Iodonium analogs as inhibitors of NADPH oxidases and other flavin dehydrogenases; formulations thereof; and uses thereof

Patent metadata

Field	Value
Publication number	US-10131659-B2
Application number	US-201515302566-A
Country	US
Kind code	B2
Filing date	Apr 6, 2015
Priority date	Apr 7, 2014
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

Disclosed herein are novel iodonium analogs having anticancer and anti-inflammatory activity.

First claim

What is claimed is:

1. A method of treating a cancer, inhibiting tumor growth, or treating or preventing an inflammatory condition, comprising:
administering a therapeutically effective amount of a compound of any one of Formulae Ia, Ib, Id, If, Ig, Ih, and Ii to a human patient or a non-human mammal in need thereof,

wherein
X is an anion;
Z is absent, a bond, O, S, CH 2 , —C(═O)—, or NR c where R c is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 2 -C 6 alkanoyl; wherein
a) when the compound is of any one of Formulae Ia, Id, Ig, Ih or Ii, each instance of R a and R b is independently a halogen, hydroxyl, amino, nitro, cyano, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, —COOR d , —CHO, —N(R e ) 2 , —CON(R e ) 2 , C 1 -C 6 alkoxy, C 2 -C 6 alkanoyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, optionally substituted aryl, or optionally substituted heteroaryl,
where each optionally substituted C 1 -C 6 alkyl can independently be substituted with hydroxyl, halogen, amino, nitro, cyano, —COOR d , —CHO, —N(R e ) 2 , —CON(R e ) 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 6 alkanoyl, —NHCO(CH 2 ) 1-2 N(R e ) 2 ,
where each R d is independently hydrogen or C 1 -C 3 alkyl,
where each R e is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 haloalkyl, or fluorenylmethyloxycarbonyl (“Fmoc”),
where each optionally substituted aryl and optionally substituted heteroaryl can independently be substituted with halogen, hydroxyl, amino, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, —COOR d , —CHO, —N(R e ) 2 , —CON(R e ) 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 6 alkanoyl, —NHCO(CH 2 ) 1-2 N(R e ) 2 ;

m is 0, 1, 2, 3, or 4; and
n is 0, 1, 2, 3, or 4;
b) when the compound is of Formula If,
Z is absent or O;
each instance of R a and R b is independently a halogen, hydroxyl, amino, nitro, cyano, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, —COOR d , —CHO, —N(R e ) 2 , —CON(R e ) 2 , C 1 -C 6 alkoxy, C 2 -C 6 alkanoyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, optionally substituted aryl, or optionally substituted heteroaryl,
where each optionally substituted C 1 -C 6 alkyl can independently be substituted with hydroxyl, halogen, amino, nitro, cyano, —COOR d , —CHO, —N(R e ) 2 , —CON(R e ) 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 6 alkanoyl, —NHCO(CH 2 ) 1-2 N(R e ) 2 ,
where each R d is independently hydrogen or C 1 -C 3 alkyl,
where each R e is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 haloalkyl, or fluorenylmethyloxycarbonyl (“Fmoc”),
where each optionally substituted aryl and optionally substituted heteroaryl can independently be substituted with halogen, hydroxyl, amino, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, —COOR d , —CHO, —N(R e ) 2 , —CON(R e ) 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 6 alkanoyl, —NHCO(CH 2 ) 1-2 N(R e ) 2 ;

m is 0, 1, 2, 3, or 4; and
n is 0, 1, 2, 3, or 4; and
c) when the compound is of Formula Ib, each instance of R a and R b is independently hydroxyl, nitro, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, —CHO, —CON(R e ) 2 , C 1 -C 6 haloalkoxy, optionally substituted aryl, or optionally substituted heteroaryl,
where each substituted C 1 -C 6 alkyl can independently be substituted with hydroxyl, halogen, amino, nitro, cyano, —COOR d , —CHO, —N(R e ) 2 , —CON(R e ) 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 6 alkanoyl, —NHCO(CH 2 ) 1-2 N(R e ) 2 ,
where each R d is independently hydrogen or C 1 -C 3 alkyl,
where each R e is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 haloalkyl, or fluorenylmethyloxycarbonyl (“Fmoc”),
where each optionally substituted aryl and optionally substituted heteroaryl can independently be substituted with halogen, hydroxyl, amino, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, —COOR d , —CHO, —N(R e ) 2 , —CON(R e ) 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 6 alkanoyl, —NHCO(CH 2 ) 1-2 N(R e ) 2 ;

m is 1, 2, 3, or 4; and
n is 1, 2, 3, or 4,
with the proviso that
when R a and R b are each independently nitro, then the nitro groups are in the 1 and 9 positions of the compound of Formula Ib.

