US 2010/0160392 A1 · HISTONE DEACETYLASE INHIBITORS

Abstract

The present invention provides histone deacetylase inhibitors of general formula (I), a process for the preparation of such compounds and uses of the compounds in medicine, especially in the treatment of cancers: in which R1 is an optionally substituted aryl, arylalkyl, heteroaryl, heterocycloalkenyl, cycloalkene ring, cycloalkyl, heterocycloalkyl or a combination of such rings to form a linked or fused ring system, R2 and R3 is each independently hydrogen, optionally substituted saturated or unsaturated alkyl, optionally substituted aryl or heteroaryl, or a combination thereof to form a linked or fused ring system, alkoxy, thioalkoxy, hydroxyl, hydroxyalkyl, halo, haloalkyl, cyano, nitro, amino, amido, alkylamino, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl, alkylthiocarbonyl, alkylsulfonylamino, aminosulfonyl, alkylsulfinyl, or alkylsulfonyl, or R3 is absent when Y stands for O or S, or R2 and R3 may be linked together and such that, together with the intervening atoms, they form a 5, 6 or 7-membered ring containing one or more heteroatoms, which may be a heteroaryl ring, heterocycloalkenyl ring, or heterocycloalkyl ring, optionally containing up to 4 heteroatoms, e.g. oxygen, nitrogen or sulphur, which ring may be fused to further rings as part of a fused ring system, and which may bear 1, 2 or 3 substituents, which substituents independently have the same meaning as R2 on any or all of those rings, Q stands for an (alkyl, which may be unsaturated; aryl, arylalkyl, alkylaryl or alkylarylalkyl, all of which may be optionally substituted; and may be optionally interrupted by O, S, NR, CO, C(N═R), where R may be independently hydrogen, alkyl, alkenyl, alkynyl, or alkoxy; V is OH, SH, SR, OR, NH2, NHR, NRR, NROH, NHOR, NROR where R may independently be hydrogen or (C1-C6) alkyl, Y is oxygen, or sulphur or N, and Z is O, S, S(═O), S(O)2, NR4, —N═, CR4R5, or —C(R4)=, where R4 and R5 independently have the same meaning as R2.

A compound of general formula (I):

in which:
R1 is (C6 or C10) aryl, (C6 or C10) arylalkyl, (C6 or C10) heteroaryl, (C3-C8) heterocycloalkenyl, (C5-C8) cycloalkene ring, (C5-C8) cycloalkyl, (C5-C8) heterocycloalkyl or a combination of such rings to form a linked or fused ring system, the cyclic moiety being optionally substituted with 1, 2 or 3 substituents, the substituents being selected from (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, (C1-C10) thioalkoxy, hydroxyl, hydroxyl, (C1-C10) hydroxyalkyl, halo, (C1-C10) haloalkyl, amino, amido, (C1-C10) alkylamino, (C1-C10) alkylcarbonyloxy, (C1-C10) alkoxycarbonyl, (C1-C10) alkylcarbonyl, (C1-C10) alkylthiocarbonyl, (C1-C10) alkylsulfonylamino, aminosulfonyl, (C1-C10) alkylsulfinyl, and (C1-C10) alkylsulfonyl, in which any of the saturated or an unsaturated hydrocarbon chains in the substituents is optionally interrupted by one or more of O, S, NR, CO, C(N═R), N(R)SO2, SO2N(R), N(R)C(O)O, OC(O)N(R), N(R)C(O)N(R), OC(O), C(O)O, OSO2, SO2O, or OC(O)O, where R may be independently hydrogen, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) hydroxyalkyl, hydroxyl, or (C1-C6) halolalkyl, and in which any of the saturated or unsaturated hydrocarbon chains in the substituents may be optionally substituted with (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, hydroxyl, hydroxyl, (C1-C6) hydroxyalkyl, halo, (C1-C6) haloalkyl, amino, (C1-C6) alkylcarbonyloxy, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylsulfonylamino, aminosulfonyl, or (C1-C6) alkylsulfonyl,
R2 and R3 are each independently hydrogen, (C1-C6) alkyl, substituted (C1-C6) alkyl, or unsaturated (C2-C6) alkenyl or alkynyl comprising one or more C═C bond or C≡C bonds, (C6 or C10) aryl or (C6 or C10) heteroaryl, or a combination thereof to form a linked or fused ring system, (C1-C6) alkoxy, (C1-C6) thioalkoxy, hydroxyl, (C1-C6) hydroxyalkyl, halo, (C1-C6) haloalkyl, cyano, nitro, amino, amido, (C1-C6) alkylamino, (C1-C6) alkylcarbonyloxy, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C10) alkylthiocarbonyl, (C1-C6) alkylsulfonylamino, aminosulfonyl, (C1-C6) alkylsulfinyl, or (C1-C6) alkylsulfonyl, in which the saturated or an unsaturated hydrocarbon chain is optionally interrupted by O, S, NR, CO, C(N═R), N(R)SO2, SO2N(R), N(R)C(O)O, OC(O)N(R), N(R)C(O)N(R), OC(O), C(O)O, OSO2, SO2O, or OC(O)O, where R may be independently hydrogen, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) hydroxyalkyl, hydroxyl, or (C1-C6) halolalkyl, and in which any of the saturated or unsaturated hydrocarbon chains may be optionally substituted with (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, hydroxyl, hydroxyl, (C1-C6) hydroxylalkyl, halo, (C1-C6) haloalkyl, amino, (C1-C6) alkylcarbonyloxy, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylsulfonylamino, aminosulfonyl, or (C1-C6) alkylsulfonyl,
R3 is absent when Y stands for O or S,
or R2 and R3 may be linked together and such that, together with the intervening atoms, they form a 5, 6 or 7-membered ring containing one or more heteroatoms, which may be a (C6 or C10) heteroaryl ring, (C3-C8) heterocycloalkenyl ring, or (C5-C8) heterocycloalkyl ring, optionally containing up to 4 heteroatoms, which ring may be fused to further rings as part of a fused ring system, and which may bear 1, 2 or 3 substituents, which substituents independently have the same meaning as R2 on any or all of those rings,
Q stands for (C1-C8) alkyl;
C6 aryl, which may be either unsubstituted or bear from 1 to 3 substituents each of which independently has the same meaning as R2;
(C6 aryl)C1-4 alkyl, C1-4alkyl(C6 aryl) or C1-4 alkyl(C6 aryl)C1-4 alkyl, in which aryl is either unsubstituted or bears from 1 to 3 substituents each of which is independently defined by R2;
substituted (C1-C8) alkyl where each substituent is independently defined by R2;
or (C2-C6) alkenyl or (C2-C6) alkynyl comprising one or more C═C bond or C≡C bond;
wherein any saturated or unsaturated hydrocarbon chain may be optionally interrupted by O, S, NR, CO, C(N═R), where R may be independently hydrogen, (C1-C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, or (C1-C4) alkoxy, and wherein any of the saturated or unsaturated hydrocarbon chains may be optionally substituted with (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) alkoxy or amino;
V is OH, SH, SR, OR, NH2, NHR, NRR, NROH, NHOR, NROR where R may independently be hydrogen or (C1-C6) alkyl,
Y is oxygen, or sulphur, in which case R3 is absent, or N, in which case R3 is present and has the meaning defined above;
and
Z is O, S, S(═O), S(═O)2, NR4, —N═, CR4R5, or —C(R4)═, where R4 and R5 independently have the same meaning as R2,
or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof.

13 more elements

Histone deacetylase inhibitors

Life of this patent

Histone deacetylase inhibitors

Life of this patent

Abstract

Claims41