Oligooxopiperazines and methods of making and using them

Patent metadata

Field	Value
Publication number	US-9624203-B2
Application number	US-201615096013-A
Country	US
Kind code	B2
Filing date	Apr 11, 2016
Priority date	Aug 12, 2010
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

The present invention relates to oligooxopiperazines and their use. Methods for preparing oligooxopiperazines are also disclosed.

First claim

What is claimed:

1. An oligooxopiperazine of Formula I:

wherein:
each of R 1 , R 2 , R 3 , and R 4 is independently an amino acid side chain, H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl;
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;
A is X 1 wherein:
X 1 is H, COR′, CO 2 R′, CON H R′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of an amine, 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

B is Y or D, wherein:
Y is OR′, COR′, N(R′″) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, 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
each R′″ is independently H, CO 2 R′, CON H R′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and

D is a moiety of the formula

 wherein:
R 5 is an amino acid side chain, H, N(R) 2 , OR, halogen, an alkyl, or an aryl;
wherein each R is independently H, an alkyl, or an aryl;

R 6 is H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl; and
E is X 2 or F, wherein:
X 2 is H, COR′, CO 2 R′, CON H R′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of an amine, 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
F is a moiety of the formula

 wherein:
 R 6 is H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl;
 R 7 is an amino acid side chain; and
 Y is OR′, COR′, N(R′″) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, 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
 each R′″ is independently H, CO 2 R′, CON H R′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag.

2. The oligooxopiperazine according to claim 1 , wherein the oligooxopiperazine is:
(i) an oligooxopiperazine of Formula IA:

or
(ii) an oligooxopiperazine of Formula IB:

3. The oligooxopiperazine according to claim 1 , wherein the oligooxopiperazine mimics an α-helix involved in a protein-protein interaction.

4. The oligooxopiperazine according to claim 3 , wherein the oligooxopiperazine is:
(i) an oligooxopiperazine of Formula IA:

or
(ii) an oligooxopiperazine of Formula IB:

5. The oligooxopiperazine according to claim 4 , wherein:
(i) the oligooxopiperazine is an oligooxopiperazine of Formula IA and R 1 , R 2 , R 4 , and R 5 mimic the amino acid side chain of, respectively, residues i, i+4, i+6, and i+7 of the α-helix;
(ii) the oligooxopiperazine is an oligooxopiperazine of Formula IB and R 1 , R 2 , and R 4 mimic the amino acid side chain of, respectively, residues i, i+4, and i+7 of the α-helix; or
(iii) the oligooxopiperazine is an oligooxopiperazine of Formula IB and R 1 , R 2 , and R 4 mimic the amino acid side chain of, respectively, residues i, i+4, and i+6 of the α-helix.

6. The oligooxopiperazine according to claim 3 , wherein the α-helix is selected from the group consisting of SEQ ID NOs: 1-181.

7. A pharmaceutical formulation comprising:
an oligooxopiperazine according to claim 1 and
a pharmaceutically acceptable vehicle.

8. An oligooxopiperazine of Formula I:

wherein:
each of R 1 , R 2 , R 3 , and R 4 is independently an amino acid side chain, H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl;
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;
A is X 1 or C, wherein:
X 1 is H, COR′, CO 2 R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of an amine, 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
C is a moiety of the formula

 wherein:
each X′ is independently H, COR′, CO 2 R′, CONHR′, N(R″) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, 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
each R″ is independently H, CO 2 R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;

R 0 is an amino acid side chain, H, N(R) 2 , OR, halogen, an alkyl, or an aryl;
wherein each R is independently H, an alkyl, or an aryl; and

R 6 is H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl; and

B is Y wherein:
Y is OR′, COR′, N(R′″) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, 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
each R′″ is independently H, CO 2 R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag.

9. The oligooxopiperazine according to claim 8 , wherein the oligooxopiperazine is:
(i) an oligooxopiperazine of Formula IB:

or
(ii) an oligooxopiperazine of Formula IC:

10. The oligooxopiperazine according to claim 8 , wherein the oligooxopiperazine mimics an α-helix involved in a protein-protein interaction.

11. The oligooxopiperazine according to claim 10 , wherein the oligooxopiperazine is:
(i) an oligooxopiperazine of Formula IB:

or
(ii) an oligooxopiperazine of Formula IC:

Assignees

• Univ New York

Inventors

• Arora Paramjit S
• To{Hacek Over (S)}Ovská Petra
• Guarracino Danielle
• Lao Brooke Bullock

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• C07D403/06

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