Antibiotic compounds
The present invention relates to novel thiazolyl peptide antibiotics capable of treating serious bacterial infections in mammals, and particularly, in humans. Some of the analogs can also be 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 diasteriomer 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, or —(CH 2 ) n C 5-10 heterocyclyl;
R 2 represents R 1 OR 1 ;
R 3 represents —C(O)NR 5 R 6 , —C(O)NHC(R 7 R 8 )C(O)NR 5 R 6 or C(O)OR 5 ;
R 4 represents
R 4a represents C 1-12 alkyl, C(O)H, C(O)C 1-12 alkyl, —C(R 5 ) 2 C 5-10 heterocyclyl, —COOR, —(CH 2 ) n C(O)NR 5 R 6 , —(CH 2 ) n NR 5 R 6 , —(CH 2 ) n C 5-10 heterocyclyl, or —(CH 2 ) n P(O)(OR) 2 , said heterocyclyl optionally substituted with one or more groups of R a ; said alkyl optionally substituted with 1 to 6 hydroxy and/or optionally substituted by one or more groups of R a ,
R 5 and R 6 independently represent hydrogen, C 1-12 alkyl, —(CH 2 ) n C(═CH 2 )C(O)NH 2 , —(CH 2 ) n C(═CH 2 )CN, —(CH 2 ) n C 5-10 heterocyclyl, —(CH 2 ) n NR 7 R 8 , CHO, —(CH 2 ) n NR(CH 2 ) n NR 7 R 8 , —(CH 2 ) n NR(CH 2 ) n C 5-10 heterocyclyl, —(CH 2 ) n C 6-10 aryl, —(CH 2 ) n (O(CH 2 ) 2 ) 1-6 R 9 , or —(CH 2 ) n NHC(O)(CH 2 ) n NR 7 R 8 , said aryl, and heterocyclyl optionally substituted with one or more groups of R a ; said alkyl 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, —(CH 2 ) n NR 5 R 6 , —(CH 2 ) n SR 5 ; or —(CH 2 ) n C 5-10 heterocyclyl said heterocyclyl optionally substituted with one or more groups of R a ; said alkyl optionally substituted with 1 to 6 hydroxy and/or optionally substituted by one or more groups of R a ;
R 9 represents hydrogen, C 1-6 alkyl, (CH 2 ) n C 5-10 heterocyclyl, or —C(O)OR, CN, OR, said alkyl and heterocyclyl optionally substituted with one or more groups of R a
R a represents hydrogen, halogen, (CH 2 ) n OR, CF 3 , (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, (C 1-6 alkyl)O—, (aryl)O—, (C 1-6 alkyl)S(O) 0-2 —, or C 1-12 alkyl, said alkyl, heterocyclyl, and aryl 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 1 represents hydrogen, R 2 represents OH, R 3 represents —C(O)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 , —(CHR) n NHC(O)(CH 2 ) n NH 2 , —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, said aryl, and heterocyclyl optionally substituted with one or more groups of R a ; said alkyl 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:
and R 4a is C 1-12 alkyl, C(O)C 1-12 alkyl, —(CH 2 ) n C(O)NR 5 R 6 , —(CH 2 ) n NR 5 R 6 , —(CH 2 ) n C 5-10 heterocylyl, said heterocyclyl optionally substituted with one or more groups of R a ; said alkyl optionally substituted with 1 to 6 hydroxy and/or optionally substituted by one or more groups of R a .
5 . The compound according to claim 1 wherein R 4 is
and R 4a is C 1-12 alkyl, C(O)C 1-12 alkyl, —(CH 2 ) n C(O)NR 5 R 6 , —(CH 2 ) n NR 5 R 6 , —(CH 2 ) n C 5-10 heterocylyl, said heterocyclyl optionally substituted with one or more groups of R a ; said alkyl 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 having structural formula II:
wherein R 1 is hydrogen, R 2 is hydroxy and R 4a , is C 1-12 alkyl, C(O)C 1-12 alkyl, —(CH 2 ) n C(O)NR 5 R 6 , —(CH 2 ) n NR 5 R 6 , or —(CH 2 ) n C 5-10 heterocylyl, said heterocyclyl optionally substituted with one or more groups of R a ; said alkyl optionally substituted with 1 to 6 hydroxy and/or optionally substituted by one or more groups of R a .
7 . A compound according to claim 1 which is:
wherein the compound is selected from the group consisting of:
Compound
R 1
R 2
R 3
R 4
1
H
—OH
2
H
OH
3
H
OH
4
H
OH
5
H
OH
6
H
OH
7
H
OH
8
H
OH
9
H
OH
10
H
OH
11
H
OH
12
H
OH
13
H
OH
14
H
OH
15
CH 3
OH
16
CH 3
OH
17
H
OH
18
H
OH
19
H
OH
20
H
OH
and pharmaceutically acceptable salts, esters, enantiomers, diastereomers and mixtures thereof.
8 . A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.
9 . A method for treating a bacterial infection in a mammal in need thereof which comprises administering to the mammal a compound of formula I of claim 1 in an amount effective to treat the infection.
10 . (canceled)