Compounds and methods for treating cancer

Patent metadata

Field	Value
Publication number	US-2017226073-A1
Application number	US-201515502301-A
Country	US
Kind code	A1
Filing date	Aug 7, 2015
Priority date	Aug 7, 2014
Publication date	Aug 10, 2017
Grant date	—

Abstract

This document provides compounds, compositions, and methods for treating cancers including renal cancer (e.g., renal cell carcinoma) as well as ovarian, breast, prostate, colon, pancreatic, bladder, liver, lung, and thyroid cancers and melanoma. For example, compounds, compositions, and methods for using one or more inhibitors of SCD1 to treat renal cell carcinoma (e.g., clear cell renal cell carcinoma (ccRCC)), thyroid cancer, or liver cancer; or to increase the efficacy of treatment for the same.

First claim

What is claimed is:

1 . A compound according to Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is an unsubstituted C 1-6 alkyl or C 1-6 haloalkyl;
X is

Y is selected from the group consisting of:

m is 0 or 1;
n is 0, 1, or 2;
V is NR 4 or O;
R 2 , R 3 , and R 4 are each independently H or an unsubstituted C 1-6 alkyl; and
Z is an unsubstituted aryl.

2 . The compound of claim 1 , wherein the compound according to Formula (I) has the structure of Formula (Ia):

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 or 2 , wherein R 1 is CF 3 .

4 . The compound of any one of claims 1 - 3 , wherein m is 0.

5 . The compound of any one of claims 1 - 4 , wherein V is NH.

6 . The compound of any one of claims 1 - 5 , wherein Y is

7 . The compound of any one of claims 1 - 5 , wherein Y is N

8 . The compound of any one of claims 1 - 3 , wherein m is 1.

9 . The compound of any one of claims 1 - 3 and 8 , wherein V is O.

10 . The compound of claim 9 , wherein Y is

11 . The compound of any one of claims 1 - 4 , 9 , and 10 , wherein R 2 is H; and R 3 is CH 3 .

12 . The compound of claim 11 , wherein Y is

13 . The compound of any one of claims 1 - 12 , wherein n is 1.

14 . The compound of any one of claims 1 - 13 , wherein Z is phenyl.

15 . The compound of claim 1 , wherein the compound according to Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

16 . A compound according to Formula (II):

or a pharmaceutically acceptable salt thereof,
wherein
R 1 is halo;
X is —(C═O)NR 4 —;
Y is

 and
R 2 , R 3 , and R 4 are each independently H or an unsubstituted C 1-6 alkyl.

17 . The compound of claim 16 , wherein the compound according to Formula (II) has the structure of Formula (IIa):

or a pharmaceutically acceptable salt thereof.

18 . The compound of claim 16 or 17 , wherein R 1 is Cl.

19 . The compound of any one of claims 16 - 18 , wherein R 4 is H.

20 . The compound of any one of claims 16 - 19 , wherein R 2 is H; and R 3 is CH 3 .

21 . The compound of claim 16 , wherein the compound according to Formula (II) is

or a pharmaceutically acceptable salt thereof.

22 . A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 - 21 , and a pharmaceutically acceptable carrier.

23 . A method for inhibiting SCD1 in a cell, the method comprising contacting the cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 - 21 , or a pharmaceutical composition of claim 22 .

24 . The method of claim 23 , wherein the cell is a cancer cell.

25 . The method of claim 24 , wherein the cancer cell is selected from the group consisting of a kidney cancer cell, a liver cancer cell, a breast cancer cell, a lung cancer cell, a pancreatic cancer cell, a bladder cancer cell, a colon cancer cell, a melanoma cell, a thyroid cancer cell, an ovarian cancer cell, and a prostate cancer cell.

26 . The method of claim 24 or 25 , wherein the cancer cell is a kidney cancer cell.

27 . The method of any one of claims 23 - 26 , wherein the contacting is in vitro.

28 . The method of any one of claims 23 - 26 , wherein the contacting is in vivo.

29 . A method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 - 21 , or a pharmaceutical composition of claim 22 .

30 . The method of claim 29 , wherein the subject is a mammal.

31 . The method of claim 29 or 30 , wherein the subject is human.

32 . The method of any one of claims 29 - 31 , wherein the cancer comprises a solid tumor.

33 . The method of any one of claims 29 - 32 , wherein the cancer is selected from the group consisting of: a kidney cancer, a liver cancer, a breast cancer, a lung cancer, a pancreatic cancer, a bladder cancer, a colon cancer, a melanoma, a thyroid cancer, an ovarian cancer, and a prostate cancer.

34 . The method of any one of claims 29 - 33 , wherein the cancer is a kidney cancer or a bladder cancer.

35 . The method of any one of claims 29 - 34 , wherein the cancer is a kidney cancer.

36 . The method of any one of claims 29 - 35 , wherein the kidney cancer is clear cell renal cell carcinoma.

37 . The method of any one of claims 29 - 34 , wherein the cancer is a bladder cancer.

38 . The method of claim 37 , wherein the bladder cancer is selected from the group consisting of: transitional cell carcinoma, urothelial carcinoma, papillary carcinoma, flat carcinoma, squamous cell carcinoma, adenocarcinoma, small-cell carcinoma, and sarcoma.

39 . The method of claim 37 or 38 , wherein the bladder cancer is transitional cell carcinoma.

40 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an SCD1 inhibitor and a proteasome inhibitor, or pharmaceutically acceptable salts thereof, or a composition comprising the SCD1 inhibitor and the proteasome inhibitor.

41 . The method of claim 40 , wherein the SCD1 inhibitor and the proteasome inhibitor are admixed prior to administration.

42 . The method of claim 41 or 42 , wherein the SCD1 inhibitor and the proteasome inhibitor are administered concurrently.

43 . The method of claim 40 , wherein the SCD1 inhibitor and the proteasome i

Assignees

• Tun Han W
• Caulfield Thomas R
• Von Roemeling Christina
• Marlow Laura Ann
• Mayo Foundation

Inventors

• Copland Iii John A
• Tun Han W
• Caulfield Thomas R
• Von Roemeling Christina
• Marlow Laura Ann

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

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

• C07D213/75

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• C07D211/64

  having an aryl radical as the second substituent in position 4 · CPC title