Poly-beta-peptides from functionalized beta-lactam monomers and antibacterial compositions containing same

Patent metadata

Field	Value
Publication number	US-9683081-B2
Application number	US-201514804619-A
Country	US
Kind code	B2
Filing date	Jul 21, 2015
Priority date	Aug 26, 2005
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

Disclosed is a method of making β-polypeptides. The method includes polymerizing β-lactam-containing monomers in the presence of a base initiator and a co-initiator which is not a metal-containing molecule to yield the product β-polypeptides. Specifically disclosed are methods wherein the base initiator is potassium t-butoxide, lithium bis(trimethylsilyl)amide (LiN(TMS) 2 ), potassium bis(trimethyl-silyl)amide, and sodium ethoxide, and the reaction is carried out in a solvent such as chloroform, dichloromethane, dimethylsulfoxide, or tetrahydrofuran.

First claim

What is claimed is:

1. A β-polypeptide comprising:
internal subunits having a structure selected from the group consisting of:

wherein R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and

wherein A together with the carbon atoms to which it is attached is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic;
wherein at least one of the internal subunits has a structure of:

wherein at least one of R 3 , R 4 , R 5 , and R 6 in the at least one of the internal subunits is selected from the group consisting of amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
a terminal subunit selected from the group consisting of:

wherein R 3 , R 4 , R 5 , and R 6 in the terminal subunit are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl and A in the terminal subunit is as previously defined.

2. The β-polypeptide of claim 1 , wherein at least one of R 3 , R 4 , R 5 , and R 6 in the terminal subunit is selected from the group consisting of amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.

3. The β-polypeptide of claim 1 , wherein at least one of R 5 and R 6 in the terminal subunit is selected from the group consisting of amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.

4. The β-polypeptide of claim 1 , wherein each internal subunit has a structure of:

wherein at least one of R 3 , R 4 , R 5 , and R 6 in each internal subunit is selected from the group consisting of amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.

5. A β-polypeptide comprising:
internal subunits having a structure selected from the group consisting of:

wherein R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and

wherein A together with the carbon atoms to which it is attached is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic;
a terminal subunit selected from the group consisting of:

wherein R 3 , R 4 , R 5 , R 6 , and A are as previously defined; and
a second terminal subunit having a structure of:

wherein R is selected from the group consisting of linear, branched, or cyclic alkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted arylalkyl.

6. The β-polypeptide of claim 5 , wherein the second terminal subunit is:

wherein R 7 is tert-butyl or chloromethyl.

7. A β-polypeptide comprising:
internal subunits having a structure selected from the group consisting of:

wherein R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and

wherein A together with the carbon atoms to which it is attached is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic;
wherein at least one internal subunit has a structure of:

wherein A is as previously defined; and
a terminal subunit selected from the group consisting of:

wherein R 3 , R 4 , R 5 , R 6 , and A are as previously defined.

8. The β-polypeptide of claim 7 , wherein A is selected from the group consisting of substituted or unsubstituted cyclohexane, cyclooctane, cyclooctene, and dodecane.

9. An antibiotic composition comprising, in combination:
an antibiotic-effective amount of at least one β-polypeptide or salt thereof, the at least one β-polypeptide or salt thereof comprising:
internal subunits having a structure selected from the group consisting of:

wherein R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and

wherein A together with the carbon atoms to which it is attached is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic; and
a terminal subunit selected from the group consisting of:

wherein R 3 , R 4 , R 5 , R 6 , and A are as previously defined; and
a pharmaceutically acceptable carrier.

10. The antibiotic composition of claim 9 , wherein at least one of R 3 , R 4 , R 5 , and R 6 in the terminal subunit is selected from the group consisting of amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.

11. The antibiotic composition of claim 9 , wherein at least one of R 5 and R 6 in the terminal subunit is selected from the group consisting of amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.

12. The antibiotic composition of claim 9 , wherein the β-polypeptide comprises a second terminal subunit having a structure of:

wherein R is selected

Assignees

• Wisconsin Alumni Res Found

Inventors

• Stahl Shannon S
• Gellman Samuel H
• Lee Sarah E
• Ilker Mehmet F
• Weisblum Bernard
• Kissounko Denis

Classifications

• C07K1/02

  in solution {(C07K1/003, C07K1/006 take precedence)} · CPC title

• C08G69/22 Primary

  Beta-lactams · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07D205/12

  condensed with carbocyclic rings or ring systems · CPC title