Oxopiperazine helix mimetics as inhibitors of the p53-MDM2 interaction

Patent metadata

Field	Value
Publication number	US-11180481-B2
Application number	US-201515304490-A
Country	US
Kind code	B2
Filing date	Apr 15, 2015
Priority date	Apr 15, 2014
Publication date	Nov 23, 2021
Grant date	Nov 23, 2021

Abstract

The present invention relates to oligooxopiperazines for modulating the p53-Mdm2 interaction. Exemplary oligooxopiperazines include those of Formula IA, Formula IB, and Formula IC below (wherein the various substituents are as defined herein). Methods of using the oligooxopiperazines are also disclosed.

First claim

What is claimed:

1. An oligooxopiperazine having a formula selected from the group consisting of:
(i) Formula IA:

wherein:
R 1 is a side chain of a non-natural amino acid selected from the group consisting of Tyr(O—R′), —CH 2 -naphthyl, 3-halo-Phe, 4-halo-Phe, 3-R′-Phe, and 4-R′-Phe, wherein R′ is an alkyl, an aryl, an arylalkyl, a cycloalkyl, or a heteroaryl;
R 2 is an aromatic amino acid side chain or a side chain of an amino acid selected from the group consisting of Leu, Phe, Met, Trp, Ile, Val, Ser, Tyr, Tyr(O—R′), —CH 2 -naphthyl, 2-halo-Phe, 3-halo-Phe, 4-halo-Phe, 2-R′-Phe, 3-R′-Phe, and 4-R′-Phe, wherein R′ is an alkyl, an aryl, an arylalkyl, a cycloalkyl, or a heteroaryl;
R 3 is an alkyl, aryl, or a side chain of an amino acid selected from the group consisting of Ala, Leu, Phe, Met, Trp, Ile, Val, Ser, Tyr, Asp, Glu, Asn, Gln, Cys, His, Thr, and Arg;
R 4 is a solubilizing group, a hydrophobic amino acid side chain, H, N(R) 2 , OR, halogen, an alkyl, an aryl, or a side chain of an amino acid selected from the group consisting of Leu, Ile, Val, Ala, Ser, Met, and Nle; wherein each R is independently H, an alkyl, or an aryl;
R 5 is an alkyl other than methyl or a side chain of an amino acid selected from the group consisting of Leu, Phe, Met, Trp, Ile, Val, Ser, Tyr, Tyr(O—R′), —CH 2 -naphthyl, 2-halo-Phe, 3-halo-Phe, 4-halo-Phe, 2-R′-Phe, 3-R′-Phe, and 4-R′-Phe, wherein R′ is an alkyl, an aryl, an arylalkyl, a cycloalkyl, or a heteroaryl;
each R 6 is independently H, halogen, an alkyl, or an aryl;
R 7 is a solubilizing group, a hydrophobic amino acid side chain, H, N(R) 2 , OR, halogen, an alkyl, an aryl, or a side chain of an amino acid selected from the group consisting of Leu, Ile, Val, Ala, Ser, Met, and Nle; wherein each R is independently H, an alkyl, or an aryl;
X 1 is H, N(R) 2 , OR, COR′, CO 2 R′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a peptide of 1 to 5 amino acid residues, a peptide of 1 to 6 amino acid residues, a peptide of 1 to 7 amino acid residues, a peptide of 1 to 8 amino acid residues, a peptide of 1 to 9 amino acid residues, a peptide of 1 to 10 amino acid residues, 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;
each A 1 -W 1 is independently:

and
Y is OR′, COR′, N(R′″) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, an amino acid, a peptide of 1 to 5 amino acid residues, a peptide of 1 to 6 amino acid residues, a peptide of 1 to 7 amino acid residues, a peptide of 1 to 8 amino acid residues, a peptide of 1 to 9 amino acid residues, a peptide of 1 to 10 amino acid residues, 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′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
(ii) Formula IB:

