Peptoid oligomers, pharmaceutical compositions and methods of using the same

Patent metadata

Field	Value
Publication number	US-9315548-B2
Application number	US-201414481148-A
Country	US
Kind code	B2
Filing date	Sep 9, 2014
Priority date	Feb 24, 2009
Publication date	Apr 19, 2016
Grant date	Apr 19, 2016

Abstract

Novel peptoid oligomers are disclosed that have a formula represented by the following formula I:

The peptoids demonstrate antimicrobial activity and may be prepared as pharmaceutical compositions and used for the prevention or treatment of a variety of conditions in mammals including humans where microbial invasion is involved. The present cyclic and linear peptoids are particularly valuable as their effect is rapid, broad in spectrum and mostly indifferent to resistance provoked by standard antibiotics.

First claim

What is claimed is:

1. A peptoid oligomer according to formula lb:

wherein
each R 1 is independently R 1a , R 1b , or R 1c ;
each R 2 is independently hydrogen, or substituted or unsubstituted alkyl; or each R 1 and R 2 are joined together to form a 4-7 membered heterocyclic ring;
each R 1a is independently unsubstituted alkyl, or alkyl substituted with halo, hydroxy, amino, nitro, or alkoxy;
each R 1b is independently aminoalkyl, guanidinoalkyl (H 2 N—C(═NH)—NH-alkyl), or N-containing heteroarylalkyl, and each R 1b is unsubstituted or substituted with one or more F;
each R 1c is independently substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted diarylalkyl;
and n is an integer between 4 and 20;
provided that at least one of R 1 s is R 1b ;
a pharmaceutically acceptable salt, a stereoisomer, an isotopic variant, or a tautomer thereof.

2. The peptoid oligomer according to claim 1 , wherein R 1a is Me, Et, n-Pr,i-Pr, n-Bu, sec-Bu, or i-Bu.

3. The peptoid oligomer according to claim 1 , wherein R 1c is phenyl, benzyl, phenethyl, naphthyl, 2,2-diphenylethyl, or furanyl, and each R 1c is unsubstituted or substituted with one or more groups selected from alkyl, halo, hydroxy, amino, nitro, and alkoxy.

4. The peptoid oligomer according to claim 1 , wherein R 1b is aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 3-guanidinopropyl, 4-guanidinobutyl, 5-guanidinopentyl, or 6-guanidinohexyl.

5. The peptoid oligomer according to claim 1 , wherein R 1b is methyl, n-propyl, n-butyl, n-pentyl, and n-hexyl, each of which is substituted with pyrrolyl, oxazolyl, imidazolyl, isoxazolyl, thiazolyl, thiadiazolyl, triazolyl, or tetrazolyl.

6. The peptoid oligomer according to claim 1 , wherein n is 6, 8 or 10.

7. The peptoid oligomer according to claim 1 , wherein n is 6; and
the peptoid oligomer consists of one to five units of monomer where R 1 is R 1b ; and one to five units of monomer where R 1 is R 1c .

8. The peptoid oligomer according to claim 7 , wherein R 1b is 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 6-aminohexyl, or guanidinobutyl.

9. The peptoid oligomer according to claim 7 , wherein R 1c is benzyl, naphthyl, or diphenylethyl.

10. The peptoid oligomer according to claim 1 , wherein the said peptoid oligomer comprises one or more monomers selected from Nap, Nab, Nah, Ngb, Npm, Nnm, Ndp, Nip, Nib and Pro:

provided that at least one of the monomers in the peptoid oligomer is Nap, Nab, Nah, or Ngb.

11. The peptoid oligomer according to claim 10 , wherein n is 6; and the said peptoid oligomer consists of
three Ngb, Nah, Nap, or Nab monomers; and three Ndp, Nnm, or Npm, monomers,
four Npm monomers; and two Nap monomers,
four Nap monomers; and two Npm monomers, or
four Ndp monomers; and two Ngb monomers.

12. The peptoid oligomer according to claim 10 , wherein n is 8; and the said peptoid oligomer consists of four Nap monomers; and four Npm monomers.

13. The peptoid oligomer according to claim 10 , wherein n is 10; and the said peptoid oligomer consists of
two Nip monomers; two Nap monomers; two Nib monomers; two Npm
monomers; and two Pro monomers,
two Ndp monomers; two Nib monomers; two Ngb monomers; two Nip monomers;
and two Pro monomers,
two Npm monomers; two Nib monomers; two Nap monomers; two Nip
monomers; and two Pro monomers,
five Nap monomers; and five Npm monomers, or
five Ngb monomers; and five Ndp monomers.

14. The peptoid oligomer according to claim 1 , selected from the group consisting of

15. A pharmaceutical or antimicrobial composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the peptoid oligomer of claim 1 .

16. The pharmaceutical composition of claim 15 , wherein the carrier is a parenteral carrier, oral or topical carrier.

17. A method for treating, ameliorating or managing a disease or condition which comprises administering to a patient in need of such treatment, amelioration or management, a therapeutically effective amount of a therapeutically acceptable amount of a cyclic peptoid of claim 1 .

18. The method of claim 17 , wherein the disease or condition is or results from a bacterial infection,
from gram positive or gram negative bacterial strains, or
from Methicillin-resistant Staphylococcus aureus (MRSA).

19. A method for generating an antiseptic or sterile environment, which comprises applying the pharmaceutical or antimicrobial composition of claim 15 to a surface of the environment to coat the surface, thereby generating the antiseptic or sterile environment.

20. A method for treating, ameliorating or managing a disease or condition, which comprises administering to a patient in need of such treatment, amelioration or management a therapeutically effective amount of a therapeutically acceptable amount of a cyclic peptoid of claim 1 wherein the disease or condition results from or is caused by bacterial infection.

21. An antimicrobial substrate comprising at least one peptoid oligomer according to claim 1 bound to or incorporated into the substrate.

22. An article comprising an antimicrobial substrate of claim 21 , wherein the article is selected from the group consisting of a personal care item, an agricultural item, a cosmetic, a package, a food handling item, a food delivery item, a personal garment, a medical device, a personal hygiene item, an article intended for oral contact, a household item, a toy, and a liquid separation article.

23. The peptoid oligomer according to claim 1 , wherein n is 6; and
the peptoid oligomer consists of three units of monomer where R 1 is R 1b and three units of monomer where R 1 is R 1c ; where each of R 1b is 2-aminoethyl and each of R 1c is 2,2-diphenylethyl.

24. The peptoid oligomer according to claim 1 , wherein n is 6; and
the peptoid oligomer consists of three units of monomer where R 1 is R 1b and three units of monomer where R 1 is R 1c ; where each of R 2 is H, each of R 1b is 2-aminoethyl, and each of R 1c is benzyl.

Assignees

• Univ New York

Inventors

• Kirshenbaum Kent
• Shin Sung Bin

Classifications

• A61K38/12

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• A01N37/26

  containing the group [IMAGE cpc-sch-A01N-0936.gif]; Thio analogues thereof · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A01N43/90

  having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system · CPC title

• A61K38/08 Primary

  Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title