2. The method of claim 1 , wherein Xis a halide, an alkyl sulfonate, an aryl sulfonate, a phosphate, or a nitrate.

3. The method of claim 1 , wherein X is chloride, bromide, iodide, CH 3 SO 3 —, C 2 H 5 SO 3 —, CF 3 SO 3 —, 4-CH 3 C 6 H 4 SO 3 —, or C 6 H 5 SO 3 —.

4. The method of claim 1 , wherein the compound is of Formula Ia.

5. The method of claim 1 , wherein the compound is of Formula Id.

6. The method of claim 1 , wherein the compound is of Formula If and
Z is absent or O.

7. The method of claim 1 , wherein the compound is of Formula Ig or Ii; and R b group is optionally substituted phenyl.

8. The method of claim 1 , wherein the compound is of Formula Ih.

9. The method of claim 1 , wherein the compound is of Formula Ib.

10. A method of treating a cancer, inhibiting tumor growth, or treating or preventing an inflammatory condition, comprising:
administering a therapeutically effective amount of a compound to a human patient or a non-human mammal in need thereof, wherein the compound is Iodonium, di-2-thienyl-, salt with methanesulfonic acid (1:1);
Iodonium, di-2-thienyl-, salt with with ethanesulfonic acid (1:1);
Iodonium, (5-nitro-2-thienyl)-2-thienyl-, salt with methane-sulfonic acid (1:1);
Iodonium, [5-[2-(dimethylamino)-2-oxoethyl]-2-thienyl]-2-thienyl-, salt with 4-methylbenzenesulfonic acid (1:1);
Iodonium, (5-iodo-2-thienyl)-2-thienyl-, salt with 4-methyl-benzenesulfonic acid (1:1);
Iodonium, [5-(hydroxymethyl)-2-thienyl]-2-thienyl-, salt with 4-methylbenzenesulfonic acid (1:1);
Iodonium, [5-[2-(acetylamino)-ethyl]-2-thienyl]-2-thienyl-, salt with 4-methylbenzene-sulfonic acid (1:1);
Iodonium, [5-(2-formyl-6-pyridinyl)-2-thienyl]-2-thienyl-, salt with 4-methylbenzenesulfonic acid (1:1)
Iodonium, [5-[[(9-fluorenyl-methoxycarbonyl)amino]methyl]-2-thienyl]-2-thienyl-, salt with p-toluenesulfonic acid (1:1);
Dibenziodolium, 3,7-bis(dimethylamino)-, Iodide;
Dibenziodolium, 3,7-bis(dimethyl-amino)-, methanesulfonate Dibenz[b,d]iodolium, 3-(methoxy-carbonyl)-, salt with 4-methyl-benzenesulfonic acid (1:1);
Dibenziodolium, 3,7-bis[(di-methylamino)methyl]-, iodide hydroiodide;
Dibenziodolium, 3,7-bis[[[(di-methylamino)methyl]carbonyl]-amino]-, chloride (˜94:6 bisamide:monoamide);
Dibenziodolium, 3,7-bis[(di-methylamino)methyl]-, iodide;
Iodonium, 3-nitrophenyl-2-thienyl-, salt with 4-methylbenzenesulfonic acid (1:1);
Iodonium, phenyl(5-iodo-4-phenyl-2-thienyl)-, salt with 4-methyl-benzenesulfonic acid (1:1);
10H-Dibenz[b,e]iodinium, 3,7-bis(dimethylamino)-, methanesulfonate
10H-Dibenz[b,e]iodinium, 3,7-bis(dimethylamino)-, iodide, dihydroiodide;
[1,4]Iodoxino[2,3-f:6,5-f′]diquinolin-14-ium, iodide;
[1,4]Iodoxino[2,3-f:6,5-f]-diquinolin-14-ium, methane-sulfonate;
Iodonium, (2-phenylimidazo-[1,2-a]pyridin-3-yl)phenyl-, salt with 4-methylbenzenesulfonic acid (1:1);
Iodonium, [2-(4-fluorophenyl)-imidazo[1,2-a]pyridin-3-yl]phenyl-, salt with 4-methylbenzenesulfonic acid (1:1);
Iodonium, (2-hydroxy-4,4-di-methyl-6-oxo-1-cyclohexen-1-yl)-2-thienyl-, salt with 4-methyl-benzenesulfonic acid (1:1);
Iodonium, (2-hydroxy-3-methoxy-carbonyl-4,4-dimethyl-6-oxo-1-carbonyl-4,4-dimethyl-6-oxo-1-salt with 4-methylbenzenesulfonic acid (1:1);
Iodonium, [2-hydroxy-3-(3-methyl-5-isoxazoly

Assignees

• Us Health
• Starks Ass Inc
• Us Health

Inventors

• Doroshow James Halpern
• Risbood Prabhakar
• Lu Jiamo
• Roy Krishnendu
• Kane Jr Charles T
• Hossain Md Tafazzal

Classifications

• C07D409/12

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

• A61K31/381

  having five-membered rings · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• C07D333/28

  Halogen atoms · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title