IP Library › Granted Patent US 9,469,616
Granted Patent B2
US 9,469,616 · App. 14/365,148 · Granted Oct 18, 2016

Cyclic compounds and methods of making and using the same

Inventors: Yan Li (Boston, MA); Hitesh Thaker (Boston, MA); Gregory N. Tew (Boston, MA); Dahui Liu (Radnor, PA); Wenxi Pan (Radnor, PA); Richard W Scott (Radnor, PA); Xiaodong Fan (Radnor, PA)
Assignees: Cellceutix Corporation; University of Massachusetts
C07D249/06A01N39/00A01N43/38A01N43/647A01N47/44C07C217/04C07C217/16C07C279/02C07C279/08C07D209/08C07D209/12C07D295/135
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Quick Facts
Patent No.
US 9,469,616
App. No.
14/365,148
Granted
Oct 18, 2016
Kind
B2
Abstract

The present invention provides compounds, or pharmaceutically acceptable salts thereof, for inhibiting the growth of a microbe; treating a mammal having a microbial infection, mucositis, an ophthalmic infection, an otic infection, a cancer, or a Mycobacterium infection; inhibiting the growth of a Mycobacterium species; modulating an immune response in a mammal; or antagonizing unfractionated heparin, low molecular weight heparin, or a heparin/low molecular weight heparin derivative.

Claims (40)

1. A compound of the formula

wherein:

X is

R 2 is H, —NH(CH 2 ) n NH 2 , —NH(CH 2 ) n NC(═N)NH 2 , —(CH 2 ) n NH 2 , —O—(CH 2 ) n NH 2 , —(CH 2 ) n NC(═N)NH 2 , —O—(CH 2 ) n NC(═N)NH 2 , —CH═CH—CH 2 NH 2 , —CH═CH—CH 2 NC(═N)NH 2 , —CH═CH—(CH 2 ) 2 NH 2 , —CH═CH—(CH 2 ) 2 NC(═N)NH 2 , —C≡C—CH 2 NH 2 , —C≡C—(CH 2 ) 2 NH 2 , —C≡C—CH 2 NC(═N)NH 2 , or —C≡C—(CH 2 ) 2 —NC(═N)NH 2 , where n is 2, 3, or 4;

R 3 is H, —NH(CH 2 ) n NH 2 , —NH(CH 2 ) n NC(═N)NH 2 , —(CH 2 ) n NH 2 , —O—(CH 2 ) n NH 2 , —(CH 2 ) n NC(═N)NH 2 , —O—(CH 2 ) n NC(═N)NH 2 , —CH═CH—CH 2 NH 2 , —CH═CH—CH 2 NC(═N)NH 2 , —CH═CH—(CH 2 ) 2 NH 2 , —CH═CH—(CH 2 ) 2 NC(═N)NH 2 , —C≡C—CH 2 NH 2 , —C≡C—(CH 2 ) 2 NH 2 , —C≡C—CH 2 NC(═N)NH 2 , or —C≡C—(CH 2 ) 2 —NC(═N)NH 2 , where n is 2, 3, or 4;

R 4 is H, —NH(CH 2 ) n NH 2 , —NH(CH 2 ) n NC(═N)NH 2 , —(CH 2 ) n NH 2 , —O—(CH 2 ) n NH 2 , —(CH 2 ) n NC(═N)NH 2 , —O—(CH 2 ) n NC(═N)NH 2 , —CH═CH—CH 2 NH 2 , —CH═CH—CH 2 NC(═N)NH 2 , —CH═CH—(CH 2 ) 2 NH 2 , —CH═CH—(CH 2 ) 2 NC(═N)NH 2 , —C≡C—CH 2 NH 2 , —C≡C—(CH 2 ) 2 NH 2 , —C≡C—CH 2 NC(═N)NH 2 , or —C≡C—(CH 2 ) 2 —NC(═N)NH 2 , where n is 2, 3, or 4;

