Antibacterial agents
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.
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 wherein X—W-L-V is of formula (VI):
in which:
X, W and L are as defined in claim 1 ;
R 7 is hydrogen, a carbohydrate, or an amino carbohydrate including but not limited to 4-epi-vancosaminyl, actinosaminyl, or ristosaminyl;
R 8 is hydrogen, OH, or —O-mannose;
R 9 is —NH 2 , —NHCH 3 , or —N(CH 3 ) 2 ;
R 10 is —CH 2 CH(CH 3 ) 2 , [p-OH, m-Cl]phenyl, p-rhamnose-phenyl, [p-rhamnose-galactose]phenyl, [p-galactose-galactose]phenyl, [p-CH 3 O-rhamnose]phenyl, or is linked to R 11 via [p-OH,m-(O-{m-OH,m-R 11 }phenyl)]phenyl to form a cyclic ring system;
R 11 is —CH 2 —(CO)NH 2 , benzyl, [p-OH]phenyl, [p-OH, m-Cl]phenyl; [p-OH, m-Cl]phenyl, or is linked to R 10 via [m-OH,m-(O-{o-OH,m-R 10 }phenyl)]phenyl to form a cyclic ring system;
R 12 is hydrogen, or mannose;
R 13 is hydrogen, OH, or CH 2 NHCH 2 PO 3 H 2 ;
R 14 is hydrogen, beta-D-glucopyranose, beta-D-glucosamine, 2-O-(alpha-L-vancosaminyl)-beta-D-glucopyranose, 2-O-(alpha-L-4-epi-vancosaminyl)-beta-D-glucopyranose, (alpha- actinosaminyl)-beta-D-glucopyranose, (alpha-ristosaminyl)-beta-D-glucopyranose, or (alpha-acosaminyl)-beta-D-glucopyranose; or any one of said glucosamine or glucopyranose groups optionally substituted on a primary amine thereof with R 17 , wherein R 17 is; and
R 15 and R 16 are independently hydrogen or chloro 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.
11. The compound according to claim 1 wherein W is a basic amino acid or a basic peptide comprising from 2 to 5 amino acids, provided that W is not or does not contain any amino acids with a sulphur-containing side chain.
12. The compound according to claim 11 wherein W consists of 1 residue or from 2 to 10 contiguous residues of the formula (V):
in which:
Y is a group of formula —(CR 20 R 21 ) g —;
R 18a is selected from the group consisting of H, 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 3 -C 12 cycloalkyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 heteroaryl, —C(═NR 22 )—NR 23 R 24 , and OR 22 ,
R 18b is selected from the group consisting of H, 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 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, or
R 18a and R 18b when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic moiety, or
one of R 18a and R 18b when taken together with any R 20 or R 21 and the atoms to which they are attached forms an optionally substituted heterocyclic moiety;
R 19 is selected from the group consisting of H and optionally substituted C 1 -C 12 alkyl;
R 20 and R 21 are each independently selected from the group consisting of H, halogen, OH, C 1 -C 12 alkyl, C 6 -C 18 aryl, C 1 -C 12 haloalkyl, C 1 -C 12 hydroxyalkyl, C 1 -C 12 alkyloxy and C 1 -C 12 haloalkyloxy, or
when taken together with the carbon to which they are attached R 20 and R 21 form an optionally substituted C 3 -C 12 cycloalkyl, or an optionally substituted C 1 -C 12 heterocycloalkyl group, or
one of R 20 and R 21 when taken together with one of R 18a and R 18b and the atoms to which they are attached form an optionally substituted heterocyclic moiety;
each R 22 , R 23 , and R 24 is independently selected from the group consisting of H, optionally substituted C 1 -C 12 alkyl, optionally substituted C 1 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 -C 18 heteroaryl, or
any two of R 22 , R 23 and R 24 when taken together with the atoms to which they are attached form an optionally substituted cyclic group;
g is an integer selected from the group consisting of 1, 2, 3, 4, and 5;
r is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.
