Hybrid polymers, pharmaceutical compositions and methods of synthesizing the same

Patent metadata

Field	Value
Publication number	US-9458449-B2
Application number	US-201414282228-A
Country	US
Kind code	B2
Filing date	May 20, 2014
Priority date	May 20, 2013
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

Novel hybrid polymers are disclosed that have a structure represented by the following

wherein Abiotic oligomer, Polypeptide, X, Y, and R 1 are as described herein. The methods to prepare the hybrid polymers via novel oxazolidinyl compounds are also described.

First claim

What is claimed is:

1. A hybrid polymer comprising an abiotic oligomer segment and a polypeptide segment; and wherein the polypeptide segment comprises at least one serine or threonine residue at its N-terminus, and the abiotic oligomer segment is bonded to the polypeptide through the serine or the threonine residue; and wherein
the said abiotic oligomer segment comprises N-substituted glycine peptoid oligomers, beta-peptoids, beta-peptides, alternating alpha/beta peptides, gamma-peptides, pyridine oligoamides, quinoline oligoamides, aryl oligoamides, aedemers, peptide nucleic acids, other abiotic oligoamides, sulfonamidopeptides, aminoxy acid oligomers, hydrazone-linked pyrimidines, oligo-ureidophthalimides, triazine-based oligomers, triazole-based oligomers, oligooxopiperazine oligomers, and oligoureas or any combinations thereof;
provided that the hybrid polymer is other than HP1, HP2, HP3, HP4, HP5, or HP6.

2. The hybrid polymer according to claim 1 , wherein the hybrid polymer is according to formula I:

or a pharmaceutically acceptable salt, stereoisomer, isotopic variant or tautomer thereof;
wherein
abiotic oligomer is selected from N-substituted glycine peptoid oligomers, beta-peptoids, beta-peptides, alternating alpha/beta peptides, gamma-peptides, pyridine oligoamides, quinoline oligoamides, aryl oligoamides, aedemers, peptide nucleic acids, other abiotic oligoamides, sulfonamidopeptides, aminoxy acid oligomers, hydrazone-linked pyrimidines, oligo-ureidophthalimides, triazine-based oligomers, triazole-based oligomers, oligooxopiperazine oligomers, and oligoureas;
the group

 is a serine or threonine residue;
X is hydroxyl, alkoxy, amino or substituted amino;
Y is H or acetyl;
R 1 is H or methyl; and
wherein the terminal nitrogen of abiotic oligomer is attached to Y; and the terminal carbonyl carbon, —C(═O)—, of the abiotic oligomer is attached to the nitrogen of the serine or threonine residue;

provided that the hybrid polymer is other than HP1, HP2, HP3, HP4, HP5, or HP6.

3. The hybrid polymer according to claim 1 , wherein the hybrid polymer is according to formula II:

or a pharmaceutically acceptable salt, stereoisomer, isotopic variant or tautomer thereof;
wherein
X is hydroxyl, alkoxy, amino or substituted amino;
Y is H or acetyl;
R 1 is H or methyl;
each R 2 is independently selected from a group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and
the subscript m is an integer from 2-200;

provided that the hybrid polymer is other than HP1, HP2, HP3, HP4, HP5, or HP6.

4. The hybrid polymer according to claim 1 , wherein the hybrid polymer is according to formula III:

or a pharmaceutically acceptable salt, stereoisomer, isotopic variant or tautomer thereof;
wherein
X is hydroxyl, alkoxy, amino or substituted amino;
Y is H or acetyl;
R 1 is H or methyl;
each R 2 is independently selected from a group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
each R 3 is independently selected from a group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
the subscript m is an integer from 2-200; and the subscript n is an integer from 2-1000;

provided that the oligomer is other than HP1, HP2, HP3, HP4, HP5, or HP6.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the hybrid polymer of claim 1 .

6. A compound according to formula SI-5:

or a stereoisomer, or a tautomer thereof;
wherein
Abiotic oligomer is selected from N-substituted glycine peptoid oligomers, beta-peptoids, beta-peptides, alternating alpha/beta peptides, gamma-peptides, pyridine oligoamides, quinoline oligoamides, aryl oligoamides, aedemers, peptide nucleic acids, other abiotic oligoamides, sulfonamidopeptides, aminoxy acid oligomers, hydrazone-linked pyrimidines, oligo-ureidophthalimides, triazine-based oligomers, triazole-based oligomers, oligooxopiperazine oligomers, and oligoureas, and combinations thereof;
X is hydroxyl, alkoxy, amino or substituted amino;
Y is H or acetyl;
R 1 is H or methyl;
each R 4 is independently H or substituted or unsubstituted alkyl; and
wherein the terminal nitrogen of the abiotic oligomer is attached to Y; and the terminal carbonyl carbon, —C(═O)—, of the abiotic oligomer is attached to the nitrogen of oxazolidine.

7. The compound of claim 6 , wherein the compound is according to formula SI-5-1:

or a stereoisomer, or a tautomer thereof;
wherein
X is hydroxyl, alkoxy, amino or substituted amino;
Y is H or acetyl;
R 1 is H or methyl;
each R 2 is independently selected from a group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
each R 3 is independently selected from a group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
each R 4 is independently H or substituted or unsubstituted alkyl;
and
the subscript m is an integer from 2-200; the subscript n is an integer from 2-1000; and

the subscript t is 1, 2, 3, or 4.

8. The compound according to claim 7 , wherein each of R 2 or each of R 3 is independently phenyl, benzyl, phenethyl, 2-napthyl, 2,2-diphenylethyl, furanyl, thienyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, hydroxy, amino, nitro, and alkoxy.

9. The compound according to claim 7 , wherein each of R 2 or each of R 3 is independently guanidinoalkyl.

10. The compound according to claim 7 , wherein each of R 2 or each of R 3 is independently imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, 4-imidazolylbutyl, 5-imidazolylpentyl, or 6-imidazolylhexyl.

11. The compound according to claim 7 , wherein each of R 2 or each of R 3 is independently methyl, n-propyl, n-butyl, n-pentyl, and n-hexyl, substituted with pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, triazolyl, or tetrazolyl.

12. The compound according to claim 7 , whe

Assignees

• Kirshenbaum Kent
• Levine Paul
• Craven Timothy
• Univ New York

Inventors

• Kirshenbaum Kent
• Levine Paul
• Craven Timothy

Classifications

• C12N9/22

  Ribonucleases {[RNase]; Deoxyribonucleases [DNase]} · CPC title

• C07K1/13

  Labelling of peptides · CPC title

• C07K5/081

  the side chain containing O or S as heteroatoms, e.g. Cys, Ser · CPC title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C07K1/026

  by fragment condensation in solution · CPC title