Tricyclic 3-keto derivatives of 6-O-methylerthromycin

Details Tricyclic 3-keto derivatives of 6-O-methylerthromycin Tricyclic 3-keto derivatives of 6-O-methylerthromycin

2000-02-18

2001-06-19

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400

Reexamination Certificate

active

06248719

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to tricyclic 3-keto derivatives of 6-O-methylerythromycin A. The compounds of this invention are useful as antibiotic agents in mammals, including man, as well as in fish and birds. The compounds of the present invention are broad-spectrum macrolide antibiotics that are effective against infections caused by certain gram-positive and gram-negative bacteria as well as protozoa.
Macrolide antibiotics are known to be useful in the treatment of a broad spectrum of bacterial infections and protozoa 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. Additional macrolides are referred to in U.S. patent application Ser. No. 60/063676, filed Oct. 29, 1997 (Yong-Jin Wu), U.S. application Ser. No. 60/063161, filed Oct. 29, 1997 (Yong-Jin Wu), U.S. application Ser. No. 60/054866, filed Aug. 6, 1997(Hiroko Masamune, Yong-Jin Wu, Takushi Kaneko and Paul R. McGuirk), all of which 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 infections and protozoa infections as described below.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
and to pharmaceutically acceptable salts thereof, wherein:
R
1
is selected from H, —(CR
4
R
5
)
m
R
6
, —C(O)(CR
4
R
5
)
m
R
6
, —C(O)O(CR
4
R
5
)
m
R
6
, —C(O)NR
4
(CR
4
R
5
)
m
R
6,
wherein m is an integer ranging from 0 to 6 and both R
4
and R
5
may vary for each iteration where m is greater than 1;
each R
2
and R
3
are independently selected from H and C
1
-C
18
alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents independently selected from the group consisting of —C(O)O(C
1
-C
10
)alkyl, —O(C
1
-C
10
)alkyl, C
1
-C
10
alkanoyl, halo, nitro, cyano, C
1
-C
10
alkyl, 4-10 membered heterocyclic, C
6
-C
10
aryl, —NH(C
1
-C
10
)alkyl, —S(C
1
-C
10
alkyl), —SO(C
1
-C
10
)alkyl, —SO
2
(C
1
-C
10
)alkyl and —SO
2
N(C
1
-C
10
)alkyl, provided that two O atoms, two S atoms or an S and an O atom are not bonded to each other;
each R
4
and R
5
are independently selected from H, halo and C
1
-C
6
alkyl, wherein 1 to 3 carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N and each R
4
and R
5
may vary independently when m is greater than 1, provided that two O atoms, two S atoms or an S and an O atom are not bonded to each other; or
each R
4
and R
5
taken together with the carbon to which they are attached can form a 3-10 membered ring, wherein one or more carbons of said ring are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents independently selected from the group consisting of —C(O)O(C
1
-C
10
)alkyl, —O(C
1
-C
10
)alkyl, C
1
-C
10
alkanoyl, halo, nitro, cyano, C
1
-C
10
alkyl, 4-10 membered heterocyclic, C
6
-C
10
aryl, —NH(C
1
-C
10
)alkyl, —N((C
1
-C
10
)alkyl)
2
, —S(C
1
-C
10
)alkyl, —SO(C
1
-C
10
)alkyl, —SO
2
(C
2
(C
1
-C
10
)alkyl and —SO
2
N(C
1
-C
10
)alkyl, provided that two O atoms, two S atoms or an S and an O atom are not bonded to each other;
R
6
is (C
1
-C
18
)alkyl, a 4-10 membered heterocyclic or C
6
-C
10
aryl, wherein 1 to 3 carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N and said heterocycic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of —C(O)O(C
1
-C
10
)alkyl, —O(C
1
-C
10
)alkyl, C
1
-C
10
alkanoyl, halo, nitro, cyano, (C
1
-C
10
) alkyl, —NH(C
1
-C
10
)alkyl, —N((C
1
-C
10
)alkyl)
2
, —S(C
1
-C
10
alkyl), —SO(C
1
-C
10
)alkyl, —SO
2
(C
1
-C
10
)alkyl and —SO
2
N(C
1
-C
10
)alkyl, provided that two O atoms, two S atoms or an S and an O atom are not bonded to each other; and
R
7
is H, —C(O)O(C
1
-C
18
)alkyl or —C(O)(C
1
-C
18
)alkyl, wherein 1 to 3 carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N and wherein in the alkyl portion of said alkanoyl one or two carbons optionally may be replaced by a heteroatom selected from O, S and N, provided that two O atoms, two S atoms or an S and an O atom are not bonded to each other.
More specific embodiments of this invention include compounds of formula 1 wherein R
7
is H.
More specific embodiments of this invention include compounds of formula 1 wherein R
3
is H.
More specific embodiments of this invention include compounds of formula 1 wherein R
3
=R
2
=H.
More specific embodiments of this invention include compounds of formula 1 wherein R
3
=R
2
=R
7
=H.
Other more specific embodiments of this invention include compounds of formula 1 wherein R
2
is (CH
2
)
m
R
6
, wherein m is an integer ranging from 0 to 6. Specific embodiments of compounds of formula 1 wherein R
2
is (CH
2
)
m
R
6
and wherein m is an integer ranging from 0 to 6 include such compounds wherein R
6
is quinolin-4-yl, quinolin-5-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, 4-pyridin-3-yl-imidazol-1-yl, or imidazo(4,5-b)pyridin-3-yl. More specific embodiments of this invention include compounds of formula 1 wherein R
2
is (CH
2
)
m
R
6
and m is 3. Specific embodiments of compounds of formula 1 wherein R
2
is (CH
2
)
m
R
6
and m is 3 include such compounds wherein R
6
is quinolin-4-yl, quinolin-5-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, 4-pyridin-3-yl-imidazol-1-yl or imidazo(4,5-b)pyridin-3-yl.
Examples of preferred compounds of this invention include:
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-quinolin-4-yl-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=7-methoxy-quinolin-4-yl)-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-benzoimidazol-1-yl-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-indol-1-yl-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-indazol-1-yl-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-carbazol-1-yl-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-(5-phenyl-1H -pyrrol-2-yl)-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-(4-phenyl-imidazol-1-yl)-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-(imidazo(4,5-b)pyridin-3-yl)-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-(4-pyridin-3-yl-imidazol-1-yl)-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-(3-(4-chlorophenyl)-(1,2,4)oxadizol-5-yl)-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-(3-(4-methoxyphenyl)-(1,2,4)oxadizol-5-yl)-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-(3-(4-pyridin-4-yl)-(1,2,4)oxadizol-5-yl)-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-benzotriazol-1-yl-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-benzotriazol-2-yl-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-(1H-indol-3-yl)-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-pyridin-4-yl-propyl;
the compound of formula 1 wherein R
7
=H, R
3
=R
2
=H, R
1
=3-pyridin-3-yl-propyl;
the compound of formula 1 wherein R
7
=H, R
3
&eq

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