Oxopiperazine helix mimetics for control of hypoxia-inducible gene expression

Patent metadata

Field	Value
Publication number	US-11560359-B2
Application number	US-202016984041-A
Country	US
Kind code	B2
Filing date	Aug 3, 2020
Priority date	May 21, 2014
Publication date	Jan 24, 2023
Grant date	Jan 24, 2023

Abstract

The present invention relates to oxopiperazines that mimic helix αB of the C-terminal transactivation domain of HIF1α. Also disclosed are pharmaceutical compositions containing these oxopiperazines and methods of using these oxopiperazines (e.g., to reduce gene transcription, treat or prevent disorders mediated by interaction of HIF1α with CREB-binding protein and/or p300, reduce or prevent angiogenesis in a tissue, induce apoptosis, and decrease cell survival and/or proliferation).

First claim

What is claimed is:

1. An oxopiperazine having a formula of Formula IA:

wherein:
R 1 is hydrophobic and is an amino acid side chain, OR, SR, an alkyl, or an aryl; wherein R is independently H, an alkyl, or an aryl;
R 2 is an amino acid side chain, OR, SR, an alkyl, or an aryl; wherein R is independently H, an alkyl, or an aryl; wherein R 2 is either a leucine side chain or longer than a leucine side chain by at least one backbone methylene; and with the proviso that R 1 and R 2 are not both an aryl;
R 3 is hydrophobic and is an amino acid side chain, SR, or an alkyl; wherein R is independently H, an alkyl, or an aryl;
R 4 is a hydrogen bond donor, a hydrophobic amino acid side chain, or an amide;
each R 6 is independently H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl;
X 1 is H, N(R) 2 , OR, COR′, CO 2 R′, CONR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a peptide of 1 to about 10 amino acid residues, a protecting group for protection of an amine, a solubilizing group, a targeting moiety, or a tag; wherein each R is independently H, an alkyl, or an aryl; and wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; with the proviso that X 1 is absent when Z is O or S;
Z is N, O, or S;
A 1 -W 1 is:

 and
Y is OR′, N(R″′) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, an amino acid, a peptide of 1 to about 10 amino acid residues, a protecting group for protection of a carboxylic acid, a targeting moiety, or a tag; wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and wherein each R″′ is independently H, CO 2 R′, CONR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag, wherein
R 1 is OR, SR, a C 3 -C 6 alkyl, an aryl, or a side chain of an amino acid selected from the group consisting of leucine, methionine, and homoleucine; R 2 is OR, SR, a C 3 -C 6 alkyl, an aryl, or a side chain of an amino acid selected from the group consisting of norleucine, methionine, leucine, and homoleucine; R 3 is SR, a C 1 -C 3 alkyl, or a side chain of an amino acid selected from the group consisting of glycine and alanine; R 4 is a side chain of an amino acid selected from the group consisting of glutamine, alanine, valine, asparagine, serine, and homoserine; and Y is OH, OR′, NHR′, NR′ 2 , or NH 2 .

2. An oxopiperazine having a formula of Formula IB:

wherein:
R 0 is hydrophobic and is an amino acid side chain, OR, SR, an alkyl, or an aryl; wherein R is independently H, an alkyl, or an aryl;
R 1 and R 2 are each independently a solubilizing group, a hydrophobic amino acid side chain, H, N(R) 2 , OR, SR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl;
R 3 is an amino acid side chain, OR, SR, an alkyl, or an aryl; wherein R is independently H, an alkyl, or an aryl; wherein R 3 is either a leucine side chain or longer than a leucine side chain by at least one backbone methylene; and with the proviso that R 0 and R 3 are not both an aryl;
R 4 is a hydrogen bond donor, a hydrophobic amino acid side chain, or an amide;
each R 6 is independently H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl;
X′ is H, COR′, CO 2 R′, CONR′, OR′, N(R″) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a solubilizing group, a targeting moiety, or a tag; wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, an amino acid residue, a peptide of 1 to about 10 amino acid residues, a targeting moiety, or a tag; and wherein each R″ is independently H, CO 2 R′, CONR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
A 1 -W 1 is:

 and
Y is OR′, N(R″′) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, an amino acid, a peptide of 1 to about 10 amino acid residues, a protecting group for protection of a carboxylic acid, a targeting moiety, or a tag; wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and wherein each R″′ is independently H, CO 2 R′, CONR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag.

