Phenazine derivatives as anti-neoplastic agents and anti-infective agents

Patent metadata

Field	Value
Publication number	US-9745273-B2
Application number	US-201415032778-A
Country	US
Kind code	B2
Filing date	Nov 3, 2014
Priority date	Nov 1, 2013
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

Novel phenazine derivatives, methods for their preparation and their medical use, in particular as anti-neoplastic agents and anti-infective agents, are provided. Novel methods for the preparation of iodinin and myxin are also provided.

First claim

The invention claimed is:

1. A compound of formula I, or a physiologically acceptable salt thereof:

wherein
R 1 is selected from:
hydrogen,
methyl, and
a group -L-X in which L and X are as defined herein;

R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each hydrogen;
L is either a direct bond or a linker;
X is a functional group selected from:
—PO 2 OH

wherein * denotes the point of attachment to L, where present, or directly to the O atom, or
X is a functional group selected from lactic acid, lactide and a vinylic group, or
X is a biocompatible polymer selected from polylysine, dextran, polylactic acid, chitosan and alginate; and
wherein, when R 1 is a group -L-X, each L and X may be the same or different.

2. A compound as claimed in claim 1 , wherein L is a linker which is a C 1-8 alkylene group optionally substituted by one or more groups selected from C 1-3 alkyl, hydroxy, C 1-6 alkoxy,
wherein one or more methylene groups within the backbone of the linker may each additionally be replaced by a group selected from —O—, —S—, —NH—, —NR— wherein R is C 1-3 alkyl, and —CO—,
and wherein two adjacent methylene groups within the backbone of the linker may each additionally carry substituents which, together with the intervening atoms of the linker backbone, form an optionally substituted, 5- or 6-membered saturated ring.

3. A compound as claimed in claim 1 , wherein L is a linker which includes one or more groups selected from —C(O)O—, —OC(O)—NR—, —OC(O)—O—, —C(O)—NR—, and —CO— wherein R is hydrogen or C 1-3 alkyl.

4. A compound as claimed in claim 1 , wherein L represents the following group:

where R a and R b are independently selected from hydrogen and C 1-3 alkyl; and
* denotes the point of attachment of the linker to adjacent groups within the molecule.

5. A compound as claimed in claim 1 , wherein X is acrylic acid.

6. A compound as claimed in claim 1 , wherein X is polylysine.

7. A compound as claimed in claim 1 , which is provided in the form of a physiologically acceptable salt.

8. A compound as claimed in claim 7 , wherein the salt is selected from Na + , K + , Ca + , Mg + , or hydrophilic ammonium salts with methyl-glucamine, glucosamine, chitosan or alginate.

9. A compound as claimed in claim 1 , which is provided in the form of a complex with at least one chelating agent.

10. A compound as claimed in claim 9 , wherein said agent is an inclusion agent.

11. A compound as claimed in claim 10 , wherein the inclusion agent is selected from the group consisting of cyclodextrins and calixarenes.

12. A compound as claimed in claim 9 provided in the form of nanoparticles.

13. A compound as claimed in claim 1 , which is provided in the form of nanoparticles comprising micelles or liposomes formed from one or more surface active agents.

14. A compound as claimed in claim 13 , wherein the surface active agents are selected from triglycerides, soaps and other carboxylates, anionic surfactants, proteins, sulfates sulfonates, ethoxylated alcohols and alkylphenols, fatty acid esters, nitrogenated nonionic surfactants, linear alkyl-amines, alkyl-ammoniums, nitrogenated surfactants with a second hydrophile, amphoteric surfactants, silicon surfactants, fluorinated surfactants, polymeric surfactants or surfactant polymers or association polymers.

15. A compound which is a polymer having the formula:

wherein n is an integer of at least 2;
each of R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is hydrogen; and
L is either a direct bond or a linker.

16. A compound as claimed in claim 15 , wherein L is selected from the following structures:

wherein each * denotes the point of attachment of the linker, L, to adjacent groups within the molecule.

17. A pharmaceutical composition comprising a compound as claimed in claim 1 or a physiologically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers or excipients.

Assignees

• Univ Oslo
• Bergen Teknologioverføring As
• Univ Claude Bernard Lyon

Inventors

• Døskeland Stein Ove
• Rongved Pål
• Herfindal Lars
• Le Borgne Marc
• Viktorsson Elvar Örn
• Åstrand Ove Alexander Høgmoen

Classifications

• C08G73/0273

  Polyamines containing heterocyclic moieties in the main chain · CPC title

• C07D241/52 Primary

  Oxygen atoms · CPC title

• A61K31/498

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title

• C07F9/650994

  condensed with carbocyclic rings or carbocyclic ring systems · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title