Cyclic compounds and methods of making and using the same

Patent metadata

Field	Value
Publication number	US-9469616-B2
Application number	US-201214365148-A
Country	US
Kind code	B2
Filing date	Dec 10, 2012
Priority date	Dec 13, 2011
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

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.

First claim

What is claimed is:

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 .

Assignees

• Cellceutix Corp
• Univ Massachusetts

Inventors

• Li Yan
• Thaker Hitesh
• Tew Gregory N
• Liu Dahui
• Pan Wenxi
• Scott Richard W
• Fan Xiaodong

Classifications

• A01N43/647

  Triazoles; Hydrogenated triazoles · CPC title

• C07D209/12

  Radicals substituted by oxygen atoms · CPC title

• C07C217/04

  the carbon skeleton being acyclic and saturated · CPC title

• C07D295/135

  with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• A01N39/00

  Biocides, pest repellants or attractants, or plant growth regulators containing aryloxy- or arylthio-aliphatic or cycloaliphatic compounds, containing the group [IMAGE cpc-sch-A01N-0940.gif] or [IMAGE cpc-sch-A01N-0941.gif], e.g. phenoxyethylamine, phenylthio-acetonitrile, phenoxyacetone · CPC title