# US 10,370,409 B2 · Synthesis of libraries of peptide tertiary amides

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- Number: US 10,370,409 B2
- Document ID: US10370409B2
- Status: Granted
- Kind: B2
- Application number: 14/354,031
- Filed: 2012-10-25
- Published: 2014-10-23
- Granted: 2019-08-06
- Earliest claimed: 2011-10-25
- Assignees: The Scripps Research Institute
- Applicants: The Scripps Research Institute
- Inventors: Thomas Kodadek; Yu Gao
- Web page: https://patentgrep.com/patent/US10370409B2

## CPC

- C07K 7/06: having 5 to 11 amino acids
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- C07C 51/363: by introduction of halogen; by substitution of halogen atoms by other halogen atoms
- C07C 231/02: from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
- C07K 1/042: {characterised by the nature of the carrier}
- C07K 1/047: {Simultaneous synthesis of different peptide species; Peptide libraries}
- C07K 5/06026: {the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala}
- C07K 5/0806: {the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala}
- C07K 14/001: {by chemical synthesis}
- G01N 33/6845: {Methods of identifying protein-protein interactions in protein mixtures}
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present disclosure is directed to a novel class of peptide-like oligomers called peptide tertiary amides (PTAs) and a combinatorial library of PTAs along with synthetic routes for the preparation of large combinatorial libraries of these compounds. The peptide tertiary amides provide an exceptional source of high affinity and selective protein ligands that are useful as tools for biological research and as drug leads, among others.

## Claims

### Claim 1

A process for preparing a peptide tertiary amide of formula (I) or its enantiomer with the opposite stereochemistry at Cα:
wherein
R1 is selected from optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted alkoxyl, optionally substituted heteroaryl, arylalkoxyl, optionally substituted acyl, OH, OR′, NH2, NHR′, NR′2, SH, SR′, C(O)R′, and an amino acid side chain;
R2 is selected from optionally substituted C2-C10 alkyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted alkoxyl, optionally substituted heteroaryl, arylalkoxyl, optionally substituted acyl, OH, OR′, NH2, NHR′, NR′2, SH, SR′, C(O)R′, and an amino acid side chain;
wherein
R′ is selected from optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkenyl, optionally substituted C1-C10 alkynyl, optionally substituted aryl, optionally substituted alkaryl, and optionally substituted acyl;
comprising:
oxidizing a primary amine of an amino acid of formula (II)
with an oxidizing agent followed by treatment with a nucleophilic bromide source to give an optically pure 2-bromo acid of formula (III):
wherein the synthesis further comprises a solid or semi-solid phase synthetic step
wherein the solid or semi-solid phase synthetic step comprises bonding the 2-bromo acid of formula (III)
to the solid-phase bead using a coupling agent in a solvent to give a compound of formula (V)
wherein the compound of formula (V) is reacted with an amine of formula (IV)
H2N—R2 (IV)
to give a compound of formula (VI):
and wherein the compound of formula (VI) is further reacted with additional 2-bromo acid of formula (III) followed by an amine of formula (IV) to obtain oligomers of the compound of formula (VI).

### Claim 2 (depends on 1)

The process of claim 1, wherein the oxidizing agent comprises one of nitrous acid and sulfuric acid.

### Claim 3 (depends on 1)

The process of claim 1, wherein the bromide source comprises a chemical selected from the group consisting of potassium bromide, hydrogen bromide, and sodium bromide.

### Claim 4 (depends on 1)

The process of claim 1, wherein the amine of formula (IV) is a primary amine.

### Claim 5 (depends on 1)

The process of claim 1, wherein the peptide tertiary amide comprises at least 90% enantiomeric excess of the (R) enantiomer.

### Claim 6 (depends on 1)

The process of claim 1, wherein the peptide tertiary amide comprises at least 90% enantiomeric excess of the (S) enantiomer.

### Claim 7 (depends on 1)

The process of claim 1, wherein the peptide tertiary amide comprises one or more Cα- and N-substitutions.

### Claim 8 (depends on 1)

The process of claim 1, wherein the solid-phase comprises a bead.

### Claim 9 (depends on 8)

The process of claim 8, wherein the solid-phase comprises a bead having a methionine linker.

### Claim 10 (depends on 1)

The process of claim 1, wherein the solvent is N,N-dimethylformamide.

### Claim 11 (depends on 1)

The process of claim 1, wherein the oligomers of the compound of formula (VI) are released from the bead by cleaving the oligomers from the solid-phase bead by reacting the bound oligomer with cyanogen bromide.