Peptoid oligomers, pharmaceutical compositions and methods of using the same

• US 8,828,413 B2
• Filed: 02/24/2010
• Issued: 09/09/2014
• Est. Priority Date: 02/24/2009
• Status: Active Grant

• Current Assignee: New York University
• Original Assignee: New York University
• Inventors: Kirshenbaum, Kent, Shin, Sung Bin
• Primary Examiner(s): Schnizer, Richard
• Assistant Examiner(s): Pipic, Alma
• Application Number:
  US12/711,663
• Publication Number:
  US 20100222255A1
• Time in Patent Office: 1,658 Days
• Field of Search: 514/2.9, 514/2.3, 530/317, 530/327, 530/328, 424/405
• US Class Current: 424/405
• CPC Class Codes: A01N 37/26 containing the group; Thio analogues thereof
• CPC Class Codes: A01N 43/36 five-membered rings
• CPC Class Codes: A01N 43/713 having rings with four or more nitrogen atoms as the only ring hetero atoms
• CPC Class Codes: A01N 43/90 having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
• CPC Class Codes: A01N 47/44 Guanidine; Derivatives thereof
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links
• CPC Class Codes: C07K 7/66 Gramicidins S, C; Tyrocidins A, B, C; Related peptides
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.

Claims

1. A peptoid oligomer according to formula (Ia) or (Ib):

2. The peptoid oligomer according to claim 1, wherein R^1a is 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, wherein each of which is unsubstituted or substituted with one or more groups selected from alkyl, halo, hydroxy, —

NH₂, nitro, and alkoxy.

4. The peptoid oligomer according to claim 1, R^1b is —

CH₂—

CH₂—

CH₂—

NH₂—

, —

CH₂—

CH₂—

CH₂—

CH₂—

NH₂, —

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

NH₂, —

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

NH₂, 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, or n-hexyl, each of which substituted with pyrrolyl, oxazolyl, 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 the peptoid oligomer is according to formula (Ia);

and X is C(O)R²⁰, or C(O)R²¹.

8. The peptoid oligomer according to claim 1, wherein the peptoid oligomer is according to formula (Ia);

and Y is NH₂.

9. The peptoid oligomer according to claim 1, wherein n is 6;

and the peptoid oligomer consists of

two units of monomer where R¹ is R^1b, and four units of monomer where R¹ is R^1c,

three units of monomer where R¹ is R^1b, and three units of monomer where R¹ is R^1c, or

four units of monomer where R¹ is R^1b, and two units of monomer where R¹ is R^1c.

10. The peptoid oligomer according to claim 9, wherein R^1b is —

CH₂—

CH₂—

CH₂—

NH₂, —

CH₂—

CH₂—

CH₂—

CH₂—

NH₂, —

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

NH₂, or 4-guanidinobutyl.

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

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

13. The peptoid oligomer according to claim 12, 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.

14. The peptoid oligomer according to claim 12, wherein n is 8;

and the said peptoid oligomer consists of four Nap monomers; and

four Npm monomers.

15. The peptoid oligomer according to claim 12, 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.

16. The peptoid oligomer according to claim 12, wherein the peptoid oligomer is according to formula (Ia);

X is C(O)R²⁰, or C(O)R²¹; and

Y is NH₂.

17. The peptoid oligomer according to claim 12, selected from the group consisting of:

Ac(NgbNpm)₃NH₂;

Ac(NahNpm)₃NH₂;

Ac(NapNdp)₃NH₂;

Ac(NapNnm)₃NH₂;

Ac(NapNpm)₂Nap₂NH₂;

Ac(NapNpm)₃NH₂;

Ac(NapNpm)₄NH₂;

Ac(NapNpm)₅NH₂;

Ac(NpmNap)₂Npm₂NH₂;

Ac(NipNapNibNpmPro)₂NH₂;

Ac(NdpNibNgbNipPro)₂NH₂;

Ac(NpmNibNapNipPro)₂NH₂;

Ac(NabNpm)₃NH₂;

Ac(NgbNdp)₅NH₂; and

Ac(NdpNgb)₂Ndp₂NH₂;

wherein Ac is acetyl or MeCO; and

the peptoid oligomer is according to formula (Ia).

18. The peptoid oligomer according to claim 12, selected from the group consisting of:

C(NgbNpm)₃;

C(NahNpm)₃;

C(NapNdp)₃;

C(NapNnm)₃;

C(NapNpm)₂Nap₂;

C(NapNpm)₃;

C(NapNpm)₄;

C(NapNpm)₅;

C(NpmNap)₂Npm₂;

C(NipNapNibNpmPro)₂;

C(NdpNibNgbNipPro)₂;

C(NpmNibNapNipPro)₂;

C(NabNpm)₃;

C(NgbNdp)₅; and

C(NdpNgb)₂Ndp₂;

wherein C is cyclic; and

the peptoid oligomer is according to formula (Ib).

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

20. The pharmaceutical composition of claim 19, wherein the carrier is a parenteral carrier, oral or topical carrier.

21. An antimicrobial composition comprising at least one peptoid oligomer according to claim 1.

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

23. An article comprising an antimicrobial substrate of claim 22, 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.

24. A peptoid oligomer selected from the group consisting of