Claims for Patent: 8,906,954
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Summary for Patent: 8,906,954
Title: | Selective inhibitors of histone deacetylase |
Abstract: | Described herein are compounds and pharmaceutical compositions containing such compounds, which inhibit the activity of histone deacetylase 8 (HDAC8). Also described herein are methods of using such HDAC8 inhibitors, alone and in combination with other compounds, for treating diseases or conditions that would benefit from inhibition of HDAC8 activity. |
Inventor(s): | Verner; Erik (Belmont, CA), Balasubramanian; Sriram (San Carlos, CA), Buggy; Joseph J. (Mountain View, CA) |
Assignee: | Pharmacyclics, Inc. (Sunnyvale, CA) |
Application Number: | 13/897,582 |
Patent Claims: | 1. A method of treating T-cell lymphoma or leukemia in a mammal in need thereof, comprising administering to the mammal a pharmaceutical composition comprising: (a) a
therapeutically effective amount of a compound of Formula B: ##STR00121## wherein: R.sup.1 is --C(.dbd.O)NHOH; X.sup.2 is a bond, --C.sub.1-C.sub.6alkylene-, --C.sub.2-C.sub.6alkenylene-, --C.sub.2-C.sub.6alkynylene-, --C.sub.1-C.sub.6heteroalkylene-,
C.sub.1-C.sub.6fluoroalkylene, C.sub.2-C.sub.6fluoroalkenylene, C.sub.1-C.sub.6haloalkylene, C.sub.2-C.sub.6haloalkenylene, --C.sub.1-C.sub.6alkylene-O--, --C.sub.1-C.sub.3alkylene-O--C.sub.1-C.sub.3alkylene-, --C.sub.1-C.sub.6alkylene-NH--,
--C.sub.1-C.sub.3alkylene-NH--C.sub.1-C.sub.3 alkylene-, --C.sub.1-C.sub.6alkylene-C(.dbd.O)NH--, --C.sub.1-C.sub.3alkylene-C(.dbd.O)NH--C.sub.1-C.sub.3alkylene-, --C.sub.1-C.sub.6alkylene-NHC(.dbd.O)--,
--C.sub.1-C.sub.3alkylene-NHC(.dbd.O)--C.sub.1-C.sub.3alkylene-, --C.sub.1-C.sub.6alkylene-S--, --C.sub.1-C.sub.3 alkylene-S--C.sub.1-C.sub.3alkylene-, --C.sub.1-C.sub.6alkylene-S(.dbd.O)--, --C.sub.1-C.sub.3alkylene-S(.dbd.O)--C.sub.1-C.sub.3alkylene,
--C.sub.1-C.sub.6alkylene-S(.dbd.O).sub.2--, --C.sub.1-C.sub.3alkylene-S(.dbd.O).sub.2--C.sub.1-C.sub.3alkylene,-C(.db- d.O)--, or --C(.dbd.O)--C.sub.1-C.sub.6alkylene; R.sup.2 is a substituted or unsubstituted group selected from aryl, heteroaryl,
C.sub.3-C.sub.10cycloalkyl, and C.sub.2-C.sub.10heterocycloalkyl; where if R.sup.2 is substituted, then R.sup.2 is substituted with 1, 2, or 3 groups selected from among halogen, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6fluoroalkoxy,
aminoC.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.3 alkylaminoC.sub.1-C.sub.3alkoxy, hydroxyC.sub.1-C.sub.3alkylaminoC.sub.1-C.sub.3alkoxy, C.sub.2-C.sub.8heterocycloalkylC.sub.1-C.sub.3alkoxy, C.sub.2-C.sub.8heterocycloalkylC.sub.1-C.sub.2alkyl, --CN,
--NO.sub.2, --CO.sub.2R.sup.10, --C(.dbd.O)R.sup.11, --S--R.sup.11, --S(.dbd.O)--R.sup.11, --S(.dbd.O).sub.2--R.sup.11, --NR.sup.10C(.dbd.O)--R.sup.11, --C(.dbd.O)N(R.sup.10).sub.2, --S(.dbd.O).sub.2N(R.sup.10).sub.2,
--NR.sup.10S(.dbd.O).sub.2--R.sup.11, --OC(.dbd.O)N(R.sup.10).sub.2, --NR.sup.10C(.dbd.O)O--R.sup.11, --OC(.dbd.O)O--R.sup.11, --NHC(.dbd.O)NH--R.sup.11, --OC(.dbd.O)--R.sup.11, --N(R10).sub.2, --C.sub.1-C.sub.2alkylN(R.sup.10).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6heteroalkyl, C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.2-C.sub.10heterocycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl; R.sup.10 is hydrogen, or a substituted or unsubstituted group selected from among C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6heteroalkyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.2-C.sub.8heterocycloalkyl, aryl, and heteroaryl; R.sup.11 is a substituted or unsubstituted group selected from among C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl, aryl, and
heteroaryl; each R.sup.3 is independently hydrogen, substituted or unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted C.sub.2-C.sub.6alkenyl, substituted or unsubstituted C.sub.2-C.sub.6alkynyl, substituted or unsubstituted
C.sub.1-C.sub.6alkoxy, substituted or unsubstituted C.sub.1-C.sub.6fluoroalkoxy, substituted or unsubstituted C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted phenyl, or C.sub.1-C.sub.6aminoalkyl; or a pharmaceutically acceptable salt,
pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof; and (b) a pharmaceutically acceptable diluent, excipient, or carrier.