R 5 is H, —NH(CH 2 ) n NH 2 , —NH(CH 2 ) n NC(═N)NH 2 , —(CH 2 ) n NH 2 , —O—(CH 2 ) n NH 2 , —(CH 2 ) n NC(═N)NH 2 , —O—(CH 2 ) n NC(═N)NH 2 , —CH═CH—CH 2 NH 2 , —CH═CH—CH 2 NC(═N)NH 2 , —CH═CH—(CH 2 ) 2 NH 2 , —CH═CH—(CH 2 ) 2 NC(═N)NH 2 , —C≡C—CH 2 NH 2 , —C≡C—(CH 2 ) 2 NH 2 , —C≡C—CH 2 NC(═N)NH 2 , or —C≡C—(CH 2 ) 2 —NC(═N)NH 2 , where n is 2, 3, or 4;

R 6 is H, —NH(CH 2 ) n NH 2 , —NH(CH 2 ) n NC(═N)NH 2 , —(CH 2 ) n NH 2 , —O—(CH 2 ) n NH 2 , —(CH 2 ) n NC(═N)NH 2 , —O—(CH 2 ) n NC(═N)NH 2 , —CH═CH—CH 2 NH 2 , —CH═CH—CH 2 NC(═N)NH 2 , —CH═CH—(CH 2 ) 2 NH 2 , —CH═CH—(CH 2 ) 2 NC(═N)NH 2 , —C≡C—CH 2 NH 2 , —C≡C—(CH 2 ) 2 NH 2 , —C≡C—CH 2 NC(═N)NH 2 , or —C≡C—(CH 2 ) 2 —NC(═N)NH 2 , where n is 2, 3, or 4; and

R 7 is H, —NH(CH 2 ) n NH 2 , —NH(CH 2 ) n NC(═N)NH 2 , —(CH 2 ) n NH 2 , —O—(CH 2 ) n NH 2 , —(CH 2 ) n NC(═N)NH 2 , —O—(CH 2 ) n NC(═N)NH 2 , —CH═CH—CH 2 NH 2 , —CH═CH—CH 2 NC(═N)NH 2 , —CH═CH—(CH 2 ) 2 NH 2 , —CH═CH—(CH 2 ) 2 NC(═N)NH 2 , —C≡C—CH 2 NH 2 , —C≡C—(CH 2 ) 2 NH 2 , —C≡C—CH 2 NC(═N)NH 2 , or —C≡C—(CH 2 ) 2 —NC(═N)NH 2 , where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —O—(CH 2 ) n NH 2 or —O—(CH 2 ) n NC(═N)NH 2 , where n is 2, 3, or 4.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —O—(CH 2 ) n NH 2 or —O—(CH 2 ) n NC(═N)NH 2 , where n is 2, 3, or 4.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H, —O—(CH 2 ) n NH 2 , or —O—(CH 2 ) n NC(═N)NH 2 , where n is 2, 3, or 4.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H, —O—(CH 2 ) n NH 2 , or —O—(CH 2 ) n NC(═N)NH 2 , where n is 2, 3, or 4.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H, —O—(CH 2 ) n NH 2 , or —O—(CH 2 ) n NC(═N)NH 2 , where n is 2, 3, or 4.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H, —O—(CH 2 ) n NH 2 , or —O—(CH 2 ) n NC(═N)NH 2 , where n is 2, 3, or 4.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 2 is —O—(CH 2 ) n NH 2 or —O—(CH 2 ) n NC(═N)NH 2 , where n is 2, 3, or 4;

R 3 is —O—(CH 2 ) n NH 2 or —O—(CH 2 ) n NC(═N)NH 2 , where n is 2, 3, or 4;

R 4 is H, —O—(CH 2 ) n NH 2 , or —O—(CH 2 ) n NC(═N)NH 2 , where n is 2, 3, or 4;

R 5 is H, —O—(CH 2 ) n NH 2 , or —O—(CH 2 ) n NC(═N)NH 2 , where n is 2, 3, or 4;

