Oligooxopiperazines and methods of making and using them

Patent metadata

Field	Value
Publication number	US-9309230-B2
Application number	US-201414304304-A
Country	US
Kind code	B2
Filing date	Jun 13, 2014
Priority date	Aug 12, 2010
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

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

First claim

What is claimed:

1. A pharmaceutical formulation comprising:
(i) 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 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′, CONHR′, 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′, 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
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′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;

with the proviso that A and B are not both, respectively, C and D, and
(ii) a pharmaceutically acceptable vehicle.

2. The pharmaceutical formulation according to claim 1 , wherein the oligooxopiperazine is an oligooxopiperazine of Formula IA:

3. The pharmaceutical formulation according to claim 2 , wherein the oligooxopiperazine is selected from the group consisting of

wherein X is H, COCH 3 , or any amino acid, and Y is OH, NH 2 , OMe, or any amino acid.

4. The pharmaceutical formulation according to claim 1 , wherein the oligooxopiperazine is an oligooxopiperazine of Formula IB:

5. The pharmaceutical formulation according to claim 4 , wherein the oligooxopiperazine is selected from the group consisting of

wherein X is H, COCH 3 , or any amino acid, and Y is OH, NH 2 , OMe, or any amino acid.

6. The pharmaceutical formulation according to claim 1 , wherein the oligooxopiperazine is an oligooxopiperazine of Formula IC:

7. The pharmaceutical formulation according to claim 6 , wherein the oligooxopiperazine is selected from the group consisting of

wherein X is H, COCH 3 , or any amino acid, and Y is OH, NH 2 , OMe, or any amino acid.

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

9. The pharmaceutical formulation according to claim 2 , wherein 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 an α-helix involved in a protein-protein interaction.

10. The pharmaceutical formulation according to claim 4 , wherein R 1 , R 2 , and R 4 mimic the amino acid side chain of, respectively, residues i, i+4, and i+7 of an α-helix involved in a protein-protein interaction.

11. The pharmaceutical formulation according to claim 4 , wherein R 1 , R 2 , and R 4 mimic the amino acid side chain of, respectively, residues i, i+4, and i+6 of an α-helix involved in a protein-protein interaction.

12. The pharmaceutical formulation according to claim 6 , wherein R 0 , R 1 , R 2 , R 3 , and R 4 mimic the amino acid side chain of, respectively, residues i, i+2, i+3, i+4, and i+7 of an α-helix involved in a protein-protein interaction.

13. The pharmaceutical formulation according to claim 8 , wherein the α-helix is selected from the group consisting of those identified in FIGS. 11A-11I .

14. A method of making an oligooxopiperazine of Formula IA:

wherein:
each of R 1 , R 2 , R 3 , R 4 , and R 5 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;
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
E is X 2 or F, wherein:
X 2 is H, COR′, CO 2 R′, CONHR′, an alkyl, an a

Assignees

• Univ New York

Inventors

• Arora Paramjit S
• To Hacek Over S Ovská Petra
• Guarracino Danielle
• Lao Brooke Bullock

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · 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

• C07D403/14 Primary

  containing three or more hetero rings · CPC title