Antibiotic compounds
Certain water-soluble thiazolyl peptides are antibiotic capable of treating serious bacterial infections in mammals, and particularly, in humans. Some of the analogs can also be employed as versatile intermediates for the preparation of new derivatives with useful antibacterial activity.
1 . A compound of structural formula I:
or a pharmaceutically acceptable salt, ester, enantiomer, diastereomer or mixture thereof,
wherein:
R independently represents hydrogen or C 1-12 alkyl;
R 1 represents hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, —(CH 2 ) n C 5-10 heterocyclyl, or —C(O)NR(CH 2 ) n C 5-10 heterocyclyl;
R 2 represents R 1 or OR 1 ;
R 3 represents —CH 2 NR 5 R 6 or C(O)H;
R 4 represents
R 4a represents N(R) 2 ;
R 5 and R 6 independently represent hydrogen, C 1-12 alkyl, —C(═NH)N(R 1 ) 2 , —(CH 2 ) n C 5-10 heterocyclyl, —(CH 2 ) n NR 7 R 8 , —(CH 2 ) n NR(CH 2 ) n NR 7 R 8 , —(CH 2 ) n (C 5-10 heterocyclyl, —(CH 2 ) n C(R) 2 C 5-10 heterocyclyl, —(CH 2 ) n C 5-10 aryl, —(CH 2 ) n (O(CH 2 ) 2 ) 1-6 R 9, —(CHR) n NHC(O)(CH 2 ) n NR 7 R 8 , —(CH 2 ) n S(O) p (CH 2 ) n C 5-10 heterocyclyl, —(CH 2 ) n CHR 7 CF 3 , —C(O)C 1-6 alkyl, —C(O)CF 3 , —C(O)(C(R) 2 ) n NR 1 R 7 , —C(O)NR(CH 2 ) n C 5-10 heterocyclyl, —C(O)NR(CH 2 ) n NR 7 R 8 , —C(O)C(R) 2 NHC(O)(CH 2 ) n NR 7 R 8 , —C(O)CHR 7 (CH 2 ) n C(O)NR 1 R 1 , —C(O)C(O)NR 1 R 1 , —C(O)(CH 2 ) n C 5-10 heterocyclyl, —C(R) 2 (CH 2 ) n NHC(O)N(CH 2 ) n C 5-10 heterocyclyl, or —C(R) 2 (CH 2 ) n OR, wherein said aryl and heterocyclyl are optionally substituted with one or more groups of R a ; said alkyl is optionally substituted with 1 to 6 hydroxy and/or optionally substituted by one or more groups of R a ; or
R 5 and R 6 together with the nitrogen atom they are attached form a 5 to 10 heterocyclic ring optionally containing 1 to 2 additional heteroatoms selected from the group consisting of N, S and O and optionally substituted with one or more groups of R a ;
R 7 and R 8 independently represent hydrogen, hydroxyl, C 1-6 alkoxy, C 1-12 alkyl, —N(R) 2 —(CH 2 ) n NR 5 R 6 , —(CH 2 ) n C 5-10 heterocyclyl, —(CH 2 ) n C 6-10 aryl, —(CH 2 ) n OR, —C(O)R, —C(O)C 5-10 heterocyclyl, —C(O)NH(CH 2 ) n C 5-10 heterocyclyl, or —C(O)(CH 2 ) n N(R) 2, wherein said aryl and heterocyclyl are optionally substituted with one or more groups of R a ; said alkyl is optionally substituted with 1 to 6 hydroxyl and/or optionally substituted by one to more groups of R a or
R 7 and R 8 together with the nitrogen atom they are attached form a 5 to 10 membered heterocyclic ring optionally containing 1 to 2 additional heteroatoms selected from the group consisting of N, S and O and optionally substituted with one or more groups of R a ; or
R 7 and R 8 together with the carbon atom they are attached form a 3 to 10 membered carbocyclic ring optionally and optionally substituted with one or more groups of R a ;
R 9 represents hydrogen, C 1-6 alkyl, (CH 2 ) n C 5-10 heterocyclyl, —C(O)OR, CN, or OR, wherein said alkyl and heterocyclyl are optionally substituted with one or more groups of R a ;
R a represents hydrogen, halogen, (CH 2 ) n OR, CF 3, NHC(O)R, (CH 2 ) n C(O)OR, (CH 2 ) n C(O)NR 7 R 8, (CH 2 ) n C 5-10 heterocyclyl, SO 2 NR 5 R 6, (CH 2 )C 6-10 aryl, N(R) 2, NO 2, CN, —OP(O)(OR) 2, (C 1-6 alkyl)O—, (aryl)O—, (C 1-6 alkyl)S(O) 0-2 —, or C 1-12 alkyl, wherein said alkyl, heterocyclyl, and aryl are optionally substituted with 1 to 4 groups selected from the group consisting of C 1-6 alkyl, (CH 2 ) n OR, (CH 2 ) n N(R) 2, and —O—; and n represent 0-6, and p represents 0, 1 or 2.
