6-O-acyl ketolide antibacterials

Details 6-O-acyl ketolide antibacterials 6-O-acyl ketolide antibacterials

2002-11-21

2004-11-30

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400, C536S018500

Reexamination Certificate

active

06825170

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the field of macrolide compounds having antibacterial activity, pharmaceutical compositions containing the compounds, and methods of treating bacterial infections with the compounds.
BACKGROUND OF THE INVENTION
Erythromycins are well-known antibacterial agents widely used to treat and prevent bacterial infection caused by Gram-positive and Gram-negative bacteria. However, due to their low stability in acidic environment, they often carry side effects such as poor and erratic oral absorption. As with other antibacterial agents, bacterial strains having resistance or insufficient susceptibility to erythromycin have developed over time and are identified in patients suffering from such ailments as community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections. Particularly problematic pathogens include methicillin-resistant
Staphylococcus aureus
(MRSA), vancomycin-resistant enterococci (VRE) and penicillin- and macrolide-resistant
Streptococcus pneumoniae
. Therefore, continuing efforts are called for to identify new erythromycin derivative compounds with improved antibacterial activity, and/or unanticipated selectivity against various target microorganisms, particularly erythromycin-resistant strains.
The following references relate to various erythromycin derivatives disclosed as having antibacterial activity:
EP 216,169 and U.S. Pat. No. 4,826,820 to Brain et al. disclose antibacterially active 6-carbamate erythromycin derivatives stated to “have antibacterial properties, in particular against Gram-positive bacteria but also against some Gram-negative bacteria.”
U.S. Pat. Nos. 5,444,051, 5,561,118, and 5,770,579, all to Agouridas et al., disclose erythromycin compounds such as those of the formulae
wherein substituents are as described in the respective references, which are all stated to be useful as antibiotics.
U.S. Pat. No. 5,866,549 to Or et al. and WO 98/09978 (Or et al.) disclose 6-O-substituted ketolides stated to have increased acid stability relative to erythromycin A and 6-O-methyl erythromycin A and enhanced activity toward gram negative bacteria and macrolide resistant gram positive bacteria.
WO 97/17356 (Or et al.) discloses tricyclic erythromycin derivatives stated to be useful in the treatment and prevention of bacterial infections.
WO 99/21871 (Phan et al.) discloses 2-halo-6-O-substituted ketolide derivatives of the formula
wherein substituents are as described in the respective reference, which are stated to possess antibacterial activity.
WO 99/21864 (Or et al.) discloses 6,11-bridged erythromycin derivatives having antibacterial activity.
WO 00/75156 (Phan et al.) discloses 6-O-carbamate ketolide derivatives that are useful as antibacterial agents for the treatment and prevention of infection in a mammal.
EP1146051 to Kaneko et al. discloses macrolide compounds of the following formula that are useful as antibacterial and antiprotozoal agents in mammals,
wherein substituents are as described in the reference.
EP1114826 to Kaneko and McMillen discloses novel erythromycin derivatives useful as antibacterial, antiprotozoal and/or prokinetic agents.
WO 00/71557 to Dirlam et al. discloses 13-methyl-erythromycin derivatives that are useful as antibacterial and antiprotozoal agents in mammals (including humans), fish and birds.
U.S. Pat. No. 6,355,620 to Ma et al. discloses C-2 modified erythromycin derivatives that are useful in treating bacterial infections.
WO 02/032918 to Hlasta et al. discloses a series of erythromycin ketolides that possess anti-infective activity and are useful for the treatment of bacterial and protozoal infections.
