COMBINATIONS OF CLASS-I SPECIFIC HISTONE DEACETYLASE INHIBITORS WITH PROTEASOME INHIBITORS
First Claim
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1. A combination of a proteasome inhibitor and a histone deacetylase inhibitor of formula (I) the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein is a radical selected from R5 is selected from hydrogen;
- thienyl;
thienyl substituted with di(C1-6alkyl)aminoC1-6alkyl, or C1-16alkylpiperazinylC1-6alkyl;
furanyl;
phenyl;
phenyl substituted with one substituents independently selected from di(C1-4alkyl)aminoC1-4alkyloxy, di(C1-4alkyl)amino, di(C1-4alkyl)aminoC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl(C1-4alkyl)aminoC1-4alkyl, pyrrolidinylC1-4alkyl, pyrrolidinylC1-4alkyloxy or C1-14alkylpiperazinylC1-4alkyl.
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Abstract
The present invention is concerned with combinations of a proteasome inhibitor and a class-I specific histone deacetylase inhibitor for inhibiting the growth of tumor cells, useful in the treatment of cancer.
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Citations
21 Claims
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1. A combination of a proteasome inhibitor and a histone deacetylase inhibitor of formula (I)
the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein is a radical selected from R5 is selected from hydrogen; - thienyl;
thienyl substituted with di(C1-6alkyl)aminoC1-6alkyl, or C1-16alkylpiperazinylC1-6alkyl;
furanyl;
phenyl;
phenyl substituted with one substituents independently selected from di(C1-4alkyl)aminoC1-4alkyloxy, di(C1-4alkyl)amino, di(C1-4alkyl)aminoC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl(C1-4alkyl)aminoC1-4alkyl, pyrrolidinylC1-4alkyl, pyrrolidinylC1-4alkyloxy or C1-14alkylpiperazinylC1-4alkyl. - View Dependent Claims (3, 4, 5, 6, 13, 14, 17, 19, 20)
- thienyl;
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2. A combination of a proteasome inhibitor and a histone deacetylase inhibitor wherein the histone deacetylase inhibitor is selected from compounds No. 6 (R306465), No. 100, No. 104, No. 128, No. 144, No. 124, No. 154, No. 125, No. 157, No. 156, No. 159, No. 163, No. 164, No. 168, No. 169, No. 127, No. 171, No. 170, No. 172 and No. 173:
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- View Dependent Claims (15, 16, 18)
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16. A combination as claimed in claim 2 wherein the proteasome inhibitor is bortezomib.
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18. A combination as claimed in claim 2 in the form of a pharmaceutical composition comprising a proteasome inhibitor and a histone deacetylase inhibitor of formula (I) together with one or more pharmaceutical carriers.
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7. (canceled)
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8. (canceled)
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9. A method for the treatment of acute lymphoblastic leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute monocytic leukemia, lymphoma, chronic B cell leukemia, chronic myeloid leukemia, chronic myeloid leukemia in blast crisis, Burkitt'"'"'s lymphoma and multiple myeloma in a subject in need of treatment, said method comprising administering a therapeutically effective amount of a histone deactylase inhibitor is a compound of formula (I):
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the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein is a radical selected from R5 is selected from hydrogen;
thienyl;
thienyl substituted with di(C1-6alkyl)aminoC1-6alkyl, or C1-16alkylpiperazinylC1-6alkyl;
furanyl;
phenyl;
phenyl substituted with one substituents independently selected from di(C1-4alkyl)aminoC1-4alkyloxy, di(C1-4alkyl)amino, di(C1-4alkyl)aminoC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl(C1-14alkyl)aminoC1-4alkyl, pyrrolidinylC1-4alkyl, pyrrolidinylC1-4alkyloxy or C1-14alkylpiperazinylC1-4alkyl.- View Dependent Claims (11, 12)
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10. A method for the treatment of drug resistant acute lymphoblastic leukemia, drug resistant acute myelogenous leukemia, drug resistant acute promyelocytic leukemia, drug resistant acute myeloid leukemia, drug resistant acute monocytic leukemia, drug resistant lymphoma, drug resistant chronic B cell leukemia, drug resistant chronic myeloid leukemia, drug resistant chronic myeloid leukemia in blast crisis, drug resistant Burkitt'"'"'s lymphoma and drug resistant multiple myeloma in a subject in need of treatment, said method comprising administering a therapeutically effective amount of a histone deactylase inhibitor is a compound of formula (I):
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the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein is a radical selected from R5 is selected from hydrogen;
thienyl;
thienyl substituted with di(C1-6alkyl)aminoC1-6alkyl, or C1-6alkylpiperazinylC1-6alkyl;
furanyl;
phenyl;
phenyl substituted with one substituents independently selected from di(C1-4alkyl)aminoC1-4alkyloxy, di(C1-4alkyl)amino, di(C1-4alkyl)aminoC1-14alkyl, di(C1-4alkyl)aminoC1-4alkyl(C1-4alkyl)aminoC1-4alkyl, pyrrolidinylC1-4alkyl, pyrrolidinylC1-4alkyloxy or C1-4alkylpiperazinylC1-4alkyl.- View Dependent Claims (21)
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Specification