Claims for Patent: 10,626,100

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 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