Selective HDAC6 inhibitors

Patent metadata

Field	Value
Publication number	US-10626100-B2
Application number	US-201715850123-A
Country	US
Kind code	B2
Filing date	Dec 21, 2017
Priority date	Dec 23, 2013
Publication date	Apr 21, 2020
Grant date	Apr 21, 2020

Abstract

The present invention provides a compound having the structure:

wherein
R 1 is halogen, —NR 5 R 6 , —NR 5 —C(═O)—R 6 , —NH—C(═O)—OR 7 , —OR 7 , —NO 2 , —CN, —SR 7 , —SO 2 R 7 , —CO 2 R 7 , CF 3 , —SOR 7 , —POR 7 , —C(═S)R 7 , —C(═O)—NR 5 R 6 , —CH 2 —C(═O)—NR 5 R 6 , —C(═NR 5 )R 6 , —P(═O)(OR 5 )(OR 6 ), —P(OR 5 )(OR 6 ), —C(═S)R 7 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, aryl, heteroaryl, or heterocyclyl,
wherein R 5 , R 6 , and R 7 and are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-5 alkyl-aryl, or C 1-5 alkyl-NH-aryl;

Ar 1 is phenyl or thiophene;
wherein when Ar 1 is phenyl, then R 1 is other than —C(═O)—NR 5 R 6 , where one of R 5 or R 6 is phenyl or quinoline and the other of R 5 or R 6 is hydroxyalkyl, or where one of R 5 or R 6 is quinoline and the other of R 5 or R 6 is H; and
wherein when Ar 1 is phenyl, then R 1 is other than —NR 5 —C(═O)—R 6 , where one of R 5 is H and R 6 is quinoline,

or a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

1. A compound having the structure:

wherein
R 1 is —NR 5 —C(═O)—R 6 , —CO 2 R 7 , or —C(═O)—NR 5 R 6 ,
wherein R 5 and R 6 are each, independently, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-5 alkyl-aryl, or C 1-5 alkyl-NH-aryl, and
R 7 is H, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-5 alkyl-aryl, or C 1-5 alkyl-NH-aryl;

Ar 1 is phenyl or thiophene;
wherein when Ar 1 is phenyl, then R 1 is other than —C(═O)—NR 5 R 6 , where one of R 5 or R 6 is phenyl or quinoline and the other of R 5 or R 6 is —CH 2 CH 2 OH,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 ,
wherein
Ar 1 is

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

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

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

6. The compound of claim 5 ,
wherein
R 1 is —C(═O)—NR 5 R 6 , —NR 5 —C(═O)—R 6 , or —CO 2 R 7 ,
wherein R 5 , R 6 , and R 7 and are each, independently,

 or

R 1 is —C(═O)—NR 5 R 6 ,
wherein R 5 is

 or

R 1 is —NR 5 —C(═O)—R 6 ,
wherein R 5 is

 or

R 1 is —CO 2 R 7 ,
wherein R 7

7. The compound of claim 1 having the structure:

wherein
R 1 is —NR 5 —C(═O)—R 6 or —C(═O)—NR 5 R 6 ,
wherein R 5 and R 6 are each, independently, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-5 alkyl-aryl, or C 1-5 alkyl-NH-aryl;

wherein R 1 is other than —C(═O)—NR 5 R 6 , where one of R 5 or R 6 is phenyl or quinoline and the other of R 5 or R 6 is —CH 2 CH 2 OH,

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 having the structure:

wherein
R 1 is —NR 5 —C(═O)—R 6 or —C(═O)—NR 5 R 6 ,
wherein R 5 and R 6 are each, independently, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-5 alkyl-aryl, or C 1-5 alkyl-NH-aryl,

or a pharmaceutically acceptable salt thereof.

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

Ar 1 is phenyl or thiophene,

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 having the structure:

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 5 and R 6 are each, independently, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, C 1-5 hydroxyalkyl, cycloalkyl, heterocycloalkyl, a

Assignees

• Univ Columbia
• Memorial Sloan Kettering Cancer Center

Inventors

• Breslow Ronald
• Marks Paul
• Mahendran Adaickapillai
• Yao Yuanshan

Classifications

• A61K31/216

  of acids having aromatic rings, e.g. benactizyne, clofibrate · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61K31/381

  having five-membered rings · CPC title

• C07C237/42

  having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated · CPC title

• C07C233/69

  of an acyclic saturated carbon skeleton · CPC title