Antibacterial agents

Patent metadata

Field	Value
Publication number	US-10947271-B2
Application number	US-201515117704-A
Country	US
Kind code	B2
Filing date	Feb 10, 2015
Priority date	Feb 10, 2014
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

Abstract

The invention concerns agents with antibacterial activity, their production and use in the treatment of bacterial infections in animals, including man. The agents are derivatives of vancomycin-type antibiotics, of structure X—W-L-V, wherein X is hydrogen, acetyl or a lipophilic membrane-insertive element, W is a basic peptide or basic amino acid; L is a linking group and V is a glycopeptide moiety which inhibits peptidoglycan biosynthesis in bacteria.

First claim

The invention claimed is:

1. An antibacterial compound of formula (III):
X—W-L-V  (III)

wherein:
X is a lipophilic group attached to the N-terminus of W, is based on carbon atoms and has the following parameters;
having from 3 to 60 carbon atoms including those of any alicyclic or aromatic rings, if present;
being straight or branched, and in the case of the latter containing one to three branch points;
being saturated or unsaturated, in the case of the latter containing one to eight double or triple bonds;
optionally having up to six heteroatoms, in addition to those, if present, in aromatic rings, if present, independently selected from S, O or N, not contained in an acidic substituent;
optionally containing one or more aromatic rings, which may be fused and each of which may contain 1, 2 or 3 heteroatoms which, if present, are independently selected from N, O or S; and
optionally having from one to six substituents selected from hydroxy, amino, methyl, methylamino and halo;

W is a basic amino acid or a basic peptide consisting of from 2 to 10 amino acids, provided that W is not or does not contain any amino acids with a sulphur-containing side chain;
L is a linking group of the formula —NH—(CR 1 R 2 ) m —Z—(CR 3 R 4 ) n —NH— wherein:
Z is oxygen or an optionally substituted moiety selected from the group consisting of —NH—, —CONH—, —NHCO—, —(OCH 2 CH 2 ) p —, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 heteroalkyl, C 1 -C 10 heteroalkenyl, C 3 -C 12 cycloalkyl, C 1 -C 12 heterocycle, C 6 -C 18 aryl, and C 1 -C 18 heteroaryl; and
R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, halogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 1 -C 12 heteroalkyl, optionally substituted C 1 -C 10 heteroalkenyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 1 -C 12 heterocycle, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 heteroaryl, optionally substituted carboxy, and optionally substituted carboxamide; and
m is an integer selected from the group consisting of 0, 1, 2, and 3; and
n is an integer selected from the group consisting of 0, 1, 2, and 3;
provided that both of m and n are not 0; and
p is an integer selected from the group consisting of 1-10; or

L is selected from one of the formulae:

wherein c and d are integers selected from the group consisting of 0, 1, and 2; and
the dotted lines show points of attachment to V and W;

and
V is a glycopeptide moiety which inhibits peptidoglycan biosynthesis in bacteria; or a pharmaceutically acceptable salt or prodrug thereof, and
wherein X—W-L- is attached to V via an amide linkage to a free carboxyl group in the glycopeptide moiety.

2. The compound according to claim 1 wherein X is of formula R 27 CO— wherein R 27 is a lipophilic group having from 3 to 15 carbon atoms, wherein said lipophilic group is:
straight or branched and may include an alicyclic or aromatic ring, the total number of carbon atoms in the group including those of any such ring;
is saturated or unsaturated, in the case of the latter containing one to four double or triple bonds;
optionally having 1 or 2 heteroatoms, in addition to those, if present, in aromatic rings, if present, independently selected from O or N;
optionally containing one or two aromatic rings, either or both of which may contain 1 nitrogen heteroatom; and
optionally having from one to three substituents selected from hydroxyl, amino, methyl, methylamino and halo.

