3-descladinosyl-6-O-carbamoyl and 6-O-carbonoyl macrolide...

Details 3-descladinosyl-6-O-carbamoyl and 6-O-carbonoyl macrolide... 3-descladinosyl-6-O-carbamoyl and 6-O-carbonoyl macrolide...

2003-05-28

2004-11-30

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007300, C536S007400

Reexamination Certificate

active

06825172

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. No. 5,444,051, U.S. Pat. No. 5,561,118, and U.S. Pat. No. 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.
U.S. Pat. No. 6,169,168 to Asaka et al. discloses erythromycin A derivatives stated to “have a strong antibacterial activity not only against sensitive bacteria but also resistant bacteria.”
WO 98/23628 (Asaka et al.) discloses erythromycin A derivatives stated to have “a potent antibacterial activity against not only conventional erythromycin-sensitive bacteria but also erythromycin-resistant bacteria.”
WO 99/11651 (Or et al.) discloses 3-descladinose 6-O-substituded erythromycin derivatives for treating bacterial infections.
WO 99/21869 and WO 99/21870 (both to Asaka et al.) discloses erythromycin A derivatives stated to have “a strong antibacterial activity against not only erythromycin-sensitive bacteria but also erythromycin-resistant bacteria.”
WO 00/12522 (Randolph et al.) discloses 3′-N-desmethyl-3′-N-substituted-6-O-methyl-11,12-cyclic carbamate erythrolide A derivatives as antagonists of luteinizing hormone-releasing hormone.
WO 00/75156 (Phan et al.) discloses 6-O-carbamate ketolide compounds stated to be useful for treatment and prevention of infections in a mammal.
EP 1146051 (Kaneko et al.) discloses erythromycin A and ketolide derivatives useful for the treatment of a bacterial or protozoal infection in a mammal.
WO 02/12260 (Chen et al.) discloses 3-O-acyl macrolide antibioitic derivatives useful for the treatment of a bacterial or protozoal infection in a mammal.
WO 01/10878 (Asaka et al.) discloses erythromycin derivatives stated to be “characterized by an acyl group introduced at the 3-position, a cyclic carbamate structure fused at the 11- and 12-positions, and a five-membered heterocycle on the 11-position substituent, one of the nitrogen atoms of which is bonded to the 11-position nitrogen atom through an alkyl group.”
WO 01/10880 (Asaka et al.) discloses erythromycin derivatives stated to be “characterized by an acyl group introduced at the 3-position, a cyclic carbamate structure fused at the 11- and 12-positions, and a fused ring composed of a five-membered nitrogenous heterocycle and a five- or six-membered ring, one of the nitrogen atoms of which is bonded to the carbamate nitrogen atom through a C2-C6 alkyl group.”
WO 02/26753 (Kato et al.) discloses erythromycin A derivatives as antimicrobial agents.
Asaka et al. discloses 3-O-acyl-5-O-desosaminylerythronolide-11,12-carbamates stated to show antibacterial activities (Structure-Activity Studies Leading to Potent Acylides: 3-O-Acyl-5-O-desosaminylerythronolide-11,12-carbamates. In: 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, Calif. (1999):2159).
SUMMARY OF THE INVENTION
The invention provides compounds of Formula 1:
wherein
R
1
is selected from hydrogen, optionally substituted C
1
-C
8
-alkyl, optionally substituted C
2
-C
8
-alkenyl, and optionally substituted C
2
-C
8
-alkynyl, wherein the substituents are independently selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, —COOR
a
, —OCOR
a
, —OR
a
, —SR
a
, —SOR
a
, —SO
2
R
a
, —NR
a
R
b
, —CONR
a
R
b
, —OCONR
a
R
b
, —NHCOR
a
, —NHCOOR
a
, and —NHCONR
a
R
b
, wherein R
a
and R
b
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl;
R
2
is selected from hydrogen, alkoxy, optionally substituted C
1
-C
8
-alkyl, optionally substituted C
2
-C
8
-alkenyl, and optionally substituted C
2
-C
8
-alkynyl, wherein the substituents are independently selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, —COOR
a
, —OCOR
a
, —OR
a
, —SR
a
, —SOR
a
, —SO
2
R
a
, —NR
a
R
b
, —CONR
a
R
b
, —OCONR
a
R
b
, —NHCOR
a
, —NHCOOR
a
, and —NHCONR
a
R
b
, wherein R
a
and R
b
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl;
R
3
is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R
4
is hydrogen or a hydroxy protecting group;
R
5
is selected from hydrogen, C
1
-C
8
-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;
L is absent or C(O);
W is NH or O;
X and X′, together with the carbon atom to which they are attached, form C═O, C═NR
c
, or C═NOR
c
, wherein R
c
is independently selected from hydrogen, alkyl, alkenyl and alkynyl; and
Z is selected from C(O), C(O)—O, C(O)—NR
2
, and SO
2
; and
R
6
is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted C
1
-C
8
-alkyl, optionally substituted C
2
-C
8
-alkenyl, and optionally substituted C
2
-C
8
-alkynyl, wherein the substituents are selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, alkoxyimino, aryl, heteroaryl, heterocyclo, CN, nitro, —COOR
a
, —OCOR
a
, —OR
a
, —SR
a
, —SOR
a
, —SO
2
R
a
, —NR
a
R
b
, —CONR
a
R
b
, —OCONR
a
R
b
, —NHCOR
a
, —NHCOOR
a
, and —NHCONR
a
R
b
, wherein R
a
and R
b
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl, or NR
2

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