3. The oxopiperazine according to claim 2 , wherein R 0 is OR, SR, a C 3 -C 6 alkyl, an aryl, or a side chain of an amino acid selected from the group consisting of leucine, methionine, and homoleucine; R 3 is OR, SR, a C 3 -C 6 alkyl, an aryl, or a side chain of an amino acid selected from the group consisting of norleucine, methionine, leucine, and homoleucine; R 4 is a side chain of an amino acid selected from the group consisting of glutamine, alanine, valine, asparagine, serine, and homoserine; and Y is OH, OR′, NHR′, NR′ 2 , or NH 2 .

4. An oxopiperazine is selected from the group consisting of oxopiperazine helix mimetic (“OHM”) 23, OHM 24, OHM 25, OHM 28, OHM 29, OHM 30, and OHM 31:

OHM 23: R 1 =Leu, R 2 =Nle, R 3 =Ala, R 4 =Gln;
OHM 24: R 1 =Met, R 2 =Met, R 3 =Ala, R 4 =Gln;
OHM 25: R 1 =Hle, R 2 =Hle, R 3 =Ala, R 4 =Gln;
OHM 28: R 1 =Hle, R 2 =Leu, R 3 =Ala, R 4 =Gln;
OHM 29: R 1 =Met, R 2 =Leu, R 3 =Ala, R 4 =Gln;
OHM 30: R 1 =Leu, R 2 =Hle, R 3 =Ala, R 4 =Gln;
OHM 31: R 1 =Hle, R 2 =Nle, R 3 =Ala, R 4 =Gln.

5. A pharmaceutical formulation comprising:
an oxopiperazine and
a pharmaceutically acceptable vehicle, wherein the oxopiperazine is selected from the group consisting of
(i) Formula IA:

wherein:
R 1 is hydrophobic and is an amino acid side chain, OR, SR, an alkyl, or an aryl; wherein R is independently H, an alkyl, or an aryl;
R 2 is an amino acid side chain, OR, SR, an alkyl, or an aryl; wherein R is independently H, an alkyl, or an aryl; wherein R 2 is either a leucine side chain or longer than a leucine side chain by at least one backbone methylene; and with the proviso that R 1 and R 2 are not both an aryl;
R 3 is hydrophobic and is an amino acid side chain, SR, or an alkyl; wherein R is independently H, an alkyl, or an aryl;
R 4 is a hydrogen bond donor, a hydrophobic amino acid side chain, or an amide;
each R 6 is independently H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl;
X 1 is H, N(R) 2 , OR, COR′, CO 2 R′, CONR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a peptide of 1 to about 10 amino acid residues, a protecting group for protection of an amine, a solubilizing group, a targeting moiety, or a tag; wherein each R is independently H, an alkyl, or an aryl; and wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; with the proviso that X 1 is absent when Z is O or S;
Z is N, O, or S;
A 1 -W 1 is:

Assignees

• Univ New York

Inventors

• Arora Paramjit S
• Lao Brooke Bullock
• Bonneau Richard
• Drew Kevin

Classifications

• C07C29/88

  by treatment giving rise to a chemical modification of at least one compound (chemisorption C07C29/76) · CPC title

• C07C29/80

  by distillation · CPC title

• C07C31/225

  Glycerol · CPC title

• C07C31/04

  Methanol · CPC title

• C07D241/08 Primary

  with oxygen atoms directly attached to ring carbon atoms · CPC title