently selected from halo, amino, nitro, C1-6alkyl, C1-6alkyloxy, hydroxyC1-4alkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC1-4alkyloxy, C1-4alkylsulfonyl, C1-4alkyloxyC1-4alkyloxy, C1-4alkyloxycarbonyl, aminoC1-4alkyloxy, di(C1-4alkyl)aminoC1-4alkyloxy, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, di(C1-4alkyl)aminoC1-4alkyl, di(C1-4alkyl)aminoC1-4alkylaminoC1-4alkyl, di(C1-4alkyl)amino(C1-4alkyl)amino, di(C1-4alkyl)amino(C1-4alkyl)aminoC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl(C1-4alkyl)amino, di(C1-4alkyl)aminoC1-4alkyl(C1-4alkyl)aminoC1-4alkyl, aminosulfonylamino(C1-4alkyl)amino, aminosulfonylamino(C1-4alkyl)aminoC1-4alkyl, di(C1-4alkyl)aminosulfonylamino(C1-4alkyl)amino, di(C1-4alkyl)aminosulfonylamino(C1-4alkyl)aminoC1-6alkyl, cyano, piperidinylC1-4alkyloxy, pyrrolidinylC1-4alkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylC1-4alkyl, di(C1-4alkyl)aminosulfonylpiperazinyl, di(C1-4alkyl)aminosulfonylpiperazinylC1-4alkyl, hydroxyC1-4alkylpiperazinyl, hydroxyC1-4alkylpiperazinylC1-4alkyl, C1-4alkyloxypiperidinyl, C1-4alkyloxypiperidinylC1-4alkyl, hydroxyC1-4alkyloxyC1-4alkylpiperazinyl, hydroxyC1-4alkyloxyC1-4alkylpiperazinylC1-4alkyl, (hydroxyC1-4alkyl)(C1-4alkyl)amino, (hydroxyC1-4alkyl)(C1-4alkyl)aminoC1-4alkyl, di(hydroxyC1-4alkyl)amino, di(hydroxyC1-4alkyl)aminoC1-4alkyl, furanyl, furanyl substituted with —
CH═
CH—
CH═
CH—
, pyrrolidinylC1-4alkyl, pyrrolidinylC1-4alkyloxy, morpholinyl, morpholinylC1-4alkyloxy, morpholinylC1-4alkyl, morpholinylC1-4alkylamino, morpholinylC1-4alkylaminoC1-4alkyl, piperazinyl, C1-4alkylpiperazinyl, C1-4alkylpiperazinylC1-4alkyloxy, piperazinylC1-4alkyl, C1-4alkylpiperazinylC1-4alkyl, C1-4alkylpiperazinylC1-4alkylamino, C1-4alkylpiperazinylC1-4alkylaminoC1-6alkyl, tetrahyfropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinylC1-4alkyl, piperidinylaminoC1-4alkylamino, piperidinylaminoC1-4alkylaminoC1-4alkyl, (C1-4alkylpiperidinyl)(hydroxyC1-4alkyl)aminoC1-4alkylamino, (C1-4alkylpiperidinyl)(hydroxyC1-4alkyl)aminoC1-4alkylaminoC1-4alkyl, pyridinylC1-4alkyloxy, hydroxyC1-4alkylamino, hydroxyC1-4alkylaminoC1-4alkyl, di(C1-4alkyl)aminoC1-4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylC1-4alkyloxy, or thiophenylC1-4alkylamino;each R6 and R7 can be placed 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, C1-6alkyl, C1-6alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl. - View Dependent Claims (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)
R5 is hydrogen, C1-6alkyl, C3-10cycloalkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl or di(C1-6alkyl)aminoC1-6alkyl; is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-27), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42) (a-43) or (a-44); and each R6 and R7 are independently selected from hydrogen;
halo;
hydroxy;
amino;
nitro;
trihaloC1-6alkyl;
trihaloC1-6alkyloxy;
C1-6alkyl;
C1-6alkyloxy;
C1-6alkyloxyC1-6alkyloxy;
C1-6alkylcarbonyl;
C1-6alkylsulfonyl;
cyanoC1-6alkyl;
hydroxyC1-6alkyl;
hydroxyC1-6alkyloxy;
hydroxyC1-6alkylamino;
aminoC1-6alkyloxy;
di(C1-6alkyl)aminocarbonyl;
di(hydroxyC1-6alkyl)amino;
arylC1-6alkyl)amino;
di(C1-6alkyl)aminoC1-6alkyloxy;
di(C1-6alkyl)aminoC1-6alkylamino;
arylsulfonyl;
arylsulfonylamino;
aryloxy;
arylC2-6alkenediyl;
di(C1-6alkyl)amino;
di(C1-6alkyl)aminoC1-6alkyl;
di(C1-6alkyl)aminoC1-6alkyl(C1-6alkyl)aminoC1-6alkyl;
cyano;
thiophenyl;
