Methods, agents, and compositions for the treatment of acute myeloid leukemia

Patent metadata

Field	Value
Publication number	US-11311513-B2
Application number	US-201816608083-A
Country	US
Kind code	B2
Filing date	Apr 26, 2018
Priority date	Apr 26, 2017
Publication date	Apr 26, 2022
Grant date	Apr 26, 2022

Abstract

A method of treating a subject suffering from a condition characterized by over-expression of Ten-eleven translocation 1 (TET1) is provided, the method including administering to the subject an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the Formula I:

wherein: R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of H, hydroxyl, alkyl, alkoxy, amine, halo, and trifluoromethyl, and wherein any two adjacent moieties of R 1 , R 2 , R 3 , R 4 , and R 5 may come together to form a heterocyclic ring; R 6 is H or hydroxyl; and R 7 is selected from H,

wherein R 8 is C or O. Also provided are methods for selectively suppressing transcription of TET1 and/or reducing a level of 5-hydroxymethylcytosine in a subject by administering an effective amount of a Formula I compound and pharmaceutical compositions comprising Formula I compounds.

First claim

The invention claimed is:

1. A pharmaceutical composition effective for the treatment of acute myeloid leukemia (AML) comprising:
(a) an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:

wherein:
R 1 and R 5 are H;
R 2 , R 3 , and R 4 are each independently selected from the group consisting of hydroxyl, alkyl, alkoxy, amine, halo, and trifluoromethyl, and wherein any two adjacent moieties of R 2 , R 3 , and R 4 may come together to form a heterocyclic ring;
R 6 is H or hydroxyl; and
R 7 is selected from H,

wherein R 8 is CH 2 or O;
(b) daunorubicin; and
(c) at least one pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1 , wherein any two adjacent moieties of R 2 , R 3 , and R 4 come together to form a heterocyclic ring selected from the group consisting of azole, dioxole, and dioxolane.

3. The pharmaceutical composition of claim 1 , wherein alkyl comprises straight or branched chain C 1 -C 12 alkyl and wherein alkoxy comprises straight or branched chain C 1 -C 12 alkoxy.

4. The pharmaceutical composition of claim 1 , wherein R 2 and R 4 are methoxy or tert-butyl and R 3 is methoxy or hydroxyl.

5. The pharmaceutical composition of claim 1 , wherein the compound is selected from the group consisting of:
6-[4-Morpholinyl(3,4,5-trimethoxyphenyl)methyl]-1,3-benzodioxol-5-ol;
6-{[4-Hydroxy-3,5-bis(2-methyl-2-propanyl)phenyl](4-morpholinyl)methyl}-1,3-benzodioxol-5-ol;
6-(1-Pyrrolidinyl(3,4,5-trimethoxyphenyl)methyl)-1,3-benzodioxol-5-ol.

6. The pharmaceutical composition of claim 1 , wherein the compound is selected from the group consisting of:
6-{[4-Hydroxy-3,5-bis(2-methyl-2-propanyl)phenyl](4-morpholinyl)methyl}-1,3-benzodioxol-5-ol; and
6-(1-Pyrrolidinyl(3,4,5-trimethoxyphenyl)methyl)-1,3-benzodioxol-5-ol.

7. The pharmaceutical composition of claim 1 , further comprising a third anti-cancer agent selected from the group consisting of cytarabine, cladribine, fludarabine, topotecan, doxorubicin, epirubicin, idarubicin, decitabine, azacitidine, all-trans-retinoic acid, arsenic trioxide, gemtuzumab ozogamicin, midostaurin, nelarabine, clofarabine, dasatinib, imatinib, ponatinib, JQ1, methotrexate, corticosteroids, histamine dihydrochloride, interleukin 2, and combinations thereof.

8. A pharmaceutical composition effective for the treatment of acute myeloid leukemia (AML) comprising:
(a) an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:

(b) daunorubicin; and
(c) at least one pharmaceutically acceptable carrier.

9. A method for selectively suppressing transcription of TET1 and/or reducing a level of 5-hydroxymethylcytosine in a subject, the method comprising administering to the subject an effective amount of the composition of claim 1 .

10. The method of claim 9 , wherein the compound is selected from the group consisting of:
6-[4-Morpholinyl(3,4,5-trimethoxyphenyl)methyl]-1,3-benzodioxol-5-ol;
6-{[4-Hydroxy-3,5-bis(2-methyl-2-propanyl)phenyl](4-morpholinyl)methyl}-1,3-benzodioxol-5-ol;
and
6-(1-Pyrrolidinyl(3,4,5-trimethoxyphenyl)methyl)-1,3-benzodioxol-5-ol.

11. The method of claim 9 , wherein the compound is selected from the group consisting of:
6-{[4-Hydroxy-3,5-bis(2-methyl-2-propanyl)phenyl](4-morpholinyl)methyl}-1,3-benzodioxol-5-ol; and
6-(1-Pyrrolidinyl(3,4,5-trimethoxyphenyl)methyl)-1,3-benzodioxol-5-ol.

12. A method of treating a subject suffering from a condition characterized by over-expression of Ten-eleven translocation 1 (TET1), the method comprising administering to the subject an effective amount of the composition of claim 1 .

13. The method of claim 12 , wherein the condition characterized by over-expression of TET1 comprises a hematopoietic malignancy.

14. The method of claim 13 , wherein the hematopoietic malignancy is acute myeloid leukemia (AML).

15. The method of claim 14 , wherein the condition comprises TET1-high AML.

16. The method of claim 12 , wherein the compound is selected from the group consisting of:
6-[4-Morpholinyl(3,4,5-trimethoxyphenyl)methyl]-1,3-benzodioxol-5-ol;
6-{[4-Hydroxy-3,5-bis(2-methyl-2-propanyl)phenyl](4-morpholinyl)methyl}-1,3-benzodioxol-5-ol;
6-(1-Pyrrolidinyl(3,4,5-trimethoxyphenyl)methyl)-1,3-benzodioxol-5-ol.

17. The method of claim 12 , wherein the compound is selected from the group consisting of:
6-{[4-Hydroxy-3,5-bis(2-methyl-2-propanyl)phenyl](4-morpholinyl)methyl}-1,3-benzodioxol-5-ol; and
6-(1-Pyrrolidinyl(3,4,5-trimethoxyphenyl)methyl)-1,3-benzodioxol-5-ol.

18. The method of claim 12 , further comprising administering to the subject a third anti-cancer agent.

19. The method of claim 18 , wherein the third anti-cancer agent is selected from the group consisting of cytarabine, cladribine, fludarabine, topotecan, doxorubicin, epirubicin, idarubicin, decitabine, azacitidine, all-trans-retinoic acid, arsenic trioxide, gemtuzumab ozogamicin, midostaurin, nelarabine, clofarabine, dasatinib, imatinib, ponatinib, JQ1, methotrexate, corticosteroids, histamine dihydrochloride, interleukin 2, and combinations thereof.

20. The method of claim 18 wherein the third anti-cancer agent is co-administered with the compound according to Formula I.

Assignees

• Univ Cincinnati

Inventors

• Chen Jianjun
• Jiang Xi

Classifications

• A61K31/4025 Primary

  not condensed and containing further heterocyclic rings, e.g. cromakalim · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title