13. The compound according to claim 12 wherein Y is (CH 2 ) g .
14. The compound according to claim 11 wherein W consists of 1 residue or from 2 to 5 contiguous residues of the formula (V):
in which:
Y is a group of formula —(CR 20 R 21 ) g —;
R 18a is selected from the group consisting of H, 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 3 -C 12 cycloalkyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 heteroaryl, —C(═NR 22 )—NR 23 R 24 , and OR 22 ,
R 18b is selected from the group consisting of H, 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 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, or
R 18a and R 18b when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic moiety, or
one of R 18a and R 18b when taken together with any R 20 or R 21 and the atoms to which they are attached forms an optionally substituted heterocyclic moiety;
R 19 is selected from the group consisting of H and optionally substituted C 1 -C 12 alkyl;
R 20 and R 21 are each independently selected from the group consisting of H, halogen, OH, C 1 -C 12 alkyl, C 6 -C 18 aryl, C 1 -C 12 haloalkyl, C 1 -C 12 hydroxyalkyl, C 1 -C 12 alkyloxy and C 1 -C 12 haloalkyloxy, or
when taken together with the carbon to which they are attached R 20 and R 21 form an optionally substituted C 3 -C 12 cycloalkyl, or an optionally substituted C 1 -C 12 heterocycloalkyl group, or
one of R 20 and R 21 when taken together with one of R 18a and R 18b and the atoms to which they are attached form an optionally substituted heterocyclic moiety;
each R 22 , R 23 , and R 24 is independently selected from the group consisting of H, optionally substituted C 1 -C 12 alkyl, optionally substituted C 1 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 -C 18 heteroaryl, or
any two of R 22 , R 23 and R 24 when taken together with the atoms to which they are attached form an optionally substituted cyclic group;
g is an integer selected from the group consisting of 1, 2, 3, 4, and 5;
r is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.
15. The compound according to claim 14 wherein Y is (CH 2 ) g .
16. The compound according to claim 12 wherein the basic amino acid or basic peptide are selected from optionally substituted D- or L- lysine, ornithine, 2,4-diaminobutyric acid, 2,3-diaminopropionic acid and arginine.
17. The compound according to claim 1 wherein W is selected from the group consisting of -Lys-, -Lys-Lys-, -Lys-Lys-Lys-, -Orn-, -Orn-Orn-, -Orn-Orn-Orn-, -Lys-Orn-, -Orn-Lys, -Dab-, -Dab-Dab-, -Lys-Dab-, -Dab-Lys-, -Dab-Orn-, -Orn-Dab-, -Dap-, -Dap-Dap-, -Dap-Lys-, -Lys-Dap, -Dap-Orn, -Orn-Dap, -Dap-Dab-, and -Dab-Dap-in which any of the amino acids may be of the -L- or -D- configuration.
18. The compound according to claim 1 wherein each optional substituent in R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of: of halogen, ═O, ═S, —CN, —NO 2 , —CF 3 , —OCF 3 , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, —C(═O)OH, —C(═O)Ra, C(═O)OR a , C(═O)NR a R b , C(═NOH)R a , C(═NR a )NR b R c , NR a R b , NR a C(═O)R b , NR a C(═O)OR b , NR a C(═O)NR b R c , NR a C(═NR b )NR c R d , NR a SO 2 R b , —SRa, SO 2 NRaRb, —OR a , OC(═O)NR a R b , OC(═O)R a and acyl,
wherein R a , R b , R c and R d are each independently selected from the group consisting of H, C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 10 heteroalkyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 1 -C 12 heterocycloalkyl, C 1 -C 12 heterocycloalkenyl, C 6 -C 18 aryl, C 1 -C 18 heteroaryl, and acyl, or any two or more of R a , R b , R c and R d , when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
19. The compound according to claim 1 selected from compounds disclosed in Table 2.
20. A pharmaceutically acceptable salt of any compound described in claim 1 .
21. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
22. A method of treating a bacterial infection in a subject which method comprises administering to a subject an effective amount of the antibacterial agent of claim 1 .
23. A method of treating a bacterial infection in a subject which method comprises administering to a subject an effective amount of the composition of claim 21 .