2 . The compound according to claim 1 wherein R 1 represents hydrogen or —C 1-6 alkyl, and R 2 represents OH or OC 1-6 alkyl.
3 . The compound according to claim 1 wherein R 3 represents —CH 2 NR 5 R 6, and R 5 and R 6 independently represent hydrogen, C 1-12 alkyl, —(CH 2 ) n C 5-10 heterocyclyl, —(CH 2 ) n NR 7 R 8 , —(CH 2 ) n NHC(O)(CH 2 ) n NR 7 R 8 , —C(O)C 1-6 alkyl, —C(O)(C(R) 2 ) n NR 1 R 7, —C(O)NR(CH 2 ) n C 5-10 heterocyclyl, or —C(O)(CH 2 ) n C 5-10 heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more groups of R a ; said alkyl is optionally substituted with 1 to 6 hydroxy and/or optionally substituted by one or more groups of R a .
4 . The compound according to claim 1 wherein R 4 is:
wherein R 4a is N(R) 2 or N+(R) 20 —.
5 . The compound according to claim 4 wherein R 1 is H, R 2 is OH, R 4a is —N(CH 3 ) 2 , —NH 2 , —NHCH 3, or —N+(CH 3 ) 2 O—, and R 5 and R 6 independently represent hydrogen, C 1-12 alkyl, —(CH 2 ) n C 5-10 heterocyclyl, —(CH 2 ) n NR 7 R 8 , —(CH 2 ) n NHC(O)(CH 2 ) n NR 7 R 8 , —C(O)C 1-6 alkyl, —C(O)(C(R) 2 ) n NR 1 R 7 , —C(O)NR(CH 2 ) n C 5-10 heterocyclyl, or —C(O)(CH 2 ) n C 5-10 heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more groups of R a ; said alkyl is optionally substituted with 1 to 6 hydroxy and/or optionally substituted by one or more groups of R a .
6 . The compound according to claim 1 wherein R 4 represents
wherein R 4a represents N(R) 2 or N+(R) 2 )—.
7 . The compound according to claim 1 represented by structural formula II:
wherein R 1 is hydrogen, R 2 is OH, R 4a is N(CH 3 ) 2 , —NH 2, or —NHCH 3, and R 5 and R 6 independently represent hydrogen, C 1-12 alkyl, —(CH 2 ) n C 5-10 heterocyclyl, —(CH 2 ) n NR 7 R 8 , —(CH 2 ) n NHC(O)(CH 2 ) n NR 7 R 8 , —C(O)C 1-6 alkyl, —C(O)(C(R) 2 ) n NR 1 R 7, —C(O)NR(CH 2 ) n C 5-10 heterocyclyl, or —C(O)(CH 2 ) n C 5-10 heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more groups of R a ; said alkyl is optionally substituted with 1 to 6 hydroxy and/or optionally substituted by one or more groups of R a .
8 . The compound according to claim 1 represented by structural formula III:
which is a compound selected from the group consisting of:
Compound
R 1
R 2
R 3
1
H
OH
2
H
OH
3
H
OH
4
H
OH
5
H
OH
6
H
OH
7
H
8
H
OH
9
H
OH
C(O)H
10
H
OH
11
H
H
12
—CH 2 CH 3
13
CH 3
OH
14
H
OCH 3
15
H
OH
16
H
OH
17
H
OH
18
H
OH
19
H
OH
20
H
OH
21
H
OCH 3
22
H
OH
23
H
H
24
H
OH
25
H
OH
26
H
OH
27
H
28
H
29
H
OH
30
H
OH
31
H
OH
32
H
OH
33
H
H
34
H
OH
35
H
OH
36
H
H
37
H
OH
38
H
OH
39
H
OH
40
H
OH
41
H
OH
42
H
OH
43
H
OH
44
OH
45
OH
46
H
OH
47
H
OH
48
H
OH
49
H
OH
50
H
OH
and pharmaceutically acceptable salts, esters, enantiomers, diastereomers, and mixtures thereof.
9 . A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.
10 . A method of treating a bacterial infection in a mammal in need of such treatment which comprises administering to the mammal a compound of formula I of claim 1 in an amount effective to treat the infection.