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Last Updated: March 28, 2024

Claims for Patent: 9,890,136


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Summary for Patent: 9,890,136
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 MEMORIAL SLOAN-KETTERING CANCER CENTER (New York, NY)
Application Number:15/107,272
Patent Claims:1. A compound 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, hydroxyalkyl, aryl, heteroaryl or C.sub.1-5 alkyl-aryl; Ar.sub.1 is phenyl; 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 ##STR00038##

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 is C.sub.1-5 alkyl-aryl or hydroxyalkyl; and R.sub.6 is C.sub.1-5 alkyl-aryl or hydroxyalkyl.

4. 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, phenyl, --CH.sub.2CH.sub.2OH or --CH.sub.2-phenyl.

5. The compound of claim 4, 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, ##STR00039## or R.sub.1 is --C(.dbd.O)--NR.sub.5R.sub.6, wherein R.sub.5 is ##STR00040## and R.sub.6 is ##STR00041## or R.sub.1 is --NR.sub.5--C(.dbd.O)--R.sub.6, wherein R.sub.5 is ##STR00042## and R.sub.6 is ##STR00043##

6. The compound of claim 1 having the structure: ##STR00044## 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, aryl, heteroaryl or C.sub.1-5 alkyl-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.

7. 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 is hydroxyalkyl or aryl; R.sub.6 is hydroxyalkyl or aryl, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 having the structure: ##STR00045## or a pharmaceutically acceptable salt thereof.

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

10. 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.

11. The method of claim 10, wherein the histone deacetylase is HDAC6.

12. 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.

13. 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.

14. The method of claim 13, 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, protein-bound paclitaxel or brentuximab vedotin.

15. The compound of claim 1 having the structure: ##STR00046## 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, hydroxyalkyl or C.sub.1-5 alkyl-aryl; Ar.sub.1 is phenyl; or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 having the structure: ##STR00047## wherein R.sub.1 is --NR.sub.5--C(.dbd.O)--R.sub.6, wherein R.sub.5 and R.sub.6 are each, independently, hydroxyalkyl or C.sub.1-5 alkyl-aryl; Ar.sub.1 is phenyl; or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 having the structure: ##STR00048## wherein R.sub.1 is --NR.sub.5--C(.dbd.O)--R.sub.6, wherein R.sub.5 and R.sub.6 are each, independently, hydroxyalkyl or aryl; Ar.sub.1 is phenyl; or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 having the structure: ##STR00049## or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the compound of claim 18 and a pharmaceutically acceptable carrier.

20. A method of treating cancer in a subject afflicted therewith comprising administering an effective amount of the compound of claim 18 to the subject so as to treat the cancer in the subject.

21. A method of treating a subject afflicted with cancer comprising periodically administering to the subject a) an amount of the compound of claim 18 or a pharmaceutically acceptable salt thereof, and b) an anti-cancer agent.

22. The method of claim 21, 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, protein-bound paclitaxel or brentuximab vedotin.

Details for Patent 9,890,136

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 2033-12-23
Amgen, Inc. EPOGEN/PROCRIT epoetin alfa Injection 103234 06/01/1989 ⤷  Try a Trial 2033-12-23
Amgen, Inc. EPOGEN/PROCRIT epoetin alfa Injection 103234 ⤷  Try a Trial 2033-12-23
Amgen, Inc. PROCRIT epoetin alfa Injection 103234 ⤷  Try a Trial 2033-12-23
Clinigen, Inc. PROLEUKIN aldesleukin For Injection 103293 05/05/1992 ⤷  Try a Trial 2033-12-23
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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