# US 11,897,970 B2 · Antibacterial products

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- Number: US 11,897,970 B2
- Document ID: US11897970B2
- Status: Granted
- Kind: B2
- Application number: 16/491,852
- Filed: 2018-03-09
- Published: 2021-05-13
- Granted: 2024-02-13
- Earliest claimed: 2017-03-09
- Assignees: The University of Liverpool
- Applicants: The University of Liverpool
- Inventors: Ishwar Singh; Edward Taylor
- Web page: https://patentgrep.com/patent/US11897970B2

## CPC

- C07K 7/06: having 5 to 11 amino acids
- C07K 7/56: the cyclisation not occurring through 2,4-diamino-butanoic acid
- A61P 31/04: Antibacterial agents
- 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)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The invention provides novel antibacterial compounds of formulae IA, IB and IC as defined herein. Optionally, the antibacterial compounds can be bonded to a delivery agent that is capable of bonding to one or more structures on a bacterial cell membrane. The invention also provides the use of such compounds in treating or preventing bacterial infections, and processes for their synthesis.

## Claims

### Claim 1

A compound of formula IA,
or a pharmaceutically-acceptable salt, solvate or clathrate thereof, wherein:
R1 represents H, C1-6 alkyl, C1-6 acyl, benzyl or benzoyl;
AA1, AA2 and AA5 to AA7 each independently represents a proteinogenic or non-proteinogenic amino acid;
AA3 and AA4 each independently represents a proteinogenic or non-proteinogenic amino acid, diaminopropanoic acid, diaminobutanoic acid, or ornithine;
R8 represents hydrogen or C1-4 alkyl;
R9a, represents a proteinogenic or non-proteinogenic amino acid side chain, —CH2—NH2, —(CH2)2—NH2 or —(CH2)3—NH2;
R10a represents a side chain of an amino acid selected from the group consisting of valine, isoleucine, leucine, methionine, phenylalanine, tyrosine and tryptophan, a hydrophobic non-proteinogenic amino acid side chain, hydrogen, or R10a is linked to the adjacent nitrogen atom to form a proline ring;
R11a represents a proteinogenic or non-proteinogenic amino acid side chain;
Z is —O— or —NH—;
optionally wherein the compound of formula IA is covalently bonded to a delivery agent, which is either capable of covalently bonding to one or more structures on a bacterial cell membrane or comprises a hydrophilic portion capable of otherwise binding to one or more structures on a bacterial cell membrane.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein AA1 represents a D-phenylalanine residue, AA2 represents an L-isoleucine residue, AA5 represents a D-allo-isoleucine or D-isoleucine residue, AA6 represents an L-isoleucine residue, and AA7 represents an L-serine residue.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein the delivery agent is a fragment of formula II,
wherein D represents a dendrimer fragment to which the X2 groups shown are attached, X2 represents —NH2, boronic acid or a boronic acid derivative; and n is 2 or more (e.g. from 2 to 20); and
wherein the wavy line indicates the point of attachment to the compound of formula IA;
or wherein the delivery agent is a polypeptide or polypeptide derivative, or a pharmaceutically-acceptable salt thereof, which polypeptide or polypeptide derivative contains at least two residues selected from the group consisting of arginine and lysine.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein the delivery agent comprises one or more functional groups, which are independently selected from the list consisting of boronic acids, boronic acid derivatives, primary amines, amidines, guanidines, amides, ureas, and acid addition salts thereof.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein the delivery agent is a fragment of any one of formula III to VIII
wherein D1 to D6 each represent a dendrimer fragment to which the groups shown in parentheses are attached; Y represents O, NH or S; each n1 is 2 or more (e.g. from 2 to 20); m, p, q and r each independently represent from 1 to 8; and R4 represents a C1-6 alkyl group; or
wherein the delivery agent is a fragment of formula IXa, IXb or X;
wherein each L2 represents an aliphatic linker (e.g. a C1-6 alkyl chain); D7 and D8 independently represent a direct bond or a dendrimer fragment to which the boron-containing groups shown are attached, n2 is 1 or more, and optionally wherein D7 and D8 are attached to the boronic acid or boric acid portions of the compound of formula IXa, IXb and X via a linker group.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein the delivery agent is a fragment of any one of formula III to VIII, IXa, IXb or X, and D1 to D8 independently represent a dendrimer fragment of any one of formula A to E:

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R1 represents H, C1-6 alkyl, C1-6 acyl, benzyl or benzoyl or a delivery agent fragment of formula II to X.

