Combination therapies

Patent metadata

Field	Value
Publication number	US-2023233519-A1
Application number	US-202118001341-A
Country	US
Kind code	A1
Filing date	Jun 10, 2021
Priority date	Jun 11, 2020
Publication date	Jul 27, 2023
Grant date	—

Abstract

Provided herein are compositions, methods, and kits for treating cancer comprising a mitochondrial inhibitor and a Bcl-2 inhibitor.

First claim

What is claimed is:

1 . A method of treating cancer, comprising administering to a subject in need thereof an effective amount of:
(i) a Bcl-2 family inhibitor; and (ii) a compound of formula (II) or a pharmaceutically acceptable salt thereof:

wherein
R 1 is hydroxy, alkoxy, haloalkyl, or halo;
R 2 is hydroxy or alkoxy;
R 3 , R 4 , R 5 , and R 6 are independently hydrogen, hydroxy, alkoxy, halo, haloalkyl, or alkyl;
R 7 is alkyl or hydrogen; and
R 9 is hydroxy or alkoxy.

2 . The method of claim 1 , wherein R 1 is hydroxy or alkoxy.

3 . The method of either of claim 1 or 2 , wherein R 2 is hydroxy.

4 . The method of any one of claims 1 - 3 , wherein R 3 , R 4 , R 5 , and R 6 are independently hydrogen or alkyl.

5 . The method of any one of claims 1 - 4 , wherein R 3 , R 4 , R 5 , and R 6 are independently hydrogen.

6 . The method of any one of claims 1 - 5 , wherein R 7 is methyl or hydrogen.

7 . The method of claim 1 , wherein
R 1 is hydroxy or alkoxy; R 2 is hydroxy or alkoxy; R 3 , R 4 , R 5 , and R 6 are independently hydrogen, hydroxy, alkoxy, or alkyl; R 7 is alkyl or hydrogen; and R 9 is hydroxy or alkoxy.

8 . The method of claim 1 , wherein
R 1 is hydroxy or alkoxy; R 2 is hydroxy or alkoxy; R 3 , R 4 , R 5 , and R 6 are independently hydrogen; R 7 is alkyl or hydrogen; and R 9 is hydroxy.

9 . The method of claim 1 , wherein
R 1 is hydroxy or methoxy; R 2 is hydroxy or methoxy; R 3 , R 4 , R 5 , and R 6 are independently hydrogen, hydroxy, methoxy, methyl; R 7 is methyl or hydrogen; and R 9 is hydroxy or methoxy.

10 . The method of claim 1 , wherein
R 1 is hydroxy or methoxy; R 2 is hydroxy or methoxy; R 3 , R 4 , R 5 , and R 6 are independently hydrogen; R 7 is methyl or hydrogen; and R 9 is hydroxy.

11 . The method of claim 1 , wherein the compound of formula (II) is 3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol.

12 . The method of claim 1 , wherein the compound of formula (II) is cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol.

13 . The method of claim 1 , wherein the compound of formula (II) is d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol.

14 . The method of any one of claims 1 - 13 , wherein the Bcl-2 family inhibitor is an inhibitor of Bcl-2, Bcl-xL, Bcl-x, Bcl-w, Bcl-b, BH3-only, or MCL-1.

15 . The method of any one of claims 1 - 14 , wherein the Bcl-2 family inhibitor is an inhibitor of Bcl-2.

16 . The method of any one of claims 1 - 15 , wherein the Bcl-2 family inhibitor is a BH3-mimetic.

17 . The method of any one of claims 1 - 16 , wherein the Bcl-2 family inhibitor is venetoclax, navitoclax, obatoclax mesylate, ABT-737, APG 2575, APG 1252, or AT-101.

18 . The method of any one of claims 1 - 17 , wherein the Bcl-2 family inhibitor is venetoclax.

19 . The method of any one of claims 1 - 18 , wherein the cancer is leukemia, lymphoma, lung cancer, or a hematological malignancy.

20 . The method of any one of claims 1 - 19 , wherein the cancer is a leukemia or lymphoma.

