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Claims for Patent: 10,626,100


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Summary for Patent: 10,626,100
Title:Selective HDAC6 inhibitors
Abstract: The present invention provides a compound having the structure: ##STR00001## wherein R.sub.1 is halogen, --NR.sub.5R.sub.6, --NR.sub.5--C(.dbd.O)--R.sub.6, --NH--C(.dbd.O)--OR.sub.7, --OR.sub.7, --NO.sub.2, --CN, --SR.sub.7, --SO.sub.2R.sub.7, --CO.sub.2R.sub.7, CF.sub.3, --SOR.sub.7, --POR.sub.7, --C(.dbd.S)R.sub.7, --C(.dbd.O)--NR.sub.5R.sub.6, --CH.sub.2--C(.dbd.O)--NR.sub.5R.sub.6, --C(.dbd.NR.sub.5)R.sub.6, --P(.dbd.O)(OR.sub.5)(OR.sub.6), --P(OR.sub.5)(OR.sub.6), --C(.dbd.S)R.sub.7, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, aryl, heteroaryl, or heterocyclyl, wherein R.sub.5, R.sub.6, and R.sub.7 and are each, independently, H, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-5 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl; Ar.sub.1 is phenyl or thiophene; wherein when Ar.sub.1 is phenyl, then R.sub.1 is other than --C(.dbd.O)--NR.sub.5R.sub.6, where one of R.sub.5 or R.sub.6 is phenyl or quinoline and the other of R.sub.5 or R.sub.6 is hydroxyalkyl, or where one of R.sub.5 or R.sub.6 is quinoline and the other of R.sub.5 or R.sub.6 is H; and wherein when Ar.sub.1 is phenyl, then R.sub.1 is other than --NR.sub.5--C(.dbd.O)--R.sub.6, where one of R.sub.5 is H and R.sub.6 is quinoline, or a pharmaceutically acceptable salt thereof.
Inventor(s): Breslow; Ronald (New York, NY), Marks; Paul (Washington, CT), Mahendran; Adaickapillai (Brooklyn, NY), Yao; Yuanshan (Shanghai, CN)
Assignee: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK (New York, NY) MEMORIAL SLOAN-KETTERING CANCER CENTER (New York, NY)
Application Number:15/850,123
Patent Litigation and PTAB cases: See patent lawsuits and PTAB cases for patent 10,626,100
Patent Claims:1. A compound having the structure: ##STR00030## wherein R.sub.1 is --NR.sub.5--C(.dbd.O)--R.sub.6, --CO.sub.2R.sub.7, or --C(.dbd.O)--NR.sub.5R.sub.6, wherein R.sub.5 and R.sub.6 are each, independently, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-5 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl, and R.sub.7 is H, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-5 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl; Ar.sub.1 is phenyl or thiophene; wherein when Ar.sub.1 is phenyl, then R.sub.1 is other than --C(.dbd.O)--NR.sub.5R.sub.6, where one of R.sub.5 or R.sub.6 is phenyl or quinoline and the other of R.sub.5 or R.sub.6 is --CH.sub.2CH.sub.2OH, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein Ar.sub.1 is ##STR00031##

3. The compound of claim 1, wherein R.sub.1 is --C(.dbd.O)--NR.sub.5R.sub.6 or --NR.sub.5--C(.dbd.O)--R.sub.6, wherein R.sub.5 and R.sub.6 are each, independently, hydroxyalkyl, aryl, heteroaryl, C.sub.1-5 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl.

4. The compound of claim 1, wherein R.sub.1 is --C(.dbd.O)--NR.sub.5R.sub.6, --NR.sub.5--C(.dbd.O)--R.sub.6, or --CO.sub.2R.sub.7, wherein R.sub.5 is hydroxyalkyl, aryl or heteroaryl; R.sub.6 is hydroxyalkyl, aryl or heteroaryl; and R.sub.7 is hydroxyalkyl, aryl, heteroaryl, or C.sub.1-5 alkyl-NH-- aryl.

5. The compound of claim 1, wherein R.sub.1 is --C(.dbd.O)--NR.sub.5R.sub.6, --NR.sub.5--C(.dbd.O)--R, or --CO.sub.2R.sub.7, wherein R.sub.5, R.sub.6, and R.sub.7 are each, independently, phenyl, --CH.sub.2CH.sub.2OH, --CH.sub.2-phenyl, or --CH.sub.2CH.sub.2N(H)-phenyl.

6. The compound of claim 5, wherein R.sub.1 is --C(.dbd.O)--NR.sub.5R.sub.6, --NR.sub.5--C(.dbd.O)--R.sub.6, or --CO.sub.2R.sub.7, wherein R.sub.5, R.sub.6, and R.sub.7 and are each, independently, ##STR00032## or R.sub.1 is --C(.dbd.O)--NR.sub.5R.sub.6, wherein R.sub.5 is ##STR00033## or R.sub.1 is --NR.sub.5--C(.dbd.O)--R.sub.6, wherein R.sub.5 is ##STR00034## or R.sub.1 is --CO.sub.2R.sub.7, wherein R.sub.7 ##STR00035##

