Claims for Patent: 8,900,565

Summary for Patent: 8,900,565

Title:	Indole derivatives as 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):	Buggy; Joseph J. (Moutain View, CA), Balasubramanian; Sriram (San Carlos, CA), Verner; Erik (San Mateo, CA), Tai; Vincent W. F. (San Mateo, CA), Lee; Chang-Sun (Belle Mead, NJ)
Assignee:	Pharmacyclics, Inc. (Sunnyvale, CA)
Application Number:	13/683,880
Patent Claims:	1. A method of alleviating, abating or ameliorating T-cell lymphoma or leukemia in a subject in need thereof, comprising administering to the subject a pharmaceutical composition containing a therapeutically effective amount of a 1,3-disubstituted-1H-indole-6-carboxylic acid hydroxyamide compound, wherein the substituent at the 1-position is --X.sup.2--R.sup.2 and the substituent at the 3-position is R.sup.3, wherein: X.sup.2 is a substituted or unsubstituted group selected from among C.sub.2-C.sub.6alkylene, C.sub.1-C.sub.6heteroalkylene; --C(.dbd.O)--, and --C(.dbd.O)--C.sub.1-C.sub.6alkylene; R.sup.2 is a substituted or unsubstituted group selected from among aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; where if R.sup.2 is substituted, then each substituent on R.sup.2 is selected from among hydrogen, halogen, --CN, --NO.sub.2, --S(.dbd.O).sub.2NH.sub.2, --CO.sub.2H, --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, 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(R.sup.10).sub.2, 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.6heteroalkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or 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.6heteroalkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl, aryl, or heteroaryl; R.sup.11 is a substituted or unsubstituted group selected from among C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl, aryl, or heteroaryl; R.sup.3 is hydrogen, halogen, 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.6heteroalkyl, substituted or unsubstituted phenyl, or --X.sup.6--R.sup.6; X.sup.6 is a C.sub.1-C.sub.6alkylene, C.sub.1-C.sub.6fluoroalkylene, C.sub.2-C.sub.6alkenylene, C.sub.2-C.sub.6heteroalkylene; R.sup.6 is hydrogen, halogen, --CN, hydroxy, amino, C.sub.1-C.sub.6alkylamino, di(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl, phenyl, heteroaryl, or --X.sup.7--R.sup.7 X.sup.7 is a bond, --O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, --NR.sup.a--, --C(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--, --NHC(.dbd.O)--, --C(.dbd.O)NR.sup.a--, --S(.dbd.O).sub.2NR.sup.a--, --NHS(.dbd.O).sub.2--, --OC(.dbd.O)NR.sup.a--, --NHC(.dbd.O)O--, --OC(.dbd.O)O--, or --NHC(.dbd.O)NR.sup.a--; R.sup.7 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.1-C.sub.6heteroalkyl, C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.8cycloalkyl, cycloalkylalkyl, C.sub.2-C.sub.8heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, R.sup.a is selected from among hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, hydroxy, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6fluoroalkoxy, C.sub.1-C.sub.6heteroalkyl; or R.sup.a and R.sup.7 together with the N atom to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl; or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, or pharmaceutically acceptable prodrug thereof. 2. The method of claim 1, further comprising administering to the subject a second therapeutic agent, selected from among abarelix (Plenaxis.RTM.); aldesleukin (Prokine.RTM.); Aldesleukin (Proleukin.RTM.); Alemtuzumab (Campath.RTM.); alitretinoin (Panretin.RTM.); allopurinol (Zyloprim.RTM.); altretamine (Hexalen.RTM.); amifostine (Ethyol.RTM.); anastrozole (Arimidex.RTM.); arsenic trioxide (Trisenox.RTM.); asparaginase (Elspar.RTM.); azacitidine (Vidaza.RTM.); bevacizumab (Avastin.RTM.); bexarotene (Targretin.RTM.); bleomycin (Blenoxane.RTM.); bortezomib (Velcade.RTM.); busulfan (Busulfex.RTM.); busulfan (Myleran.RTM.); calusterone (Methosarb.RTM.); capecitabine (Xeloda.RTM.); carboplatin Paraplatin.RTM.); carmustine (BCNU, BiCNU); carmustine (Gliadel.RTM.); celecoxib (Celebrex.RTM.); cetuximab (Erbitux.RTM.); chlorambucil (Leukeran.RTM.); cisplatin (Platinol.RTM.); cladribine (Leustatin.RTM.); clofarabine (Clolar.RTM.); cyclophosphamide (Cytoxan.RTM.); cytarabine (Cytosar-U.RTM.); cytarabine liposomal (DepoCyt); dacarbazine (DTIC-Dome); dactinomycin (actinomycin D, Cosmegen.RTM.); Darbepoetin alfa (Aranesp.RTM.); dasatinib (Sprycel.RTM.); daunorubicin liposomal (DanuoXome); daunorubicin (daunomycin, Daunorubicin.RTM.); daunorubicin (daunomycin, Cerubidine.RTM.); decitabine (Dacogen.RTM.); denileukin (Ontak.RTM.); dexrazoxane (Zinecard.RTM.); docetaxel (Taxotere.RTM.); doxorubicin (Adriamycin.RTM.); doxorubicin liposomnal (Doxil.RTM.); dromostanolone propionate; epirubicin (Ellence.RTM.); Epirubicin; Epoetin alfa (EPOGEN.RTM.); erlotinib (Tarceva.RTM.); estramustine (Emcyt.RTM.); etoposide phosphate (Etopophos.RTM.); etoposide (VP-16; Vepesid.RTM.); exemestane (AROMASIN.RTM.); Filgrastim (Neupogen.RTM.); floxuridine (FUDR); fludarabine (Fludara.RTM.); fluorouracil (5-FU, Adrucil.RTM.); fulvestrant (Faslodex.RTM.), gefitinib (Iressa.TM.); gemcitabine (Gemzar.RTM.); gemtuzumab ozogamicin (Mylotarg.RTM.); goserelin acetate (Zoladex.RTM.); histrelin acetate (Histrelin.RTM.); hydroxyurea (Hydrea.RTM.); Ibritumomab Tiuxetan (Zevalin.RTM.); idarubicin (Idamycin.RTM.); ifosfamide (IFEX.RTM.); imatinib mesylate (Gleevec.RTM.); interferon alfa 2a (Roferon A.RTM.); Interferon alfa-2b (Intron A.RTM.); irinotecan (Camptosar.RTM.); lenalidomide (Revlimid.RTM.); letrozole (Femara.RTM.); leucovorin (Leucovorin.RTM.); Leuprolide Acetate (Eligard.RTM.); levamisole (Ergamisol.RTM.); lomustine, CCNU CeeBU.RTM.); meclorethamine (nitrogen mustard, Mustargen.RTM.); megestrol acetate (Megace.RTM.); melphalan (Alkeran.RTM.); mercaptopurine (6-MP, Purinethol.RTM.); methotrexate (Rheumatrex.RTM., Trexall.RTM.); methoxsalen (Uvadex.RTM.); mitomycin C (Mutamycin.RTM.); mitomycin C (Mitozytrex.RTM.); mitotane (Lysodren.RTM.); mitoxantrone (Novantrone.RTM.); nandrolone phenpropionate (Durabolin-50); nelarabine (Arranon.RTM.); Nofetumomab (Verluma.RTM.); Oprelvekin (Neumega.RTM.); oxaliplatin (Eloxatin.RTM.); paclitaxel (Paxene.RTM.); paclitaxel (Taxol.RTM.); paclitaxel protein-bound particles (Abraxane.RTM.); palifermin (Kepivance.RTM.); pamidronate (Aredia.RTM.); panitumumab (Vectibix.RTM.); pegademase (Adagen.RTM.); pegaspargase (Oncaspar.RTM.); Pegfilgrastim (Neulasta.RTM.); pemetrexed disodium (Alimta.RTM.); pentostatin (Nipent.RTM.); pipobroman (Vercyte.RTM.); plicamycin, mithramycin (Mithracin.RTM.); porfimer sodium (Photofrin.RTM.); procarbazine (Matulane.RTM.); quinacrine (Atabrine.RTM.); Rasburicase (Elitek.RTM.); rituximab (Rituxan.RTM.); sargramostim (Leukine.RTM.); Sargramostim (Prokine.RTM.); sorafenib (Nexavar.RTM.); streptozocin (Zanosar.RTM.); sunitinib maleate (Sutent.RTM.); tamoxifen (Nolvadex.RTM.); temozolomide (Terodar.TM.); teniposide (VM-26, Vumon.RTM.); testolactone (Teslac.RTM.); thalidomide (Thalomid.RTM.); thioguanine (6-TG, Thioguanine.RTM.); thiotepa (Thioplex.RTM.); topotecan (Hycamtin.RTM.); toremifene (Fareston.RTM.); tositumomab (Bexxar.RTM.); tositumomab/I-131 tositumomab (Bexxar.RTM.); trastuzumab (Herceptin.RTM.); tretinoin (ATRA, Vesanoid.RTM.); Uracil Mustard; valrubicin (Valstar.RTM.); vinblastine (Velban.RTM.); vincristine (Oncovin.RTM.): vinorelbine (Navelbine.RTM.); vorinostat (Zolinza.RTM.); zoledronate (Zometa.RTM.); or zoledronic acid (Zometa.RTM.).

Details for Patent 8,900,565

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2026-03-16
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2026-03-16
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2026-03-16