WO 00/062783 to Hlasta et al. discloses erythromycin analogs useful in the treatment of bacterial and protozoal infections and in the treatment of other conditions involving gastric motility.
U.S. Pat. No. 5,922,683 to Or et al. discloses multicyclic erythromycin compounds having antibacterial activity.
U.S. Pat. No. 6,034,069 to Or et al. discloses 3′-N-modified 6-O-substituted erythromycin ketolide compounds having antibacterial activity.
SUMMARY OF THE INVENTION
The invention provides compounds of Formula 1:
wherein
R
1
is selected from the group consisting of hydrogen, halogen, and hydroxy;
Z is selected from the group consisting of —NH—(CH
2
)
n
—, —(CH
2
)
n
—, —O—(CH
2
)
n
—, —NH—C
1
-C
6
alkenyl-, —C
1
-C
6
alkenyl-, —O—C
1
-C
6
alkenyl-, NHC
1
—C
6
alkynyl-, —C
1
-C
6
alkynyl-, and —O—C
1
-C
6
alkynyl-, wherein n is an integer from 0 to 5;
R
2
is selected from the group consisting of hydrogen, aryl, and heteroaryl;
R
3
is selected from the group consisting of hydrogen, C
1
-C
10
alkyl, C
2
-C
10
-alkenyl, C
2
-C
10
-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C
1
-C
10
)alkyl, aryl(C
2
-C
10
)alkenyl, aryl(C
2
-C
10
)alkynyl, heterocyclo(C
1
-C
10
)alkyl, heterocyclo(C
2
-C
10
)alkenyl, and heterocyclo(C
2
-C
10
)alkynyl, C
3
-C
6
-cycloalkyl, C
5
-C
8
-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group;
R
4
is hydrogen or a hydroxy protecting group;
W is selected from the group consisting of
(1) a substituted pyrrole of the formula
 wherein
R
5
and R
6
are independently selected from the group consisting of hydrogen, CN, —C(NH)CHR
10
R
11
, nitro, —C(O)R
7
, —C(O)OR
7
, —C(O)NR
7
R
8
, —SO
2
R
7
, C
1
-C
8
-alkyl, C
2
-C
8
-alkenyl, C
2
-C
8
-alkynyl, C
3
-C
8
-cycloalkyl, C
5
-C
8
-cycloalkenyl, aryl, and heteroaryl, wherein
R
7
and R
8
are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; and
R
10
and R
11
are independently selected from the group consisting of hydrogen, C
1
-C
8
-alkyl, C
3
-C
8
-alkenyl, C
3
-C
8
-alkynyl, C
3
-C
8
-cycloalkyl, C
5
-C
8
-cycloalkenyl, aryl, and heteroaryl, or R
10
and R
11
, taken together with the atoms to which they are attached, form an optionally substituted 4-8 membered carbocyclic ring wherein the substituents are selected from the group consisting of C
0
-C
8
-alkyl, C
2
-C
8
-alkenyl, C
2
-C
8
-alkynyl, aryl, and heteroaryl;
(2)—OR
9
, wherein
R
9
is independently selected from the group consisting of C
1
-C
8
-alkyl, C
3
-C
8
-alkenyl, C
3
-C
8
-alkynyl, C
3
-C
8
-cycloalkyl, and C
5
-C
8
-cycloalkenyl;
(3) —NR
10
OR
11
, wherein
R
10
and R
11
are independently selected from the group consisting of hydrogen, C
1
-C
8
-alkyl, C
3
-C
8
-alkenyl, C
3
-C
8
-alkynyl, C
3
-C
8
-cycloalkyl, C
5
-C
8
-cycloalkenyl, aryl, and heteroaryl, or R
10
and R
11
, taken together with the atoms to which they are attached, form an optionally substituted 5-8 membered heterocyclic ring wherein the substituents are selected from the group consisting of C
1
-C
8
-alkyl, C
2
-C
8
-alkenyl, C
2
-C
8
-alkynyl, aryl, and heteroaryl;
(4) —NR
12
NR
13
R
14
, wherein
R
12
, R
13
, and R
14
are independently selected from the group consisting of hydrogen, C
1
-C
8
-alkyl, C
3
-C
8
-alkenyl, C
3
-C
8
-alkynyl, C
3
-C
8
-cycloalkyl, C
5
-C
8
-cycloalkenyl, aryl, and heteroaryl,
or R
12
and R
13
, taken together with the nitrogens to which they are attached, form an optionally substituted 5-8 membered heterocyclic ring, wherein the substituents are selected from the group consisting of C
1
-C
8
-alkyl, C
2
-C
8
-alkenyl, C
2
-C
8
-alkynyl, aryl, and heteroaryl;
or R
13
and R
14
, taken together with the nitrogen to which they are attached, form an optionally substituted 3-8 membered heterocyclic ring or an optionally substituted 5-10 membered heteroaryl ring, wherein the substituents are selected from the group consisting of C
1
-C
8
-alkyl, C
2
-C
8
-alkenyl, C
2
-C
8
-alkynyl, aryl, and heteroaryl;
(5) —NR
5
N═CHR
13a
, wherein
R
15
is independently selected from the group consisting of hydrogen, C
1
-C
8
-alkyl, C
3
-C
8
-alkenyl, C
3
-C
8
-alkyn

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