Combination of histone deacetylase inhibitors with chemotherapeutic agents
0 Assignments
0 Petitions
Accused Products
Abstract
The invention relates to a combination which comprises (a) one or more chemotherapeutic agents and (b) a histone deacetylase inhibitor (“HDAI”) for simultaneous, concurrent, separate or sequential use, especially for use in the treatment of proliferative diseases including pre-malignant lesions (e.g. colon polyps) and malignancies, both solid and undifferentiated or other proliferative diseases in a mammal, particularly a human. The invention also relates to pharmaceutical compositions comprising such a combination and to a method of preventing or treating proliferative diseases including pre-malignant lesions (e.g. colon polyps) and malignancies, both solid and undifferentiated or other proliferative diseases, in a mammal, particularly a human, with such a combination. The present invention further also relates to a commercial package or product comprising such a combination.
-
Citations
65 Claims
-
1-37. -37. (canceled)
-
38. A combination which comprises (a) a chemotherapeutic agent which is selected from the group consisting of DNA topoisomerase I inhibitors;
- DNA topoisomerase II inhibitors;
microtubule active agents; and
antimetabolites including agents which are inhibitors of thymidine production, inhibitors of vascular endothethial growth factor, DNA demethylating agents, or protein-tyrosine kinase inhibitors, such as e.g., Adriamycin, discodermolides and epothilones such as epothilone B or D, 5-Fluorouracil, camptothecin or derivatives thereof such as gimatecan, Imatinib (Gleevec), 1-[4-chloroanilino]-4-[pyridylmethyl]-phthalazine succinate (PTK787), 5-Aza dC (Decitabine) and 5-Azacytidine;
pharmaceutically acceptable salts thereof; and
pharmaceutically acceptable prodrugs thereof; and
(b) a histone deacetylase inhibitor according to formula (I)wherein R1 is H, halo, or a straight chain C1-C6 alkyl;
R2 is selected from H, C1-C10 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, C4-C9 heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —
(CH2)nC(O)R6, —
(CH2)nOC(O)R6, amino acyl, HON—
C(O)—
CH═
C(R1)-aryl-alkyl- and —
(CH2)nR7;
R3 and R4 are the same or different and independently H, C1-C6 alkyl, acyl or acylamino, or R3 and R4 together with the carbon to which they are bound represent C═
O, C═
S, or C═
NR8, or R2 together with the nitrogen to which it is bound and R3 together with the carbon to which it is bound can form a C4-C9 heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring;
R5 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aromatic polycycle, non-aromatic polycycle, mixed aryl and non-aryl polycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryl and non-aryl polyheterocycle;
n, n1, n2 and n3 are the same or different and independently selected from 0-6, when n1 is 1-6, each carbon atom can be optionally and independently substituted with R3 and/or R4;
X and Y are the same or different and independently selected from H, halo, C1-C4 alkyl, NO2, C(O)R1, OR9, SR9, CN, and NR10R11;
R6 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR12, and NR13R14;
R7 is selected from OR15, SR15, S(O)R16, SO2R17, NR13R14, and NR12SO2R6;
R8 is selected from H, OR15, NR13R14, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
R9 is selected from C1-C4 alkyl and C(O)-alkyl;
R10 and R11 are the same or different and independently selected from H, C1-C4 alkyl, and —
C(O)-alkyl;
R12 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, C4-C9 heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl;
R13 and R14 are the same or different and independently selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R13 and R14 together with the nitrogen to which they are bound are C4-C9 heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle;
R15 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12;
R16 is selected from C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12;
R17 is selected from C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR13R14;
m is an integer selected from 0 to 6; and
Z is selected from O, NR13, S and S(O);
in which (a) and (b) are present in each case in free form or in the form of a pharmaceutically acceptable salt or a pharmaceutically acceptable prodrug thereof, for simultaneous, concurrent, separate or sequential use. - View Dependent Claims (39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 56, 57, 58, 62, 63, 64, 65)
wherein n4 is 0-3, R2 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, — - (CH2)nC(O)R6, amino acyl and —
(CH2)nR7;
R5′
is heteroaryl, heteroarylalkyl, an aromatic polycycle, a non-aromatic polycycle, a mixed aryl and non-aryl polycycle, polyheteroaryl, or a mixed aryl and non-aryl polyheterocycleor a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof.