R 6 is H, —O—(CH 2 ) n NH 2 , or —O—(CH 2 ) n NC(═N)NH 2 , where n is 2, 3, or 4; and

R 7 is H, —O—(CH 2 ) n NH 2 , or —O—(CH 2 ) n NC(═N)NH 2 , where n is 2, 3, or 4.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 2 is —O—(CH 2 ) 3 NH 2 or —O—(CH 2 ) 3 NC(═N)NH 2 ;

R 3 is —O—(CH 2 ) 3 NH 2 or —O—(CH 2 ) 3 NC(═N)NH 2 ;

R 4 is H, —O—(CH 2 ) 3 NH 2 , or —O—(CH 2 ) 3 NC(═N)NH 2 ;

R 5 is H, —O—(CH 2 ) 3 NH 2 , or —O—(CH 2 ) 3 NC(═N)NH 2 ;

R 6 is H, —O—(CH 2 ) 3 NH 2 , or —O—(CH 2 ) 3 NC(═N)NH 2 ; and

R 7 is H, —O—(CH 2 ) 3 NH 2 , or —O—(CH 2 ) 3 NC(═N)NH 2 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of

11. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11 further comprising an excipient chosen from purified water, propylene glycol, polyethyleneglycol (PEG) 400, glycerin, DMA, ethanol, benzyl alcohol, citric acid/sodium citrate (pH3), citric acid/sodium citrate (pH5), tris(hydroxymethyl)amino methane HCl (pH7.0), 0.9% saline, and 1.2% saline, or any combination thereof.

13. The pharmaceutical composition of claim 11 further comprising an excipient chosen from propylene glycol, purified water, and glycerin.

14. The pharmaceutical composition of claim 11 further comprising an excipient chosen from 20% w/v propylene glycol in saline, 30% w/v propylene glycol in saline, 40% w/v propylene glycol in saline, 50% w/v propylene glycol in saline, 15% w/v propylene glycol in purified water, 30% w/v propylene glycol in purified water, 50% w/v propylene glycol in purified water, 30% w/v propylene glycol and 5 w/v ethanol in purified water, 15% w/v glycerin in purified water, 30% w/v glycerin in purified water, 50% w/v glycerin in purified water, 20% w/v Kleptose in purified water, 40% w/v Kleptose in purified water, and 25% w/v Captisol in purified water.

15. The pharmaceutical composition of claim 11 further comprising an excipient chosen from 50% w/v propylene glycol in purified water, 15% w/v glycerin in purified water, 20% w/v Kleptose in purified water, 40% w/v Kleptose in purified water, and 25% w/v Captisol in purified water.

16. The pharmaceutical composition of claim 11 further comprising an excipient chosen from 20% w/v Kleptose in purified water, 20% w/v propylene glycol in purified water, and 15% w/v glycerin in purified water.

17. A method of inhibiting the growth of a bacteria comprising contacting the bacteria with a compound, or pharmaceutically acceptable salt thereof, of claim 1 .

18. The method of claim 17 , wherein the bacteriais S. aureus or E. faecalis.

19. A method of treating a mammal having a bacterial infection comprising administering to the mammal in need thereof an anti-bacterial effective amount of a compound, or pharmaceutically acceptable salt thereof, of claim 1 .

Assignments (3)
CHANGE OF NAME Recorded Nov 2, 2017
From: CELLCEUTIX CORPORATION
To: INNOVATION PHARMACEUTICALS INC.
Reel/Frame 044360/0550 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 2, 2014
From: LIU, DAHUI; PAN, WENXI
To: CELLCEUTIX CORPORATION
Reel/Frame 033875/0237 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 2, 2014
From: LI, YAN; THAKER, HITESH; TEW, GREGORY N.
To: UNIVERSITY OF MASSACHUSETTS
Reel/Frame 033875/0480 →
Continuity (4)
Provisional Application 61569847 · Dec 13, 2011
Provisional Application 61604623 · Feb 29, 2012
Provisional Application 61663584 · Jun 24, 2012
Related Publication 20150031738A1 · Jan 29, 2015