wherein:
R 1 is a side chain of a non-natural amino acid selected from the group consisting of Tyr(O—R′), —CH 2 -naphthyl, 3-halo-Phe, 4-halo-Phe, 3-R′-Phe, and 4-R′-Phe, wherein R′ is an alkyl, an aryl, an arylalkyl, a cycloalkyl, or a heteroaryl;
R 2 is an aromatic amino acid side chain or a side chain of an amino acid selected from the group consisting of Leu, Phe, Met, Trp, Ile, Val, Ser, Tyr, Tyr(O—R′), —CH 2 -naphthyl, 2-halo-Phe, 3-halo-Phe, 4-halo-Phe, 2-R′-Phe, 3-R′-Phe, and 4-R′-Phe, wherein R′ is an alkyl, an aryl, an arylalkyl, a cycloalkyl, or a heteroaryl;
R 3 is an alkyl, aryl, or a side chain of an amino acid selected from the group consisting of Ala, Leu, Phe, Met, Trp, Ile, Val, Ser, Tyr, Tyr(O—R′), —CH 2 -naphthyl, 2-halo-Phe, 3-halo-Phe, 4-halo-Phe, 2-R′-Phe, 3-R′-Phe, and 4-R′-Phe, wherein R′ is an alkyl, an aryl, an arylalkyl, a cycloalkyl, or a heteroaryl;
R 4 is an alkyl other than methyl or a side chain of an amino acid selected from the group consisting of Leu, Ile, Val, Ser, Met, and Nle;
each R 6 is independently H, halogen, an alkyl, or an aryl;
X 1 is H, N(R) 2 , OR, COR′, CO 2 R′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a peptide of 1 to 5 amino acid residues, a peptide of 1 to 6 amino acid residues, a peptide of 1 to 7 amino acid residues, a peptide of 1 to 8 amino acid residues, a peptide of 1 to 9 amino acid residues, a peptide of 1 to 10 amino acid residues, 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′, COR′, N(R′″) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, an amino acid, a peptide of 1 to 5 amino acid residues, a peptide of 1 to 6 amino acid residues, a peptide of 1 to 7 amino acid residues, a peptide of 1 to 8 amino acid residues, a peptide of 1 to 9 amino acid residues, a peptide of 1 to 10 amino acid residues, 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′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
(iii) Formula IC:

wherein:
R 0 is a side chain of a non-natural amino acid selected from the group consisting of Tyr(O—R′), —CH 2 -naphthyl, 3-halo-Phe, 4-halo-Phe, 3-R′-Phe, and 4-R′-Phe, wherein R′ is an alkyl, an aryl, an arylalkyl, a cycloalkyl, or a heteroaryl;
R 3 is an aromatic amino acid side chain or a side chain of an amino acid selected from the group consisting of Leu, Phe, Met, Trp, Ile, Val, Ser, Tyr, Tyr(O—R′), —CH 2 -naphthyl, 2-halo-Phe, 3-halo-Phe, 4-halo-Phe, 2-R′-Phe, 3-R′-Phe, and 4-R′-Phe, wherein R′ is an alkyl, an aryl, an arylalkyl, a cycloalkyl, or a heteroaryl;
R 1 is a solubilizing group, a hydrophobic amino acid side chain, H, N(R) 2 , OR, halogen, an alkyl, an aryl, or a side chain of an amino acid selected from the group consisting of Ala, Leu, Phe, Met, Trp, Ile, Val, Ser, Tyr, Asp, Glu, Asn, Gln, Cys, His, Thr, and Arg; wherein each R is independently H, an alkyl, or an aryl;
R 2 is a solubilizing group, a hydrophobic amino acid side chain, H, N(R) 2 , OR, halogen, an alkyl, an aryl, or a side chain of an amino acid selected from the group consisting of Ala, Leu, Phe, Met, Trp, Ile, Val, Ser, Tyr, Tyr(O—R′), —CH 2 -naphthyl, 2-halo-Phe, 3-halo-Phe, 4-halo-Phe, 2-R′-Phe, 3-R′-Phe, and 4-R′-Phe; wherein each R is independently H, an alkyl, or an aryl and wherein R′ is an alkyl, an aryl, an arylalkyl, a cycloalkyl, or a heteroaryl;
R 4 is an alkyl other than methyl or a side chain of an a

Assignees

• Univ New York

Inventors

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

Classifications

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D241/08

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

• C07D403/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title