Selective inhibitors of gentotoxic steress-induced IKK/NF-κB pathways

Patent metadata

Field	Value
Publication number	US-11028084-B2
Application number	US-201716349580-A
Country	US
Kind code	B2
Filing date	Nov 14, 2017
Priority date	Nov 14, 2016
Publication date	Jun 8, 2021
Grant date	Jun 8, 2021

Abstract

A method is for treatment of a disease associated with genotoxic stress-induced inhibitor of nuclear factor-κB kinase/nuclear factor kappa-light chain enhancer of activated B cells (IKK/NF-κB) signaling. The method can include administering a compound to a subject having a cancer exhibiting genotoxic stress induced IKK/NF-κB activation.

First claim

The invention claimed is:

1. A method of treatment of a cancer in a subject in need thereof comprising:
(a) identifying the subject as having a cancer exhibiting genotoxic stress-induced IKK/NF-κB signaling activation that causes growth of the cancer,
(b) selectively blocking activation of IKK/NF-κB in response to the genotoxic stress upstream of the IKK complex in the subject without blocking NF-κB activation upon signaling caused by other pathways in the subject by administering to the subject a compound according to Formula I,

wherein
R1=H, O;
R2=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein R2 is alkoxyamine, alkoxyamide;
R3=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein two (adjacent) R3 substituents can form an optionally aromatic cyclic structure of 5 or 6 members, optionally comprising 0, 1, or 2 heteroatoms;
X1 and X2=N or C;
X3=C;
ring A is an aromatic cyclic structure of 5 or 6 members, optionally comprising 0, 1, or 2 heteroatoms selected from the group consisting of O and N,
wherein said cyclic structure is optionally substituted with 0-3 substituents that can be the same or different, selected from the group consisting of H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, alkoxycarbonyl, amine, aryl, (optionally substituted with halogen, C1-C3 alkyl, alkoxy, amine) and alkoxyamine;
the bond z may be present or not present, wherein when bond z is not present:
the C of bond z of ring C is potentially substituted with R3, and X3 of the A ring is optionally substituted with H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine.

2. The method according to claim 1 , wherein the compound is, according to Formula II,

wherein
R1=H, O;
R5=H, halogen, C1-C5, alkyl, alkenyl, alkoxy, amine;
R6=H, OH, halogen, C1-C5, alkyl, alkoxy, or alkoxyamine, alkoxyamide;
R7=H, halogen, C1-C5, alkyl, or alkoxy;
R8=H, halogen, C1-C5, alkyl or alkoxy;
R9=H, halogen, C1-C5, alkyl or alkoxy;
R10=H, halogen, C1-C5, alkyl or alkoxy;
R11=H, halogen, C1-C5, alkyl, alkoxy, or carboxyl;
R12=H, halogen, C1-C5, alkyl or alkoxy;
or wherein when X1 is C, R9 and R10, R10 and R11, R11 and R12, or R12 and the C in the position of bond z of ring C, form an optionally aromatic cyclic structure of 5 or 6 members, comprising 0, 1, or 2 heteroatoms or forming phenyl;
X1=N or C;
X3=C;
ring A is an aromatic cyclic structure of 5 or 6 members, comprising 0, 1, or 2 heteroatoms selected from the group consisting of 0 and N, wherein said cyclic structure is optionally substituted with 0-3 substituents that can be the same or different, selected from the group consisting of H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, aryl, (optionally substituted with halogen, C1-C3 alkyl, alkoxy, amine), and alkoxyamine;
the bond z may be present or not present, wherein when bond z is not present:
the C in the position of bond z of ring C is substituted with halogen, preferably Cl, Br, F, C1-C7, alkyl, and X3 of the A ring is optionally substituted with H, C1-C5, alkyl, or when X3 is C with H, C1-C5, alkyl, OH, halogen.

3. The method according to claim 1 , wherein R1=0.

4. The method according to claim 1 , wherein at least one of R2 from 0-4 is not H.

5. The method according to claim 1 , wherein ring A is a heteroaromatic cyclic structure of 6 members, comprising 1 or 2 heteroatoms selected from 0 and/or N.

6. The method according to claim 1 , wherein ring A is selected from the group consisting of

7. Compound according to Formula I,

wherein:
R1=0;
R5=H, halogen, C1-C5 alkyl or alkoxy, or amine;
R6=H, OH, halogen, C1-C5 alkyl or alkoxy;
R7=H, halogen, C1-C5 alkyl or alkoxy;
R8=halogen, C1-C5 alkyl or alkoxy,
wherein at least one of R5 to R8 is not H;
R9=H, halogen, or C1-C5 alkyl or alkoxy;
R10=H, halogen, or C1-C5 alkyl or alkoxy;
R11=H, halogen, C1-C5 alkyl, alkoxy or carbonyl;
R12=H, halogen, or C1-C5 alkyl or alkoxy;
or wherein when X1 is C, R9 and R10, R10 and R11, R11 and R12, or R12 and the C in the position of bond z of ring C, form an optionally aromatic cyclic structure of 5 or 6 members, comprising 0, 1, or 2 heteroatoms or forming phenyl;
X1=N or C;
X3=C;
ring A is a heteroaromatic cyclic structure of 6 members, comprising 1 or 2 heteroatoms selected from 0 and/or N,
wherein said cyclic structure is optionally substituted with 0-3 substituents that can be the same or different, selected from the group consisting of H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, aryl and alkoxyamine;
the bond z may be present or not present, wherein when bond z is not present; and
the C in the position of bond z of ring C is substituted with halogen or C1-C5 alkyl, or X3 of the A ring is optionally substituted with H, C1-C5 alkyl, OH or halogen.

8. Compound according to claim 7 , wherein the compound is of Formula III,

wherein
R1=0;
R2=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, alkoxycarbonyl, amine, or wherein R2 is alkoxyamine or alkoxyamide, wherein at least one of R2 from 0-4 is not H;
R3=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein two (adjacent) R3 substituents form an optionally aromatic cyclic structure of 5 or 6 members, optionally comprising 0, 1, or 2 heteroatoms or forming phenyl;
X1=N or C;
X3=C;
ring A is a heteroaromatic structure of 6 members, comprising 1 or 2 N atom, wherein said cyclic structure is optionally substituted with 0-3 substituents that can be the same or different, selected from the group consisting of H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, aryl (optionally substituted with halogen, C1-C3 alkyl, alkoxy, amine), alkoxyamine, or wherein ring A is a heteroaromatic structure selected from the group consisting of:
and

9. Compound according to claim 7 , wherein the compound is of Formula VIII,

wherein
R1=O;
R2=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein R2 is alkoxyamine, alkoxyamide, wherein at least one of R2 from 0-4 is not H;
R3=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein two (adjacent) R3 substituents can form an optionally aromatic cyclic structure of 5 or 6 members, optionally comprising 0, 1, or 2 heteroatoms or form phenyl;
X1=N or C;
X4=N or C, whereby at least one X4 is N;
R16=can be 0-3, the same or different, H, halogen, C1-C5 alkoxy.

Assignees

• Max Delbrueck Centrum Fuer Molekulare Medizin Helmholtz Gemeinschaft
• Forschungsverbund Berlin Ev

Inventors

• Scheidereit Claus
• Willenbrock Michael
• Lindemann Peter
• Radetzki Silke
• Von Kries Jens-Peter
• Nazare Marc

Classifications

• C07D471/16

  Peri-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D221/06

  Ring systems of three rings · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title