Polyamine sulfonamides and uses thereof

Patent metadata

Field	Value
Publication number	US-11014876-B2
Application number	US-201615766680-A
Country	US
Kind code	B2
Filing date	Nov 4, 2016
Priority date	Nov 4, 2015
Publication date	May 25, 2021
Grant date	May 25, 2021

Abstract

Cancer is a disease for which there remains a great unmet medical need, and therefore the discovery and development of new antineoplastic agents is critically important. The present invention relates in part to new therapeutic compounds with antineoplastic activity. Provided herein are polyamine sulfonamides such as compounds of Formula (I), or pharmaceutically acceptable salts thereof, which may be used in the treatment and/or prevention of diseases such as cancer. Also provided herein are pharmaceutical compositions and kits comprising the inventive compounds. Furthermore, the present invention provides methods of treating and/or preventing diseases (e.g., cancer) using compounds of Formula (I), or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof. Other methods provided include methods for inducing apoptosis of a cell, as well as methods for inhibiting alpha-enolase enzymatic activity in vivo and in vitro.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is optionally substituted C 1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl;
R 2 is optionally substituted C 1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl;
R 3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; and
R N1 , R N2 , R N3 , and R N4 are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted acyl; or optionally R N3 and R N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
provided that neither R 1 nor R 2 is substituted or unsubstituted benzyl.

2. The compound of claim 1 , wherein R 3 is optionally substituted aryl.

3. The compound of claim 1 , wherein the compound of Formula (I) is of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
each instance of R 4 is independently hydrogen, halogen, —CN, —NO 2 , —N 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR 4a , —N(R 4b ) 2 , or —SR 4c ;
each instance of R 4a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group;
each instance of R 4b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R 4b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
each instance of R 4c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; and
n is 0, 1, 2, 3, 4, or 5.

4. The compound of claim 3 , wherein the compound of Formula (II) is of Formula (II-a):

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 3 , wherein n is 1.

6. The compound of claim 3 , wherein at least one instance of R 4 is halogen.

7. The compound of claim 3 , wherein at least one instance of R 4 is optionally substituted C 1-6 alkyl.

8. The compound of claim 3 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

9. The compound of claim 3 , wherein the compound is of Formula (II-b) or (II-c):

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 3 , wherein the compound is of Formula (II-d) or (II-e):

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 3 , wherein the compound is of Formula (II-f):

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 3 , wherein the compound is of Formula (II-g):

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 3 , wherein the compound is of Formula (II-h) or (II-i):

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 3 , wherein the compound is of Formula (II-j) or (II-k):

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 3 , wherein at least one instance of R 4 is —I.

16. The compound of claim 3 , wherein at least one instance of R 4 is tert-butyl.

17. The compound of claim 3 , wherein the compound is the following:

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 , wherein the compound of Formula (I) is of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:
each instance of R 4 is independently hydrogen, halogen, —CN, —NO 2 , —N 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR 4a , —N(R 4b ) 2 , or —SR 4c ;
each instance of R 4a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group;
each instance of R 4b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R 4b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
each instance of R 4c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; and
m is 1, 2, 3, 4, 5, 6, or 7.

19. The compound of claim 18 , wherein the compound of Formula (III) is of Formula (III-a):

Assignees

• Univ Florida
• Torrey Pines Inst For Molecular Studies

Inventors

• Cogle Christopher R
• Meacham Amy M
• Sayeski Peter P
• Giulianotti Marcello A
• Houghten Richard A
• Welmaker Gregory S

Classifications

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title

• A61K45/06

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

• A61P35/02

  specific for leukemia · CPC title

• C07C311/18 Primary

  to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups · CPC title

• C07C311/05

  to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups · CPC title