6-O-carbamoyl ketolide antibacterials

Details 6-O-carbamoyl ketolide antibacterials 6-O-carbamoyl ketolide antibacterials

2001-12-05

2003-09-02

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007100, C536S018500

Reexamination Certificate

active

06613747

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, No. 5,561,118, and 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.
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.
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.
WO 00/75156 (Phan et al.) discloses 6-O-carbamate ketolide derivatives that are useful as antibacterials for the treatment and prevention of infections in a mammal.
SUMMARY OF THE INVENTION
The invention provides compounds of Formula 1:
Wherein
R
1
and R
2
are independently selected from hydrogen, optionally substituted —CR
f
R
g
(C
1
-C
8
)alkyl, optionally substituted —CR
f
R
g
(C
2
-C
8
)alkenyl, optionally substituted —CR
f
R
g
(C
2
-C
8
)alkynyl, optionally substituted cycloalkyl, and optionally substituted (C
5
-C
7
)-cycloalkenyl, provided that R
1
and R
2
are not both hydrogen, wherein the substituents are 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; and
R
f
and R
g
are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, COOR
a
, and CONR
a
R
b
;
or R
1
and R
2
, together with the nitrogen atom to which they are attached, form an optionally substituted nitrogen-containing heterocycle, wherein the substituents are 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
;
R
3
is hydrogen or —W—V, wherein
W is selected from the group consisting of (a) —NH—(CH
2
)
p
—, (b) —(CH
2
)
q
—, (c) —O—(CH
2
)
r
—, (d) —NH—C
1
-C
6
alkenyl-, (e) —C
1
-C
6
alkenyl-, (f) —O—C
1
-C
6
alkenyl-, (g) —NH—C
1
-C
6
alkynyl-, (h) —C
1
-C
6
alkynyl-, and (i) —O—C
1
-C
6
alkynyl-;
p is 0 to 5;
q is 0 to 5; and
r is 0 to 5;
and
V is selected from the group consisting of (a) hydrogen, (b) aryl, (c) substituted aryl, (d) heteroaryl, (e) substituted heteroaryl, and (f) Ar
1
—Ar
2
, wherein Ar
1
and Ar
2
are independently selected from the group consisting of (i) aryl, (ii) substituted aryl, (iii) heteroaryl, and (iv) substituted heteroaryl;
R
4
is selected from hydrogen, halogen, and hydroxy;
R
5
is hydrogen or a hydroxy protecting group;
R
6
is selected from hydrogen, 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;
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
Y and Y′, together with the carbon atom to which they are attached, form C═O, —CHOH, C═NR
c
, or C═NOR
c
, wherein R
c
is independently selected from hydrogen, alkyl, alkenyl and alkynyl;
or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt, esters or pro-drugs thereof.
Compounds of the above formula are useful as antibacterial agents for the treatment of bacterial infections in a subject such as human and animal.
The present invention is also directed to a method of treating a subject having a condition caused by or contributed to by bacterial infection, which comprises administering to said subject a therapeutically effective amount of the compound of Formula 1.
The present invention is further directed to a method of preventing a subject from suffering from a condition caused by or contributed to by bacterial infection, which comprises administering to the subject a prophylactically effective amount of the compound of Formula 1.
Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing specification.
DETAILED DESCRIPTION
Relative to the above description, certain definitions apply as follows.
Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
Unless specified otherwise, the terms “alkyl”, “alkenyl”, and “alkynyl,” whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, or any number within this range. The term “alkyl” refers to straight or branched chain hydrocarbons. “Alkenyl” refers to a straight or branched chain hydrocarbon with at least one carbon—carbon double bond. “Alkynyl” refers to a straight or branched chain hydrocarbon with at least one carbon—carbon triple bound. For example, alkyl radicals include

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