9a, 11b-dehydro derivatives of 9-oxime-3-keto-6-O-...

Details 9a, 11b-dehydro derivatives of 9-oxime-3-keto-6-O-... 9a, 11b-dehydro derivatives of 9-oxime-3-keto-6-O-...

2001-02-27

2002-11-19

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400, C536S018500

Reexamination Certificate

active

06482801

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel 9a,11b-dehydro derivatives of 9-oxime-3-keto-6-O-methylerythromycin A, 11,12-carbazate. 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. patent application Ser. No. 60/063161, filed Oct. 29, 1997 (Yong-Jin Wu), U.S. patent 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 potent 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 H, —C(O)(CR
3
R
4
)
m
R
2
, —C(O)O(CR
3
R
4
)
m
R
2
, —C(O)N(R
3
)(CR
3
R
4
)
m
R
2
, or —CR
3
R
4
)
m
R
2
, wherein m is as integer ranging from 0 to 6 and both R
3
and R
4
may vary for each iteration where m is greater than 1;
each R
3
and R
4
is independently selected from H, halogen, or C
1
-C
6
alkyl, or R
3
and R
4
toegether with the carbon to which they are attached form a 3-10 membered cycloalkyl group, wherein 1 to 3 carbons of said alkyl or cycloalkyl are optionally replaced by a heteroatom selected from O, S and N and said cycloalkyl group is 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
-
10
alkanoyl, halo, nitro, cyano, C
1
-
10
alkyl, —N(C
1
-
10
)alkyl, —S(C
1
-C
10
)alkyl, —SO(C
1
-
10
)alkyl, —SO
2
(C
1
-C
10
)alkyl, —SO
2
N(C
1
-C
10
)alkyl, —NHC(O)C
1
-
10
alkyl and —NHC(O)N(C
1
-
10
)alkyl;
R
2
is a C
1
-
18
alkyl, a 4-10 membered heterocyclic group 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 heterocyclic 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, —N(C
1
-C
10
)alkyl, —S(C
1
-C
10
)alkyl, —SO(C
1
-C
10
)alkyl, —SO
2
(C
1
-C
10
)alkyl, —SO
2
N(C
1
-C
10
)alkyl, —NHC(O)C
1
-C
10
alkyl and —NHC(O)N(C
1
-C
10
)alkyl; and
R
5
is H, —C(O)O(C
1
-C
18
)alkyl, or C
1
-C
18
alkanoyl 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.
Other more specific embodiments of this invention include compounds of formula 1 wherein R
1
is —(CH
2
)
m
R
2
, wherein m is 3 and R
2
is a 4-10 membered heterocyclic group.
Specific embodiments of R
2
include quinolin-4-yl, 4-phenyl-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, and 4-pyridin-3-yl-imidazol-1-yl.
Examples of preferred compounds of this invention include:
the compound of formula 1 wherein R
5
=H, R
1
=3-quinolin-4-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=7-methoxy-quinolin-4-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-benzoimidazol-1-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-indol-1-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-indazol-1-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-carbazol-1-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-(5-phenyl-1H-pyrrol-2-yl)-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-(4-phenyl-imidazol-1-yl)-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-(4,5-b)-pyridin-3-yl-imidazol-1-yl)-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-(imidazo(4,5-b)pyridin-3-yl)-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-(3-(4-chlorophenyl)-(1,2,4)oxadizol-5-yl)-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-(3-(4-methoxyphenyl)-(1,2,4)oxadizol-5-yl)-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-(3-(4-pyridin-4-yl)-(1,2,4)oxadizol-5-yl)-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-benzotrizol-1-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-benzotrizol-2-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-(1H-indol-3-yl)-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-pyridin-4-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-pyridin-3-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-pyridin-2-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-phenylpropyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-(2-methoxyphenyl)-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-furan-2-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-thiophen-2-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-thiophen-2-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-pyrrol-1-yl-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=-(3-(2-pyridin-3-yl-thiazol-4-yl)-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-(2-phenyl-thiazol-5-yl)-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=-(3-(2-phenyl-thiazol-5-yl)-propyl;
the compound of formula 1 wherein R
5
=H, R
1
=3-(4-phenyl-1H-imidazol-2-yl)-propyl; and
the pharmaceutically acceptable salts of the foregoing compounds.
The invention also relates to a pharmaceutical composition for the treatment of a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formula 1 and a pharmaceutically acceptable carrier.
The invention also relates to a method of treating a bacterial infection or a protozoa 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.
The term “treatment”, as used herein, unless otherwise indicated, includes the treatment or prevention of a bacterial infection or protozoa infection as provided in the method of the present invention.
As used herein, unless otherwise indicated, the term “bacterial infection(s)” or “protozoa infection” includes bacterial infections and protozoa infections that occur in mammals, fish and birds as well as disorders related to bacterial infections and protozoa infections that may be treated or prevented by administering antibiotics such as the compounds of the present invention. Such bacterial infections and protozoa infections and disorders related to such infections include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by
Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus
, or Peptostreptococcus spp.; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by
Streptococcus pyogenes

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