7. The compound of claim 1 having the structure: ##STR00036## wherein R.sub.1 is --NR.sub.5--C(.dbd.O)--R.sub.6 or --C(.dbd.O)--NR.sub.5R.sub.6, wherein R.sub.5 and R.sub.6 are each, independently, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-5 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl; wherein R.sub.1 is other than --C(.dbd.O)--NR.sub.5R.sub.6, where one of R.sub.5 or R.sub.6 is phenyl or quinoline and the other of R.sub.5 or R.sub.6 is --CH.sub.2CH.sub.2OH, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 having the structure: ##STR00037## wherein R.sub.1 is --NR.sub.5--C(.dbd.O)--R.sub.6 or --C(.dbd.O)--NR.sub.5R.sub.6, wherein R.sub.5 and R.sub.6 are each, independently, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-5 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, wherein R.sub.1 is --C(.dbd.O)--NR.sub.5R.sub.6, --NR.sub.5--C(.dbd.O)--R.sub.6, or --CO.sub.2R.sub.7, wherein R.sub.5 is hydroxyalkyl, aryl, C.sub.1-5 alkyl-aryl or heteroaryl; R.sub.6 is hydroxyalkyl, aryl, C.sub.1-5 alkyl-aryl or heteroaryl; and R.sub.7 is hydroxyalkyl, aryl, C.sub.1-5 alkyl-aryl, heteroaryl, or C.sub.1-5 alkyl-NH-aryl; and Ar.sub.1 is phenyl or thiophene, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 having the structure: ##STR00038## or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

12. A method of inhibiting the activity of a histone deactylase in a cell comprising contacting the histone deacetylase with the compound of claim 1 so as to inhibit the activity of the histone deacetylase.

13. The method of claim 12, wherein the histone deacetylase is HDAC6.

14. A method of treating cancer in a subject afflicted therewith comprising administering an effective amount of the compound of claim 1 to the subject so as to treat the cancer in the subject.

15. A method of treating a subject afflicted with cancer comprising periodically administering to the subject a) an amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and b) an anti-cancer agent, wherein the amounts when taken together are more effective to treat the subject than when each agent at the same amount is administered alone.

16. The method of claim 15, wherein the anti-cancer agent is selected from x-radiation, ionizing radiation, a DNA damaging agent, a DNA intercalating agent, a microtubule stabilizing agent, a microtubule destabilizing agent, a spindle toxin, abarelix, aldesleukin, alemtuzumab, alitertinoin, allopurinol, altretamine, amifostin, anakinra, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, actinomycin D, dalteparin sodium, darbepoetin alfa, dasatinib, daunorubicin, daunomycin, decitabine, denileukin, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, exulizumab, epirubicin, epoetin alfa, erlotinib, estramustine, etoposide phosphate, etoposide, VP-16, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gosereline acetate, histrelin acetate, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, interferon alfa 2b, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovrin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, panitumumab, pegademase, pegaspargase, pegfilgrastim, peginterferon alfa 2b, pemetrexed disodium, pentostatin, pipobroman, plicamycin, mithramycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, SAHA, sargrmostim, sorafenib, streptozocin, sunitinib, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thalidomide, thioguanine, G-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin ATRA, uracil mustard, valrunicin, vinblastine, vincristine, vinorelbine, vorinostat, zoledronate, zoledronic acid, abraxane or brentuximab vedotin.

17. The compound of claim 1, wherein R.sub.5 and R.sub.6 are each, independently, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heteroalkyl, C.sub.1-5 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-5 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl, or wherein R.sub.5 and R.sub.6 are each, independently, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl; or a pharmaceutically acceptable salt thereof.

18. A compound having the structure: ##STR00039## wherein R.sub.1 is --NR.sub.5--C(.dbd.O)--R.sub.6 or --C(.dbd.O)--NR.sub.5R.sub.6, wherein R.sub.5 and R.sub.6 are each, independently, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-5 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl, Ar.sub.1 is thiophene; or a pharmaceutically acceptable salt thereof.

19. A compound having the structure: ##STR00040## wherein R.sub.1 is --NR.sub.5--C(.dbd.O)--R.sub.6, --CO.sub.2R.sub.7, or --C(.dbd.O)--NR.sub.5R.sub.6, wherein R.sub.5 and R.sub.6 are each, independently, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-5 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl, and R.sub.7 is H, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-5 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl; Ar.sub.1 is thiophene; or a pharmaceutically acceptable salt thereof.

20. The compound of claim 19 having the structure: ##STR00041## wherein R.sub.1 is --NR.sub.5--C(.dbd.O)--R.sub.6 or --C(.dbd.O)--NR.sub.5R.sub.6, wherein R.sub.5 and R.sub.6 are each, independently, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-5 alkyl-aryl, or C.sub.1-5 alkyl-NH-aryl, or a pharmaceutically acceptable salt thereof.

Details for Patent 10,626,100

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Recordati Rare Diseases, Inc. ELSPAR asparaginase For Injection 101063 January 10, 1978 10,626,100 2033-12-23
Merck Sharp & Dohme Llc INTRON A interferon alfa-2b For Injection 103132 June 04, 1986 10,626,100 2033-12-23
Merck Sharp & Dohme Llc INTRON A interferon alfa-2b For Injection 103132 10,626,100 2033-12-23
Merck Sharp & Dohme Llc INTRON A interferon alfa-2b Injection 103132 10,626,100 2033-12-23
Hoffmann-la Roche Inc. ROFERON-A interferon alfa-2a For Injection 103145 June 04, 1986 10,626,100 2033-12-23
Amgen Inc. EPOGEN/PROCRIT epoetin alfa Injection 103234 June 01, 1989 10,626,100 2033-12-23
Amgen Inc. EPOGEN/PROCRIT epoetin alfa Injection 103234 10,626,100 2033-12-23
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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