### Claim 8

A compound selected from the group consisting of:
and pharmaceutically-acceptable salts, solvates and clathrates thereof.

### Claim 9 (depends on 1)

A pharmaceutical formulation comprising a compound as defined in claim 1 in combination with a pharmaceutically-acceptable adjuvant, diluent or carrier.

### Claim 10 (depends on 1)

A method of treating or preventing a bacterial infection, which method comprises administration of a therapeutically effective amount of a compound as defined in claim 1 to a subject in need thereof.

### Claim 11 (depends on 1)

A process for the preparation of a compound of formula IA as defined in claim 1, which process comprises:
(i) deprotection of a compound of formula IA in which one or more hydroxyl groups are protected with an ether protecting group; in the presence of an acid;
(ii) deprotection of a compound of formula IA in which one or more primary amide groups are protected with a trityl group; in the presence of an acid;
(iii) reaction of a compound of formula XIIIA,
wherein AA2 to AA7 and are as defined in claim 1 and are optionally protected; and Z, R8, R9a, R10a, and R11a are as defined in claim 1, in a process comprising the steps of:
a) reacting the compound of formula XIIIA with a compound of formula XIV
wherein R1 is H, C1-6 alkyl, C1-6 acyl, benzyl or benzoyl or a delivery agent fragment of formula II to X, RAA1 is the side chain of the desired AA1 amino acid (optionally in protected form), and PG1 represents an optional suitable protecting group, and a suitable peptide coupling reagent; followed by
b) removal of the protecting group PG1 if present; or
(iv) reaction of a compound of formula XVA,
wherein AA1 to AA7 are as defined in claim 1 and are optionally protected, Z, R8, R9a, R10a, and R11a are as defined in claim 1, and R1 is H, C1-6 alkyl, C1-6 acyl, benzyl or benzoyl or a delivery agent fragment of formula II to X with a suitable peptide coupling agent.

### Claim 12 (depends on 1)

A compound according to claim 1, wherein R10a represents a side chain of an amino acid selected from the group consisting of valine, isoleucine, leucine, methionine, phenylalanine, tyrosine and tryptophan, a hydrophobic non-proteinogenic amino acid side chain, or hydrogen.

### Claim 13 (depends on 1)

A compound according to claim 1, wherein R10a represents a side chain of an amino acid selected from the group consisting of valine, isoleucine, leucine, methionine, phenylalanine, tyrosine and tryptophan, a hydrophobic non-proteinogenic amino acid side chain selected from the group consisting of C2-12 alkyl, C1-12 alkylthiomethyl, phenyl, naphthyl, biphenyl, toluyl, and toluylmethyl, hydrogen, or R10a is linked to the adjacent nitrogen atom to form a proline ring.

### Claim 14 (depends on 1)

The compound according to claim 1, wherein R8 represents hydrogen or a methyl group.

### Claim 15 (depends on 1)

The compound according to claim 1, wherein R9a represents —CH2—NH2, —(CH2)2—NH2, —(CH2)3—NH2, a hydroxy group, an amide functional group (which latter two groups are bound to the remainder of the molecule via a linear, branched, cyclic or part cyclic C1-8 alkylene group), or the side chain of histidine, lysine, arginine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, norvaline, cyclohexylglycine, cyclohexylalanine, phenylglycine, biphenylglycine, biphenylalanine, naphthylglycine naphthylalanine, serine, threonine, asparagine, or glutamine.

### Claim 16 (depends on 1)

The compound according to claim 1, wherein R11a represents the side chain of alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, norvaline, cyclohexylglycine, cyclohexylalanine, phenylglycine, biphenylglycine, biphenylalanine, naphthylglycine or naphthylalanine.