2. The method of claim 1, wherein: each R.sup.3 is independently hydrogen or C.sub.1-C.sub.4alkyl. 3. The method of claim 2, wherein: each R.sup.3 is hydrogen. 4. The method of claim 3, having the structure of Formula IIIb: ##STR00122## 5. The method of claim 4, wherein: X.sup.2 is a bond, --C.sub.1-C.sub.6alkylene-, --C.sub.1-C.sub.6alkylene-O--, --C.sub.1-C.sub.3alkylene-O--C.sub.1-C.sub.3alkylene-, --C.sub.1-C.sub.6alkylene-NH--, --C.sub.1-C.sub.3alkylene-NH--C.sub.1-C.sub.3alkylene-, --C.sub.1-C.sub.6alkylene-C(.dbd.O)NH--, --C.sub.1-C.sub.3alkylene-C(.dbd.O)NH--C.sub.1-C.sub.3alkylene-, --C.sub.1-C.sub.6alkylene-NHC(.dbd.O)--, --C.sub.1-C.sub.3alkylene-NHC(.dbd.O)--C.sub.1-C.sub.3alkylene-, --C.sub.1-C.sub.6alkylene-S--, --C.sub.1-C.sub.3alkylene-S--C.sub.1-C.sub.3alkylene-, --C.sub.1-C.sub.6alkylene-S(.dbd.O)--, --C.sub.1-C.sub.3alkylene-S(.dbd.O)--C.sub.1-C.sub.3alkylene, --C.sub.1-C.sub.6alkylene-S(.dbd.O).sub.2--, --C.sub.1-C.sub.3alkylene-S(.dbd.O).sub.2--C.sub.1-C.sub.3alkylene, --C(.dbd.O)--, or --C(.dbd.O)--C.sub.1-C.sub.6alkylene. 6. The method of claim 5, wherein: R.sup.2 is a substituted or unsubstituted group selected from phenyl, monocyclic heteroaryl, C.sub.3-C.sub.6cycloalkyl, and monocyclic C.sub.2-C.sub.6heterocycloalkyl; where if R.sup.2 is substituted, then R.sup.2 is substituted with 1 or 2 groups selected from among halogen, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4fluoroalkoxy, C.sub.3-C.sub.6heterocycloalkylC.sub.1-C.sub.2alkyl, --CN, --NO.sub.2, --CO.sub.2R.sup.10, --C(.dbd.O)R.sup.11, --S--R.sup.11, --S(.dbd.O)--R.sup.11, --S(.dbd.O).sub.2--R.sup.11, --NHC(.dbd.O)--R.sup.11, --C(.dbd.O)N(R.sup.10).sub.2, --S(.dbd.O).sub.2N(R.sup.10).sub.2, --NHS(.dbd.O).sub.2--R.sup.11, --OC(.dbd.O)N(R.sup.10).sub.2, --NHC(.dbd.O)O--R.sup.11, --OC(.dbd.O)O--R.sup.11, --NHC(.dbd.O)NH--R.sup.11, --OC(.dbd.O)--R.sup.11, --N(R.sup.10).sub.2, --C.sub.1-C.sub.2alkylN(R.sup.10).sub.2, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl, C.sub.1-C.sub.4heteroalkyl, C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted C.sub.2-C.sub.6heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl. 7. The method of claim 6, wherein: X.sup.2 is a bond, --C.sub.1-C.sub.4alkylene-, --C.sub.1-C.sub.4alkylene-O--, --C.sub.1-C.sub.4alkylene-C(.dbd.O)NH--, --C.sub.1-C.sub.4alkylene-NHC(.dbd.O)--, --C.sub.1-C.sub.4alkylene-S --, --C.sub.1-C.sub.4alkylene-S(.dbd.O)--, --C.sub.1-C.sub.4alkylene-S(.dbd.O).sub.2--, --C(.dbd.O)--, or --C(.dbd.O)--C.sub.1-C.sub.4alkylene. 8. The method of claim 7, wherein: X.sup.2 is --C.sub.1-C.sub.4alkylene- or --C.sub.1-C.sub.4alkylene-O--; R.sup.2 is a substituted or unsubstituted group selected from among phenyl and monocyclic heteroaryl. 9. The method of claim 8, wherein: R.sup.2 is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group; where if R.sup.2 is substituted, then R.sup.2 is substituted with 1 or 2 groups selected from among halogen, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4fluoroalkoxy, C.sub.3-C.sub.6heterocycloalkylC.sub.1-C.sub.2alkyl, --CN, --CO.sub.2R.sup.10, --C(.dbd.O)R.sup.11, --NHC(.dbd.O)--R.sup.11, --C(.dbd.O)N(R.sup.10).sub.2, --S(.dbd.O).sub.2N(R.sup.10).sub.2, --NHS(.dbd.O).sub.2--R.sup.11, --N(R.sup.10).sub.2, --C.sub.1-C.sub.2alkylN(R.sup.10).sub.2, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl, and C.sub.1-C.sub.4heteroalkyl. 