Constrained tricyclic sulfonamides

Patent metadata

Field	Value
Publication number	US-9937180-B2
Application number	US-201515124888-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

Tricyclic chemical modulators of protein phosphatase 2A are disclosed. The compounds are useful to treat cancer, age-onset proteotoxicity, stress-induced depression, inflammation, and acne. The compounds are of the following phenothiazine and dibenzoazepine compounds and similar genera:

First claim

We claim:

1. A compound of formula (I):

wherein:
B is selected from the group consisting of: —S—, —(CH 2 —CH 2 )—, and —CH═CH—;
A is selected from N and CH;
n is zero, 1 or 2;
X 1 is selected from —H, —F, —Cl, —CF 3 , and —CN;
X 2 is selected from —H, —F, —Cl, —CF 3 , and —CN; and
Y represents one or two substituents each independently selected from —H, —F, —Cl, —(C 1 -C 3 )haloalkyl, —(C 1 -C 3 )haloalkoxy, —(C 1 -C 3 )alkoxy, —C(═O)(C 1 -C 3 )alkyl, —C(═O)H, —(C 1 -C 3 )hydroxyalkyl, —(C 1 -C 3 )haloalkylthio, —N 3 , and —CN.

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

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

4. A compound according to claim 1 , wherein B is —S—.

5. A compound according to claim 1 , wherein B is —CH═CH—.

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

7. A compound according to claim 6 , wherein B is —(CH 2 —CH 2 )— and A is N.

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

9. A compound according to claim 1 , wherein n is 1.

10. A compound according to claim 1 , wherein X 1 and X 2 are both H.

11. A compound according to claim 1 , wherein one instance of Y is H or Cl, and another instance of Y is selected from —H, —F, —(C 1 -C 3 )haloalkyl, —(C 1 -C 3 )haloalkoxy, —(C 1 -C 3 )alkoxy, —C(═O)(C 1 -C 3 )alkyl, —C(═O)H, —(C 1 -C 3 )hydroxyalkyl, —(C 1 -C 3 )haloalkylthio, —N 3 , and —CN.

12. A compound according to claim 11 , wherein one instance of Y is H or Cl, and another instance of Y is —OCF 3 .

13. A compound according to claim 9 , wherein B is —(CH 2 —CH 2 )— and n is 1.

14. A compound according to claim 1 of formula:

15. A compound according to claim 14 of formula:

16. 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 .

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

18. A compound according to claim 1 selected from the following:

Example

No.
Structure

Example 1

Example 2

Example   3a

Example  3b

Example 4

Example 5

Example 17 

Example 18 

Example 20 

Example 21 

Example 7

Example 19 

Example 22 

Example 23 

Example 24 

Example 25

Assignees

• Icahn School Med Mount Sinai

Inventors

• Ohlmeyer Michael
• Kastrinsky David

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/06

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

• A61P35/02

  specific for leukemia · CPC title