# US 9,006,392 B2 · Actagardine derivatives, and pharmaceutical use thereof

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- Number: US 9,006,392 B2
- Document ID: US9006392B2
- Status: Granted
- Kind: B2
- Application number: 13/576,882
- Filed: 2011-02-01
- Published: 2012-11-29
- Granted: 2015-04-14
- Earliest claimed: 2010-02-02
- Assignees: Novacta Biosystems Limited
- Applicants: Michael John Dawson; Antony Nicholas Appleyard; Jesus Cortes Bargallo; Sjoerd Nicolaas Wadman
- Inventors: Michael John Dawson; Antony Nicholas Appleyard; Jesus Cortes Bargallo; Sjoerd Nicolaas Wadman
- Web page: https://patentgrep.com/patent/US9006392B2

## CPC

- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- 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)
- A61K 38/10: Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- C07K 16/18: against material from animals or humans
- A61K 39/39533: {against materials from animals}
- 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)

## Abstract

Described are lantibiotic-based compounds, pharmaceutical compositions comprising the same and use of the compounds and said compositions, for the treatment of microbial infection, for example Clostridium difficile or Micrococcus luteus infection. The lantibiotic-based compounds have antimicrobial activity and in comparison to one or more of actagardine, actagardine B, deoxyactagardine B and deoxyactagardine have retained activity or improved activity.

## Claims

### Claim 1

A compound of formula (I):
wherein:
X is H or an amino acid;
p is 0 or 1;
X1 is —CH(CH3)2 or —CH2CH(CH3)2;
X2 is —CH(CH3)CH2CH3 or —CH(CH3)2;
R3 is —OH or —ZNR4R5;
Z is a bond or an amino acid;
R4 is hydrogen, or a C1-10 branched or unbranched alkyl chain wherein one, two or three carbon atoms are optionally replaced by a heteroatom and the alkyl chain optionally bears 1 or 2 oxo substituents and/or optionally bears one 5- to 6-membered heterocyclyl;
R5 is hydrogen, —RA-L-Ar1 or a C1-10 branched or unbranched alkyl chain wherein one, two or three carbon atoms are optionally replaced by a heteroatom and the alkyl chain optionally bears 1 or 2 oxo substituents and/or optionally bears one 5- to 6-membered heterocyclyl, or
R4 together with R5 and the nitrogen to which they are attached form a 5- or 6-membered heterocyclic group optionally including a further heteroatom selected from N, O or S, wherein the heterocyclic group is optionally substituted by:
a C0-10 branched or unbranched alkyl chain wherein one, two or three carbon atoms are optionally replaced by a heteroatom and the alkyl chain optionally bears 1 or 2 oxo substituents, the alkyl chain optionally substituted by:
C3-7 cycloalkyl;
5- to 6-membered heteroaryl;
5- to 6-membered heterocyclyl;
C3-7 aryl;
YAr1, or
wherein the heteraryl, heterocyclyl and aryl are optionally substituted by a C1-10 branched or unbranched alkyl chain wherein one, two or three carbon atoms are optionally replaced by a heteroatom and the alkyl chain optionally bears 1 or 2 oxo substituents, or
C3-7 cycloalkyl;
5- to 6-membered heteroaryl;
5- to 6-membered heterocyclyl;
C3-7 aryl;
YAr1, or
wherein the heteraryl, heterocyclyl and aryl are optionally substituted by a C1-10 branched or unbranched alkyl chain wherein one, two or three carbon atoms are optionally replaced by a heteroatom and the alkyl chain optionally bears 1 or 2 oxo substituents;
RA is a bond, —C0-9 alkylC6-10aryl, —C0-9 alkylC5-11heteroaryl, —C0-9 alkylC3-6cycloalkyl, or —C0-9 alkylC5-11heterocycle;
L is a straight or branched C0-15 alkyl chain wherein optionally one, two or three carbon atoms are replaced by a heteroatom independently selected from N, O or S, wherein the chain is optionally substituted by one or more oxo or nitro groups, with the proviso that a replacement heteroatom is not bonded directly to the N of the group —NR3R4;
Y is a straight or branched C0-15 alkyl chain wherein optionally one or more carbon atoms are replaced by a heteroatom independently selected from N, O or S, wherein the chain is optionally substituted by one or more oxo or nitro groups;
Ar1 is phenyl substituted by one or two NO2 groups or one to five halogen groups, or one or two C1-3 haloalkyl groups, or a combination thereof, wherein the amino acid at position 15 and optionally 1, 2, or 3 amino acid(s) at position 2, 3, 4, 5, 8, 10, 11, 13, 16 or 18 in formula (I) includes replacement by an alternative amino acid, wherein
the replacement amino acid at position 2 is selected from the group consisting of Ala, Asp, Glu, Gly, Ile, Asn, Gln, Thr and Val;
the replacement amino acid at position 3 is selected from the group consisting of Ala and Ser;
the replacement amino acid at position 4 is selected from the group consisting of His and Phe;
the replacement amino acid at position 5 is selected from the group consisting of Ala, Glu, Phe, Ile, Leu, Met, Ser, Thr and Trp;
the replacement amino acid at position 8 is selected from the group consisting of Phe, Ile, Met and Val;
the replacement amino acid at position 10 is selected from the group consisting of Phe, His, Leu, Met, Ser, Thr and Val;
the replacement amino acid at position 11 is Asp;
the replacement amino acid at position 13 is selected from the group consisting of Ala and Ser;
the replacement amino acid at position 15 is selected from the group consisting of Ala, Phe, Gly, His, Ile, Met, Gln, Arg, Thr and Trp;
the replacement amino acid at position 16 is selected from the group consisting of Phe, Leu, Met, Asn, Gln, Ser, Thr and dehydrobutyrine; and
the replacement amino acid at position 18 is selected from the group consisting of Gly, Ile, Asn, Ser, Thr and Val;
with the proviso that when the amino acids are unchanged at positions 2, 3, 4, 5, 6, 10, 11, 13 and 18:
and X is selected from the group consisting of H, Ala, Lys and Ile, and p is 1, then positions 15 and 16 are not Val and Ile respectively;
and or X is selected from the group consisting of H and Ala, and p is 0, then positions 15 and 16 are not Val and Ile respectively;
or X is selected from the group consisting of H and Ala, and p is 1, then positions 15 and 16 are not Leu and Val; Val and Val; or Leu and Ile respectively;
or X is selected from the group consisting of H, Ala, Ile, Phe, Val, Lys and Trp, and p is 0, then positions 15 and 16 are not Leu and Val respectively;
and with the proviso that the compound is not V15F Actagardine (3,5-dichlorobenzylamine) monocarboxamide, and the compound is not V15F Actagardine.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein X is an amino acid selected from the group consisting of Phe, Gly, His, Asn Gln, Ser and Thr.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein the amino acid at position 2 is replaced.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein the amino acid at position 3 is replaced.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein the amino acid at position 4 is replaced.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein the amino acid at position 5 is replaced.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein the amino acid at position 8 is replaced.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein the amino acid at position 10 is replaced.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein the amino acid at position 11 is replaced.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein the amino acid at position 13 is replaced.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein the amino acid at position 16 is replaced.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein the amino acid at position 18 is replaced.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein R3 is —OH.

