Carbamate and carbazate ketolide antibiotics

Details Carbamate and carbazate ketolide antibiotics Carbamate and carbazate ketolide antibiotics

1999-12-10

2003-12-16

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S339000, C536S007200, C536S007400, C546S268100

Reexamination Certificate

active

06664238

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 spectrum 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 application number PCT/IB98/00741, filed May 15, 1998, which designates the United States, U.S. Pat. No. 5,527,780, issued Jun. 18, 1996, and U.S. provisional application No. 60/101263 (filed Sep. 22, 1998). U.S. Pat. No. 5,527,780, PCT international application number PCT/IB98/00741, and U.S. provisional application No. 60/101263 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
13
R
14
— or —NR
4
—;
X
2
is ═O or ═NOR
1
;
R
1
is H, methyl or ethyl;
R
2
is —C(R
7
)(R
8
)C(R
9
)(R
10
)C(R
11
)(R
12
)(4-10 membered heterocyclic) or —(CR
7
R
8
)
r
(C
3
-C
7
cycloalkylene)(CR
9
R
10
)
q
(4-10 membered heterocyclic), wherein q and r are each integers independently ranging from 0 to 2, and the heterocyclic moiety of the foregoing groups is substituted by —(CR
4
R
5
)
t
(4-10 membered heterocyclic) or —(CR
4
R
5
)
t
(C
6
-C
10
aryl) wherein t is an integer from 0 to 5, and the aryl and heterocyclic moieties of each of the foregoing groups are optionally substituted by 1 to 4 R
3
groups;
each R
3
is independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R
5
, —C(O)OR
5
, —OC(O)R
5
, —NR
5
C(O)R
4
, —C(O)NR
4
R
5
, —NR
4
R
5
, hydroxy, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
6
-C
10
aryl, 4-10 membered heterocyclic, and C
1
-C
6
alkoxy;
each R
4
and R
5
is independently selected from H and C
1
-C
6
alkyl;
R
6
is H or —C(O)(C
1
-C
6
alkyl);
R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
and R
14
are each independently selected from H, halo and C
1
-C
8
alkyl, provided that (a) where X
1
is —CR
13
R
14
— and R
2
is —C(R
7
)(R
8
)C(R
9
)(R
10
)C(R
11
)(R
12
)(4-10 membered heterocyclic), at least one of R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
and R
14
is halo or C
1
-C
6
alkyl, and (b) where X
1
is —NR
4
— and R
2
is —C(R
7
)(R
8
)C(R
9
)(R
10
)C(R
11
)(R
12
)(4-10 membered heterocyclic), at least one of R
7
, R
8
, R
9
, R
10
, R
11
, and R
12
is halo or C
1
-C
6
alkyl;
or R
7
and R
8
are taken together with the carbon to which each is attached to form a C
3
-C
7
cycloalkyl group and R
9
, R
10
, R
11
, R
12
, R
13
and R
14
are each independently selected from H, halo and C
1
-C
6
alkyl;
or R
9
and R
10
are taken together with the carbon to which each is attached to form a C
3
-C
6
cycloalkyl group and R
7
, R
8
, R
11
, R
12
, R
13
and R
14
are each independently selected from H, halo and C
1
-C
6
alkyl;
or R
11
and R
12
are taken together with the carbon to which each is attached to form a C
3
-C
7
cycloalkyl group and R
7
, R
8
, R
9
, R
10
, R
13
and R
14
are each independently selected from H, halo and C
1
-C
6
alkyl;
R
15
is C
1
-C
6
alkyl; and
R
16
is H or C
1
-C
10
alkyl.
Specific embodiments of the present invention include compounds of formula 1 wherein X
2
is ═NOR
1
, R
15
is methyl, R
16
is ethyl, R
6
is H or acetyl, X
1
is —NR
4
— and R
2
is —C(R
7
)(R
8
)C(R
9
)(R
10
)C(R
11
)(R
12
)(4-10 membered heterocyclic) wherein said heterocyclic group is substituted by 4-10 membered heterocyclic and the foregoing heterocyclic moieties are optionally substituted by 1 or 2 substituents independently selected from halo and C
1
-C
3
alkyl. More specifically, X
1
is —NH— and R
2
is —C(R
7
)(R
8
)C(R
9
)(R
10
)C(R
11
)(R
12
)(4-pyridin-3-yl-imidazol-1-yl), and
(a) R
7
, R
8
, R
9
and R
10
are each H, R
11
is methyl or ethyl, and R
12
is H, methyl or ethyl; or
(b) R
7
, R
8
, R
11
and R
12
are each H, R
9
is methyl or ethyl, and R
10
is H, methyl or ethyl; or
(c) R
9
, R
10
, R
11
and R
12
are each H, R
7
is methyl or ethyl, and R
8
is H, methyl or ethyl.
Specific embodiments of the present invention include the following compounds:
11-Deoxy-5-O-desosaminyl-11-(3,3-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(3(R)-methyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(3(R)-ethyll-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(3(S)-methyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(3(S)-ethyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2-(1-(4-pyridin-3-yl-imidazol-1-yl)-cyclopropyl)-ethyl)hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2-(1-(4-pyridin-3-yl-imidazol-1-yl)-cyclobutyl)-ethyl)hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2,2-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2,2-diethyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2,2-difluro-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2,2-dichloro-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2,2-dibromo-3(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(1-(4-pyridin-3-yl-imidazol-1-yl-methyl)-cyclopropyl)-methyl)hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(1-(4-pyridin-3-yl-imidazol-1-yl-methyl)-cyclobutyl)-methyl)hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2(R)-methyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2(R)-ethyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2(S)-methyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2(S)-ethyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2(R)-fluro-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-des

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