Sulfonamides derived from tricyclyl-2-aminocycloalkanols as anticancer agents

Patent metadata

Field	Value
Publication number	US-9937186-B2
Application number	US-201515124891-A
Country	US
Kind code	B2
Filing date	Mar 10, 2015
Priority date	Mar 11, 2014
Publication date	Apr 10, 2018
Grant date	Apr 10, 2018

Abstract

A genus of arylsulfonamide derivatives of aminocycloalkanols is disclosed. The compounds are of the following genus:

The compounds induce FOXO1 transcription factor translocation to the nucleus by modulating PP2A and, as a consequence, exhibit anti-proliferative effects. They are useful in the treatment of a variety of disorders, including as a monotherapy in cancer treatment, or used in combination with other drugs to restore sensitivity to chemotherapy where resistance has developed.

First claim

We claim:

1. A compound of formula (I):

wherein:
B is selected from the group consisting of: direct bond, —O—, —(CH 2 —O)—, —(O—CH 2 )—, —C(═O)N(CH 3 )— and —N(CH 3 )C(═O)—;
A is selected from N and CH;
T is a benzene ring or a five or six membered heteroaromatic ring;
U is a benzene ring or a five or six membered heteroaromatic ring;
n is zero, 1 or 2;
R 1 , R 2 , R 3 and R 4 are chosen independently from H, OH, halogen, cyano, nitro, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )acylamino, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )alkylthio, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, —CC(═O)O(C 1 -C 3 )alkyl, and (C 1 -C 3 )alkoxy;
R 5 and R 6 are chosen independently from H, halogen, cyano, nitro, azido, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and (C 1 -C 3 ) haloalkylthio.

2. A compound according to claim 1 of formula (II):

3. A substantially pure single enantiomer according to claim 2 of formula IIIa or IIIb:

4. A compound according to claim 1 wherein n is one.

5. A compound according to claim 1 wherein n is zero.

6. A compound according to claim 1 , wherein B is a direct bond.

7. A compound according to claim 1 , wherein B is —O—.

8. A compound according to claim 1 , wherein B is —(CH 2 —O)— or —(O—CH 2 )—.

9. A compound according to claim 1 , wherein B is —C(═O)N(CH 3 )— or —N(CH 3 )C(═O)—.

10. A compound according to claim 1 , wherein A is N.

11. A compound according to claim 1 , wherein A is —CH.

12. A compound according to claim 1 , wherein T and U are both benzene rings.

13. A compound according to claim 1 , wherein one of T and U is a benzene ring, and the other of T and U is selected from pyridine, pyrimidine, and thiophene.

14. A compound according to claim 1 , wherein R 2 and R 4 are H, and R 1 and R 3 are chosen independently from H, OH, F, Cl, Br, CN, CO 2 CH 3 , CH 3 , CF 3 , OCF 3 , and OCH 3 .

15. A compound according to claim 1 , wherein R 5 is H, and R 6 is chosen from H, F, Cl, CF 3 , OCF 3 , SCF 3 , N 3 and CN.

16. A compound according to claim 15 wherein R 6 is in the para position.

17. A method for treating a disease in a patient chosen from:
breast cancer, prostate cancer, leukemia, lung cancer, and glioblastoma;

the method comprising administering to the patient a therapeutically effective amount of a compound according to claim 1 .

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .

19. A compound according to claim 1 selected from:

Example

No.
Structure

 1

     1a

 1b

 2

 3

     3a

 3b

 4

 5

 6

 7

 8

 9

10

12

Assignees

• Icahn School Med Mount Sinai

Inventors

• Ohlmeyer Michael
• Kastrinsky David

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title