### Claim 14 (depends on 1)

The compound according to claim 1, wherein X is H.

### Claim 15 (depends on 1)

The compound according to claim 1, wherein X is alanine.

### Claim 16 (depends on 1)

The compound according to claim 1 wherein X is selected from the group consisting of Arg, His and Gln.

### Claim 17 (depends on 1)

The compound according to claim 1 wherein the replacement amino acid at position 2 is selected from the group consisting of Ala, Gly and Thr.

### Claim 18 (depends on 1)

The compound according to claim 1 wherein the replacement amino acid at position 5 is Ile.

### Claim 19 (depends on 1)

The compound according to claim 1 wherein the replacement amino acid at position 15 is Phe.

### Claim 20 (depends on 1)

The compound according to claim 1 wherein the replacement amino acid at position 18 is Gly.

### Claim 21 (depends on 1)

The compound according to claim 1 wherein positions 15 and 16 are not any one of the following combinations: Val and Ile; Val and Val; Leu and Ile and Leu and Val, respectively.

### Claim 22 (depends on 1)

The compound according to claim 1 wherein two amino acids at any of positions 2, 3, 4, 5, 8, 10, 11, 13, 16 and 18 have been replaced by an alternative amino acid.

### Claim 23 (depends on 1)

The compound according to claim 1 wherein one amino acid at any of positions 2, 3, 4, 5, 8, 10, 11, 13, 16 and 18 has been replaced by an alternative amino acid.