21 . The method of any one of claims 1 - 20 , wherein the leukemia is acute myeloid leukemia (AML), chronic myeloid leukemia (CIVIL), acute lymphocytic leukemia (ALL), or chronic lymphocytic leukemia (CLL).

22 . The method of claim 21 , wherein the leukemia is acute myeloid leukemia (AML).

23 . The method of any one of claims 1 - 19 , wherein the cancer is lung cancer.

24 . The method of claim 23 , wherein the lung cancer is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), a lung carcinoid tumor, or adenoid cystic carcinoma.

25 . The method of claim 24 , wherein the non-small cell lung cancer (NSCLC) is lung adenocarcinoma, squamous cell carcinoma, large cell (undifferentiated) carcinoma, adenosquamous carcinoma, or sarcomatoid carcinoma.

26 . The method of any one of claims 1 - 25 , wherein the cancer is non-responsive or resistant to the Bcl-2 inhibitor.

27 . The method of any one of claims 1 - 26 , wherein the Bcl-2 family inhibitor and compound of formula (II) are administered simultaneously.

28 . The method of any one of claims 1 - 26 , wherein the Bcl-2 family inhibitor and compound of formula (II) are administered sequentially.

29 . A method of treating leukemia comprising administering to a subject in need thereof an effective amount of:
(i) a Bcl-2 family inhibitor; and (ii) a compound of formula (II) or a pharmaceutically acceptable salt thereof:

wherein
R 1 is hydroxy, alkoxy, haloalkyl, or halo;
R 2 is hydroxy or alkoxy;
R 3 , R 4 , R 5 , and R 6 are independently hydrogen, hydroxy, alkoxy, halo, haloalkyl, or alkyl;
R 7 is alkyl or hydrogen; and
R 9 is hydroxy or alkoxy.

30 . The method of claim 29 , wherein the leukemia is acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), or chronic lymphocytic leukemia (CLL).

31 . The method of claim 29 or 30 , wherein the leukemia is acute myeloid leukemia (AML).

32 . The method of any one of claims 29 - 31 , wherein the Bcl-2 family inhibitor is venetoclax, navitoclax, obatoclax mesylate, ABT-737, APG 2575, APG 1252, or AT-101.

33 . The method of any one of claims 29 - 32 , wherein the Bcl-2 family inhibitor is venetoclax.

34 . The method of any one of claims 29 - 33 , wherein the compound of formula (II) is 3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol.

35 . The method of any one of claims 29 - 33 , wherein the compound of formula (II) is cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol.

36 . The method of any one of claims 29 - 33 , wherein the compound of formula (II) is d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol.

37 . A method of treating lung cancer comprising administering to a subject in need thereof an effective amount of:
(i) a Bcl-2 family inhibitor; and (ii) a compound of formula (II) or a pharmaceutically acceptable salt thereof:

wherein
R 1 is hydroxy, alkoxy, haloalkyl, or halo;
R 2 is hydroxy or alkoxy;
R 3 , R 4 , R 5 , and R 6 are independently hydrogen, hydroxy, alkoxy, halo, haloalkyl, or alkyl;
R 7 is alkyl or hydrogen; and
R 9 is hydroxy or alkoxy.

38 . The method of claim 7 , wherein the lung cancer is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), a lung carcinoid tumor, or adenoid cystic carcinoma.

39 . The method of claim 38 , wherein the non-small cell lung cancer (NSCLC) is lung adenocarcinoma, squamous cell carcinoma, large cell (undifferentiated) carcinoma, adenosquamous carcinoma, or sarcomatoid carcinoma.

40 . The method of any one of claims 37 - 39 , wherein the Bcl-2 family inhibitor is venetoclax, navitoclax, obatoclax mesylate, ABT-7

Assignees

• Mei Pharma Inc

Inventors

• Gold Daniel P

Classifications

• A61K31/353 Primary

  3,4-Dihydrobenzopyrans, e.g. chroman, catechin · CPC title

• A61K31/635

  having a heterocyclic ring, e.g. sulfadiazine · CPC title

• A61K45/06

  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

• A61P35/02

  specific for leukemia · CPC title