Ketolide antibiotics

Details Ketolide antibiotics Ketolide antibiotics

2001-02-26

2003-04-29

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400

Reexamination Certificate

active

06555524

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to 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 compounds, and to methods of treating bacterial and protozoal infections by administering the compounds.
Macrolide antibiotics are known to be useful in the treatment of a broad spectrum of bacterial and protozoal infections in mammals, fish and birds. Such antibiotics include derivatives of erythromycin A such as azithromycin, which is commercially available and is referred to in U.S. Pat. No. 4,474,768, issued Oct. 2, 1984, and U.S. Pat. No. 4,517,359, issued May 14, 1985. Other macrolide antibiotics are referred to in PCT published application WO 98/56800 (published Dec. 17, 1998); U.S. Pat. No. 5,527,780, issued Jun. 18, 1996; PCT application Ser. No. PCT/IB99/01502, filed Sep. 3, 1999; United States provisional patent application Ser. No. 60/111,728 (filed Dec. 10, 1998); PCT published application WO 98/01546 (published Jan. 15, 1998); PCT published application WO 98/01571 (published Jan. 15,1998); EP published application 949268 (published Oct. 13, 1999); U.S. Pat. No. 5,747,467 (issued May 5, 1998); and United States provisional patent application Ser. No. 60/117,342, filed Jan. 27, 1999. Each of the foregoing United States patents and patent applications and EP and PCT patent applications is incorporated by reference herein in its entirety.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
and to pharmaceutically acceptable salts, prodrugs, and solvates thereof, wherein:
X
1
is O, —CR
4
R
5
— or —NR
4
—;
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 to 10 membered heterocyclic, 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 to 10 membered heterocyclic) or —(CR
4
R
5
)
n
(C
6
-C
10
aryl), wherein n is an integer from 0 to 6, and wherein 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
, —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 0.2, —(CR
1
R
2
)
t
(C
6
-C
10
aryl), —(CR
4
R
5
)
t
(4 to 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 to 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 to 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 to 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
3
groups are optionally substituted by an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoing R
3
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 to 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, or R
4
and R
5
taken together form a C
3
-C
7
carbocyclic or 4 to 10 membered heterocyclic ring;
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 to 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 H, C
1
-C
10
alkyl; C
2
-C
4
alkenyl; or C
2
-C
4
alkynyl; and
R
10
is selected from chloro, bromo, iodo, fluoro, and cyano.
Specific embodiments of the present invention include compounds of formula 2 (which is a specific embodiment within the genus of formula 1)
wherein R
11
, R
12
R
13
and R
14
are each independently selected from H, halo, methyl and ethyl. More specific embodiments include the compounds of formula 2 wherein R
13
and R
14
are both H and R
11
, and R
12
are each independently selected from H and methyl. In a preferred embodiment of the compounds of formula 2, R
11
, R
12
, R
13
and R
14
are each H.
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.
DETAILED DESCRIPTION OF THE INVENTION
All patents, patent applications, and journal publications cited herein are hereby incorporated by reference in their entireties.
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 pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Enterococcus faecalis, E. faecium, E. casselflavus, S. epidermidis, S. haemolyticus
, or Peptostreptococcus spp.; pharyngitis, rheumatic fever, and glomerulonephritis related to infection by
Streptococcus pyogenes
, Groups C and G streptococci,
Corynebacterium diphtheriae
, or
Actinobacillus haemolyticum
; respiratory tract infections related to infection by
Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae
, or
Chlamydia pneumoniae
; blood and tissue infections, including endocarditis and osteomyelitis, caused by
S. aureus, S. haemolyticus, E. faecalis, E. faecium, E. durans
, including strains resistant to known antibacterials such as, but not limited

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