Ketolide antibiotics

Details Ketolide antibiotics Ketolide antibiotics

2002-04-05

2004-12-21

Peselev, Elli (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

Reexamination Certificate

active

06833444

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel macrolide compounds that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds. This invention also relates to pharmaceutical compositions containing the novel compounds and to methods of treating bacterial and protozoal infections in mammals, fish and birds by administering the novel compounds to mammals, fish and birds requiring such treatment.
Macrolide antibiotics are known to be useful in the treatment of a broad sprectrum of bacterial and protozoal infections in mammals, fish and birds. Such antibiotics include various derivatives of erythromycin A such as azithromycin which is commercially available and is referred to in U.S. Pat. Nos. 4,474,768 and 4,517,359, both of which are incorporated herein by reference in their entirety. Other macrolide antibiotics are disclosed and claimed in PCT international published application WO 98/56800 (published Dec. 17, 1998), which designates the United States; U.S. Pat. No. 5,527,780, issued Jun. 18, 1996; U.S. provisional application No. 60/101,263 (filed Sep. 22, 1998)(attorney docket No. PC 10406); U.S. provisional patent application No. 60/111,728 (filed Dec. 10, 1998)(attorney docket No. PC 10494); PCT published application WO 98/01546 (published Jan. 15, 1998); PCT published application WO 98/01571 (published Jan. 15, 1998); EP published application No. 949268 (published Oct. 13, 1999); and U.S. Pat. No. 5,747,467 (issued May 5, 1998). Each of the foregoing United States patents and patent applications and published EP and PCT international patent applications are incorporated herein by reference in their entirety. Like azithromycin and other macrolide antibiotics, the novel macrolide compounds of the present invention possess activity against various bacterial and protozoal infections as described below.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula:
and to pharmaceutically acceptable salts and solvates thereof, wherein:
X
1
is O, —CR
4
R
5
—or —NR
4
—;
X
2
is ═O or ═NOR
1
;
R
1
is H or C
1
-C
10
alkyl, wherein 1 to 3 carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and —N(R
4
)—, and said alkyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of —C(O)O(C
1
-C
10
alkyl), C
1
-C
10
alkoxy, C
1
-C
10
alkanoyl, halo, nitro, cyano, 4-10 membered heterocyclyl, C
1
-C
10
alkyl, —NR
4
R5
5
, C
6
-C
10
aryl, —S(O)
n
(C
1
-C
10
alkyl) wherein n is an integer ranging from 0 to 2, and —SO
2
NR
4
R
5
;
R
2
is —(CR
4
R
5
)
n
(4-10 membered heterocyclic) or —(CR
4
R
5
)
n
(C
6
-C
10
aryl), wherein n is an integer from 0 to 6, from 1 to 3 R
4
or R
5
groups of the —(CR
4
R
5
)
n
—moiety of the foregoing R
2
groups are optionally replaced with a halo substituent, and the heterocyclic and aryl moieties of the foregoing R
2
groups are optionally substituted with 1 to 4 R
3
groups;
each R
3
is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C
1
-C
6
alkoxy, C
1
-C
10
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, —C(O)R
6
, —C(O)OR
6
1
, —OC(O)R
6
, —NR
6
C(O)R
7
, —NR
6
C(O)NR
1
R
7
, —NR
6
C(O)OR
7
, —C(O)NR
6
R
7
, —NR
6
R
7
, —NR
6
OR
7
, —SO
2
NR
6
R
7
, —S(O)
j
(C
1
-C
6
alkyl) wherein j is an integer from 0 to 2, —(CR
1
R
2
)
t
(C
6
-C
10
aryl), —(CR
4
R
5
)
t
(4-10 membered heterocyclic), —(CR
4
R
5
)
q
C(O) (CR
4
R
5
)
t
(C
6
-C
10
aryl), —(CR
4
R
5
)
q
C(O)(CR
4
R
5
)
t
(4-10 membered heterocyclic), —(CR
4
R
5
)
t
O(CR
4
R
5
)
q
(C
6
-C
10
aryl), —(CR
4
R
5
)
t
O(CR
4
R
5
)
q
(4-10 membered heterocyclic), —(CR
4
R
5
)
q
SO
2
(CR
4
R
5
)
t
(C
6
-C
10
aryl), and —(CR
4
R
5
)
q
SO
2
(CR
4
R
5
)
t
(4-10 membered heterocyclic), wherein q and t are each independently an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic moieties of the foregoing R
10
groups are optionally substituted by an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoing R
10
groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR
6
, —C(O)R
6
, —C(O)OR
6
, —OC(O)R
6
, —NR
6
C(O)R
7
, —C(O)NR
6
R
7
, —NR
6
R
7
, —NR
6
OR
7
, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, —(CR
4
R
5
)
t
(C
6
-C
10
aryl), and —(CR
4
R
5
)
t
(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
each R
4
and R
5
is independently selected from H and C
1
-C
6
alkyl;
each R
6
and R
7
is independently selected from H, C
1
-C
6
alkyl, —(CR
4
R
5
)
t
(C
6
-C
10
aryl), and —(CR
4
R
5
)
t
(4-10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted by an oxo (═O) moiety, and the alkyl, aryl and heterocyclic moieties of the foregoing R
6
and R
7
groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, —NR
4
R
5
, trifluoromethyl, trifluoromethoxy, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, hydroxy, and C
1
-C
6
alkoxy;
R
8
is H, —C(O)(C
1
-C
6
alkyl), benzyl, benzyloxycarbonyl or (C
1
-C
6
alkyl)
3
silyl;
R
9
is C
1
-C
6
alkyl;
R
10
is H or C
1
-C
10
alkyl; and
R
11
is selected from chloro, bromo, iodo, fluoro, and cyano;
with the proviso that where X
2
is ═O then the R
11
is cyano or from 1 to 3 R
4
or R
5
groups of the —(CR
4
R
5
)
n
—moiety of the R
2
groups recited above are either C
1
-C
6
alkyl or replaced with a halo substituent.
Specific embodiments of the present invention include compounds of formula 2 (which is a specific embodiment within the genus of formula 1)
wherein R
12
, R
13
, R
14
and R
15
are each independently selected from H, halo, methyl and ethyl. More specific embodiments include the compounds of formula 2 wherein R
14
and R
15
are both H and R
12
and R
13
are each independently selected from H and methyl. In a preferred embodiment of the compounds of formula 2, R
12
, R
13
, R
14
and R
15
are each H.
Other specific embodiments of the present invention include compounds of formula 3 (which is a specific embodiment within the genus of formula 1):
wherein R
12
1
, R
13
, R
14
and R
15
are each independently selected from H, halo, methyl and ethyl with the proviso that at least one of R
12
, R
13
, R
14
and R
15
is not H. More specific embodiments include the compounds of formula 3 wherein R
14
and R
15
are both H, R
12
is methyl, and R
13
is selected from H and methyl.
The invention also relates to a pharmaceutical composition for the treatment of a bacterial infection or a protozoa infection, or a disorder related to a bacterial or protozoal infection, in a mammal, fish, or bird, which comprises a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
The invention also relates to a method of treating a bacterial infection or a protozoa infection, or a disorder related to a bacterial or protozoal infection, in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof.
The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, refers to the act of treating, as “treating” is defined immediately above.
As used herein, unless otherwise indicated, the terms or phrases “bacterial infection(s)”, “protozoal infection(s)”, and “disorders related to bacterial infections or protozoal infections” include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by
Streptococcus pn

Affiliated with

Also associated with

Rating

Ketolide antibiotics does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Ketolide antibiotics, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Ketolide antibiotics will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3279918