thiophenyl substituted with di(C1-6alkyl)aminoC1-6alkyl(C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylpiperazinylC1-6alkyl or di(hydroxyC1-6alkyl)aminoC1-6alkyl;
furanyl;
imidazolyl;
C1-6alkyltriazolyl;
tetrazolyl;
pyrrolidinyl;
piperidinylC1-6alkyloxy;
morpholinyl;
C1-6alkylmorpholinyl;
morpholinylC1-6alkyloxy;
morpholinylC1-6alkyl;
C1-6alkylpiperazinyl;
C1-6alkylpiperazinylC1-6alkyloxy;
C1-6alkylpiperazinylC1-6alkyl;
C1-6alkylpiperazinylsulfonyl;
aminosulfonylpiperazinylC1-6alkyloxy;
aminosulfonylpiperazinyl;
aminosulfonylpiperazinylC1-6alkyl;
di(C1-6alkyl)aminosulfonylpiperazinyl;
di(C1-6alkyl)aminosulfonylpiperazinylC1-6alkyl;
hydroxyC1-6alkylpiperazinyl;
hydroxyC1-6alkylpiperazinylC1-6alkyl;
C1-6alkyloxypiperidinyl;
C1-6alkyloxypiperidinylC1-6alkyl;
hydroxyC1-6alkyloxyC1-6alkylpiperazinyl;
hydroxyC1-6alkyloxyC1-6alkylpiperazinylC1-6alkyl;
(hydroxyC1-6alkyl)(C1-6alkyl)amino;
(hydroxyC1-6alkyl)(C1-6alkyl)aminoC1-6alkyl;
pyrrolidinylC1-6alkyloxy;
pyrazolyl;
thiopyrazolyl;
pyrazolyl substituted with two substituents selected from C1-6alkyl or trihaloC1-6alkyl;
pyridinyl;
pyridinyl substituted with C1-6alkyloxy or aryl;
pyrimidinyl;
quinolinyl;
indole;
phenyl;
phenyl substituted with one, two or three substituents independently selected from halo, amino, C1-6alkyl, C1-6alkyloxy, hydroxyC1-4alkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC1-4alkyloxy, C1-4alkyloxyC1-4alkyloxy, aminoC1-4alkyloxy, di(C1-4alkyl)aminoC1-4alkyloxy, di(C1-4alkyl)amino, di(C1-4alkyl)aminoC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl(C1-4alkyl)aminoC1-4alkyl, piperidinylC1-4alkyloxy, pyrrolidinylC1-4alkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylC1-4alkyl, di(C1-4alkyl)aminosulfonylpiperazinyl, di(C1-4alkyl)aminosulfonylpiperazinylC1-4alkyl, hydroxyC1-4alkylpiperazinyl, hydroxyC1-4alkylpiperazinylC1-4alkyl, C1-4alkyloxypiperidinyl, C1-4alkyloxypiperidinylC1-4alkyl, hydroxyC1-4alkyloxyC1-4alkylpiperazinyl, hydroxyC1-4alkyloxyC1-4alkylpiperazinylC1-4alkyl, (hydroxyC1-4alkyl)(C1-4alkyl)amino, (hydroxyC1-4alkyl)(C1-4alkyl)aminoC1-4alkyl, pyrrolidinylC1-4alkyloxy, morpholinylC1-4alkyloxy, morpholinylC1-4alkyl, C1-4alkylpiperazinyl, C1-4alkylpiperazinylC1-4alkyloxy, C1-4alkylpiperazinylC1-4alkyl, hydroxyC1-4alkylamino, di(hydroxyC1-4alkyl)amino, di(C1-4alkyl)aminoC1-4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylC1-4alkyloxy, or thiophenylC1-4alkylamino
-
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16. A compound as claimed in claim 14 wherein t is 0;
- m is 0;
R1 is —
C(O)NR8R9, —
C(O)—
C1-6alkanediylSR10, —
NR11C(O)N(OH)R11, —
NR11C(O)C1-6alkanediylSR10, —
NR11C(O)C═
N(OH)R10 or another Zn-chelating-group wherein R8 and R9 are each independently selected from hydrogen, hydroxy, hydroxyC1-6alkyl or aminoC1-6alkyl;R2 is hydrogen, halo, hydroxy, amino, nitro, C1-6alkyl, C1-6alkyloxy, trifluoromethyl or di(C1-6alkyl)amino; -L- is a direct bond or a bivalent radical selected from C1-6alkanediyl, C1-6alkanediyloxy, amino or carbonyl; R4 is hydrogen, hydroxy, amino, hydroxyC1-6alkyl, C1-6alkyl, C1-6alkyloxy, arylC1-6alkyl, aminocarbonyl, aminoC1-6alkyl, C1-6alkylaminoC1-6alkyl or di(C1-6alkyl)aminoC1-6alkyl; R5 is hydrogen; is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51); each s is independently 0, 1, 2, 3 or 4; R6 is hydrogen;
halo;
hydroxy;
amino;
nitro;
trihaloC1-6alkyl;
trihaloC1-6alkyloxy;
C1-6alkyl;
C1-6alkyloxy;
C1-6alkylcarbonyl;
C1-6alkyloxycarbonyl;
C1-6alkylsulfonyl;