10. The method of claim 9, wherein: R.sup.2 is a substituted or unsubstituted group selected from phenyl, pyridinyl, pyrimidinyl, triazinyl, pyrrolyl, thiophenyl, and furanyl. 11. The method of claim 10, wherein: R.sup.2 is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group. 12. The method of claim 11, wherein: R.sup.2 is a substituted or unsubstituted phenyl. 13. The method of claim 12, wherein: X.sup.2 is --C.sub.1-C.sub.4alkylene-. 14. The method of claim 13, wherein: X.sup.2 is C.sub.1-C.sub.4alkylene-O--. 15. The method of claim 1, further comprising administering to the mammal a second therapeutic agent, selected from among abarelix; aldesleukin; Alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; asparaginase; azacitidine; bevacizumab; bexarotene; bleomycin; bortezomib; busulfan; busulfan; calusterone; capecitabine; carboplatin; carmustine; celecoxib; cetuximab; chlorambucil; cisplatin; cladribine; clofarabine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; Darbepoetin alfa; dasatinib; daunorubicin liposomal; daunorubicin; daunorubicin; decitabine; denileukin; dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; dromostanolone propionate; epirubicin; Epirubicin; Epoetin alfa; erlotinib; estramustine; etoposide phosphate; etoposide; exemestane; Filgrastim; floxuridine; fludarabine; fluorouracil; fulvestrant; gefitinib; gemcitabine; gemtuzumab ozogamicin; goserelin acetate; histrelin acetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinib mesylate; interferon alfa 2a; Interferon alfa-2b; irinotecan; lenalidomide; letrozole; leucovorin; Leuprolide Acetate; levamisole; lomustine; meclorethamine, nitrogen mustard; megestrol acetate; melphalan; mercaptopurine; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nelarabine; Nofetumomab; Oprelvekin; oxaliplatin; paclitaxel; paclitaxel protein-bound particles; palifermin; pamidronate; panitumumab; pegademase; pegaspargase; Pegfilgrastim; pemetrexed disodium; pentostatin; pipobroman; plicamycin, mithramycin; porfimer sodium; procarbazine; quinacrine; Rasburicase; rituximab; sargramostim; Sargramostim; sorafenib; streptozocin; sunitinib maleate; tamoxifen; temozolomide; teniposide; testolactone; thalidomide; thioguanine; thiotepa; topotecan; toremifene; tositumomab; tositumomab/I-131 tositumomab; trastuzumab; tretinoin; Uracil Mustard; valrubicin; vinblastine; vincristine; vinorelbine; vorinostat; zoledronate; and zoledronic acid. |
Details for Patent 8,906,954
Applicant | Tradename | Biologic Ingredient | Dosage Form | BLA | Approval Date | Patent No. | Expiredate |
---|---|---|---|---|---|---|---|
Recordati Rare Diseases, Inc. | ELSPAR | asparaginase | For Injection | 101063 | 01/10/1978 | ⤷ Try a Trial | 2028-04-15 |
Merck Sharp & Dohme Corp. | INTRON A | interferon alfa-2b | For Injection | 103132 | 06/04/1986 | ⤷ Try a Trial | 2028-04-15 |
Merck Sharp & Dohme Corp. | INTRON A | interferon alfa-2b | For Injection | 103132 | ⤷ Try a Trial | 2028-04-15 | |
Merck Sharp & Dohme Corp. | INTRON A | interferon alfa-2b | Injection | 103132 | ⤷ Try a Trial | 2028-04-15 | |
Amgen, Inc. | EPOGEN/PROCRIT | epoetin alfa | Injection | 103234 | 06/01/1989 | ⤷ Try a Trial | 2028-04-15 |
Amgen, Inc. | EPOGEN/PROCRIT | epoetin alfa | Injection | 103234 | ⤷ Try a Trial | 2028-04-15 | |
>Applicant | >Tradename | >Biologic Ingredient | >Dosage Form | >BLA | >Approval Date | >Patent No. | >Expiredate |
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