- DNA topoisomerase II inhibitors;
-
43. The combination of claim 38 wherein the histone deacetylase inhibitor is a compound of the formula (Ib)
wherein R2′ - is selected from H, C1-C6 alkyl, C4-C6 cycloalkyl, cycloalkylalkyl, and (CH2)2-4OR21 where
R21 is H, methyl, ethyl, propyl, or isopropyl, and R5″
is unsubstituted or substituted 1H-indol-3-yl, benzofuran-3-yl or quinolin-3-ylor a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof.
- is selected from H, C1-C6 alkyl, C4-C6 cycloalkyl, cycloalkylalkyl, and (CH2)2-4OR21 where
-
44. The combination of claim 38 wherein the histone deacetylase inhibitor is a compound of the formula (Ie)
wherein R18 is H, halo, C1-C6alkyl, C3-C7cycloalkyl, aryl, or heteroaryl; -
R20 is H, C1-C6alkyl, C3-C9cycloalkyl-C1-C6alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, acyl or sulfonyl;
A1 is 1, 2 or 3 substituents which are independently H, C1-C-6alkyl, —
OR19, halo, alkylamino, aminoalkyl, halo, or heteroarylalkyl;
R19 is selected from H, C1-C6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and —
(CH2CH═
CH(CH3)(CH2))1-3H;
p is 0-3, and q is 1-5 and r is 0 or q is 0 and r is 1-5, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof.
-
-
45. The combination of claim 44 wherein R18 is H, fluoro, chloro, bromo, a C1-C4 alkyl group, a C3-C7 cycloalkyl group, phenyl or a heteroaryl ring, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof.
-
46. The combination of claim 45 wherein R2 is H, or —
- (CH2)sCH2OH and wherein s is 1-3, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof.
-
47. The combination of claim 46 wherein R1 is H and X and Y are each H, and wherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof.
-
48. The combination of claim 38 wherein the histone deacetylase inhibitor is selected from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof.
-
49. The combination of claim 48 wherein the histone deacetylase inhibitor is selected from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof.
-
56. A commercial package or product comprising a combination according to claim 38 together with instructions for simultaneous, concurrent, separate or sequential use thereof in the treatment of a disease in a mammal.
-
57. The commercial package or product according to claim 56 wherein the disease is a proliferative disease.
-
58. The commercial package or product of claim 56 wherein the proliferative disease is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, lymphoma, head and neck cancer and cancer of the esophagus, stomach, bladder, prostrate, uterus and cervix.
-
62. A method for the prevention or treatment of proliferative diseases in a mammal, which comprises treating the mammal with pharmaceutically effective amounts of a combination according to claim 38.
-
63. The method of claim 62 wherein the proliferative disease is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, lymphoma, head and neck cancer and cancer of the esophagus, stomach, bladder, prostrate, uterus and cervix.
-
64. The method of claim 62 wherein the proliferative diseases is selected from pre-malignant lesions, solid malignancies and undifferentiated malignancies.
-
65. The method of claim 62 wherein the histone deacetylase inhibitor is selected from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof.
- 50. A pharmaceutical composition which comprises (a) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof, and (b) a histone deacetylase inhibitor, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof, together with at least one pharmaceutically acceptable carrier.
-
53. A commercial package or product comprising a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof, together with instructions for use in combination with a histone deacetylase inhibitor, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof, for the treatment of a disease in a mammal, or
a commercial package or product comprising a histone deacetylase inhibitor, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof, together with instructions for use in combination with a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof, for the treatment of a disease in a mammal.
- 59. A combined preparation which comprises (a) one or more unit dosage forms of a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof, and (b) one or more unit dosage forms of a histone deacetylase inhibitor, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof.
Specification