3. The compound according to claim 1 wherein X is of formula (IV):

wherein each R 25 and R 26 is a lipophilic chain based on carbon atoms having the following parameters:
having from 3 to 30 carbon atoms including those of any alicyclic or aromatic rings, if present;
being straight or branched, and in the case of the latter containing one to three branch points;
being saturated or unsaturated, in the case of the latter containing one to four double or triple bonds;
optionally having 1, 2 or 3 heteroatoms, in addition to those, if present, in aromatic rings, if present, independently selected from O, S or N;
optionally containing one or more aromatic rings, which may be fused and each of which may contain 1, 2 or 3 heteroatoms which, if present, are independently selected from N, O or S; and
optionally having from one to three substituents selected from hydroxy, amino, methyl, methylamino and halo;

t is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5; and
u is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5;
provided that when one of t or u is 0, the other of t or u is not 0.

4. The compound according to claim 1 wherein -L- is of the formula —NH—(CH 2 ) m —Z—(CH 2 ) n —NH—; wherein Z, m and n are as defined in claim 1 .

5. The compound according to claim 4 wherein Z is selected from the group consisting of C 1 -C 12 alkyl, NH, O, C 1 -C 12 heterocycle, C 6 -C 18 aryl, and C 3 -C 12 cycloalkyl.

6. The compound according to claim 1 wherein -L- is of the formula —NH—(CH 2 ) 2 —NH—, —NH—(CH 2 ) 3 —NH—, —NH—(CH 2 ) 4 —NH—, —NH—(CH 2 ) 2 —NH—(CH 2 ) 2 —NH—, —NH—(CH 2 ) 2 —O—(CH 2 ) 2 —NH—, —NH—(CH 2 ) 3 —O—(CH 2 ) 3 —NH—, —NH-(1,4-Ph)-CH 2 —NH—, —NH-(1,3-Ph)-CH 2 —NH—, —NH-(1,4-cHex)-CH 2 —NH—, or —NH—CH 2 -(1,4-cHex)-CH 2 —NH—.

7. The compound according to claim 1 wherein -L- is of the formula —NH—CH(R 1 )—Z—(CH 2 ) n —NH— wherein:
R 1 is —(CO)OH, —(CO)OMe, —(CO)NH 2 , —(CO)NHNH 2 , —(CO)NHMe, —(CO)NHEt, —(CO)N(Me) 2 , —(CO)NHBn or —(CO)R 5 or an optionally substituted C 1 -C 12 heterocycle or an optionally substituted C 1 -C 18 heteroaryl moiety; and
R 5 is an optionally substituted C 1 -C 12 heterocycle or an optionally substituted C 1 -C 18 heteroaryl moiety; and
Z and n are as defined in claim 1 .

8. The compound according to claim 1 wherein -L- is of the formula —NH—CH(R 1 )—(CH 2 ) q —NH— wherein:
q is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5; and
R 1 is —(CO)OH, —(CO)OMe, —(CO)NH 2 , —(CO)NHNH 2 , —(CO)NHMe, —(CO)NHEt, —(CO)N(Me) 2 , —(CO)NHBn or —(CO)R 5 or an optionally substituted C 1 -C 12 heterocycle or an optionally substituted C 1 -C 18 heteroaryl moiety, wherein R 5 is an optionally substituted C 1 -C 12 heterocycle or an optionally substituted C 1 -C 18 heteroaryl moiety.

9. The compound according to claim 1 wherein V is selected from vancomycin, vancomycin aglycon, vancomycin desvancosamine, desmethyl vancomycin, chloroeremomycin, teicoplanain-A 2 -2, ristocetin A, eremomycin, balhimycin, actinoidin A, complestatin, chloropeptin 1, kistamycin A, avoparcin, telavancin, A40926 and oritavancin, and any one thereof optionally substituted on a primary amine with R 17 , wherein R 17 is an organic side chain moiety selected from the group consisting of hydrogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 1 -C 12 heteroalkyl, optionally substituted C 1 -C 10 heteroalkenyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 -C 18 heteroaryl.

10. The compound according to claim 1 whe

Assignees

• Univ Queensland

Inventors

• Cooper Matthew
• Blaskovich Mark

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07K9/008

  directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin · CPC title

• C07K5/0815

  with the first amino acid being basic · CPC title

• C07K5/06086

  with the first amino acid being basic · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title