hydroxyC1-6alkyl;
aryloxy;
di(C1-6alkyl)amino;
cyano;
thiophenyl;
furanyl;
furanyl substituted with hydroxyC1-6alkyl;
benzofuranyl;
imidazolyl;
oxazolyl;
oxazolyl substituted with aryl and C1-6alkyl;
C1-6alkyltriazolyl;
tetrazolyl;
pyrrolidinyl;
pyrrolyl;
morpholinyl;
C1-6alkylmorpholinyl;
piperazinyl;
C1-6alkylpiperazinyl;
hydroxyC1-6alkylpiperazinyl;
C1-6alkyloxypiperidinyl;
pyrazoly;
pyrazolyl substituted with one or two substituents selected from C1-6alkyl or trihaloC1-6alkyl;
pyridinyl;
pyridinyl substituted with C1-6 alkyloxy, aryloxy or aryl;
pyrimidinyl;
quinolinyl;
indole;
phenyl;
or phenyl substituted with one or two substituents independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl;and R7 is hydrogen;
halo;
hydroxy;
amino;
nitro;
trihaloC1-6alkyl;
trihaloC1-6alkyloxy;
C1-6alkyl;
C1-6alkyloxy;
C1-6alkylcarbonyl;
C1-6alkyloxycarbonyl;C1-6alkylsulfonyl;
hydroxyC1-6alkyl;
aryloxy;
di(C1-6alkyl)amino;
cyano;
pyridinyl;
phenyl;
or phenyl substituted with one or two substituents independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.
- m is 0;
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17. A compound as claimed in claim 14 wherein n is 1;
- m is 0 or 1;
t is 0.1 or 2;
each Q isR1 is —
C(O)NH(OH);
R2 is hydrogen or C1-6alkyl;
-L- is a direct bond;
R4 is hydrogen;
R5 is hydrogen;is a radical selected from (a-1), (a-20), (a-25), (a-27), (a-28), (a-29), (a-41) or (a-42);
each s is independently 0, 1 or 2; and
each R6 is independently selected from hydrogen, halo, C1-6alkyl or C1-6alkyloxy;
- m is 0 or 1;
-
18. A compound as claimed in claim 14 wherein n is 1;
- m is 0 or 1;
t is 0, 1 or 2;
each Q isR1 is —
C(O)NH(OH);
R2 is hydrogen;
-L- is a direct bond;
R4 is hydrogen;
R5 is hydrogen;is a radical selected from (a-1), (a-20), (a-27), (a-28), (a-29), (a-41) or (a-42);
each s is independently 0, 1 or 2; and
each R6 is independently selected from hydrogen, halo, C1-6alkyl or C1-6alkyloxy.
- m is 0 or 1;
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19. A compound according to claim 14 wherein the compound is the following compound No. 3.
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20. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 14.
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21. A process of preparing a pharmaceutical composition as claimed in claim 20 wherein the pharmaceutically acceptable carriers and the compound are intimately mixed.
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22. The method of treating proliferative disease comprising administering to a patient in need of such treatment, an anti-proliferative disease-effective amount of a compound of claim 14.
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23. A process for preparing a compound as claimed in claim 14, characterized by reacting an intermediate of formula (II) with an appropriate acid, such as for example, trifluoro acetic acid (CF3COOH), yielding a hydroxamic acid of formula (I-a), wherein R1 is —
- C(O)NH(OH).
- C(O)NH(OH).
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24. A method of detecting or identifying a histone deactylase (HDAC) in a biological sample comprising detecting or measuring the formation of a complex between a labelled compound as defined in claim 14 and a HDAC.
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25. A combination of an anti-cancer agents and a compound of claim 14.
Specification