13-membered azalides and their use as antibiotic agents

Details 13-membered azalides and their use as antibiotic agents 13-membered azalides and their use as antibiotic agents

1999-11-18

2001-12-11

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S029000, C536S007200, C536S007400

Reexamination Certificate

active

06329345

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel 13-membered azalides that are useful as antibacterial and antiprotozoa 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 infections and protozoa 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 infections and protozoa infections in mammals, fish and birds. Such antibiotics include various derivatives of erythromycin A, such as azithromycin. Azithromycin 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 serial No. 60/063676, filed Oct. 29, 1997 (Yong-Jin Wu), U.S. application serial No. 60/063161, filed Oct. 29, 1997 (Yong- Jin Wu), U.S. application serial No. 60/054866, filed Aug. 6, 1997 (Hiroko Masamune, Yong-Jin Wu, Takushi Kaneko and Paul R. McGuirk), U.S. application serial No. 60/049980, filed Jun. 11, 1997 (Brian S. Bronk, Michael A. Letavic, Takushi Kaneko and Bingwei V. Yang), International Application No. PCT/IB98/00839, filed May 29, 1998 (Brian S. Bronk, Hengmiao Cheng, E. A. Glazer, Michael A. Letavic, Takushi Kaneko and Bingwei V. Yang), U.S. application serial No. 60/049348, filed Jun. 11, 1997 (Brian S. Bronk, Hengmiao Cheng, E. A. Glazer, Michael A. Letavic, Takushi Kaneko and Bingwei V. Yang), International Application No. PCT/GB97/01810 filed Jul. 4, 1997 (Peter Francis Leadlay, James Stauton, Jesus Cortes and Michael Stephen Pacey), International Application No. PCT/GB97/01819 filed Jul. 4, 1997 (Peter Francis Leadlay, James Staunton, and Jesus Cortes), U.S. application serial No., 60/070358, filed Jan. 2, 1998 (Yong-Jin Wu), U.S. application serial No. 60/070343, filed Jan. 2, 1998 (Dirlam) and U.S. application serial No. 60/097075, filed Aug. 19, 1998 (Hengmiao Cheng, Michael A. Letavic, Carl B. Ziegler, Jason K. Dutra, Brian S. Bronk), all of which are incorporated herein by reference in their entirety.
Without admitting that the above cited patents and patent applications are prior art to the present application, there remains a need in the art for readily available, 13-membered azalide antibiotic compounds that possess potent activity against a broad range of bacteria and protozoa.
Like azithromycin and other macrolide antibiotics, the novel macrolide compounds of the present invention possess potent activity against various bacterial and protozoa infections as described below.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula 1
or a pharmaceutically acceptable salt thereof, wherein:
acetyl, 3-N,N-dimethylamino-2-propenoyl,
1-N-methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N-(3-hydroxybenzyl)-3-pyrazolyl, 3-isoxazolyl,
R
2
is hydrogen or C
1
-C
4
alkyl;
R
3
is hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
m
(C
6
-C
10
aryl), -(CH
2
)
m
(C
6
-C
10
heterocyclic) or aryl, each, other than hydrogen, being optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, —C(O)C
1
-C
10
alkyl, —C(O)C
2
-C
10
alkenyl, —C(O)C
2
-C
10
alkynyl, —OC(O)C
1
-C
10
alkyl, —OC(O)C
2
-C
10
alkenyl, —OC(O)C
2
-C
10
alkynyl, —N(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl)C(O)(C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl), —C(O)N(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl)(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl), —N(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl)(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl), C
1
-C
10
alkoxy, C
6
-C
10
aryl, 5-10 membered heterocyclic, hydroxyl, methoxyl, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylethyl and 4-pyridylethyl;
m is an integer ranging from 0 to 4;
each R
4
is hydrogen, —(CH
2
)
m
(C
6
-C
10
aryl) or —(CH
2
)
m
(C
6
-C
10
heterocyclic), each, other than hydrogen, being optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)C
1
-C
10
alkyl, —C(O)C
2
-C
10
alkenyl, —C(O)C
2
-C
10
alkynyl, —OC(O)C
1
-C
10
alkyl, —OC(O)C
2
-C
10
alkenyl, —OC(O)C
2
-C
10
alkynyl, —N(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl)C(O)(C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl), —C(O)N(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl)(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl), —N(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, or C
2
-C
10
alkynyl)(hydrogen, C
1-
10
alkyl, C
1
-C
10
alkenyl or C
2
-C
10
alkynyl), C
1
-C
10
alkoxy, C
6
-C
10
aryl and 5-10 membered heterocyclic;
n is an integer from 0 to 5;
R
6
is hydrogen or methyl;
each R
7
is independently hydrogen, C
1
-C
20
alkyl, C
2
-C
20
alkenyl, C
2
-C
20
alkynyl, —(O)C
1
-C
20
alkyl, —C(O)C
2
-C
20
alkenyl, —C(O)C
2
-C
20
alkynyl, —C(O)N(H)C
1
-C
10
alkyl, —C(O)N(H)C
2
C
20
alkenyl, —C(O)N(H)C
2
-C
20
alkynyl, —SO
2
(O)C
1
-C
20
alkyl, —SO
2
(O)C
2
-C
20
alkenyl, —SO
2
(O)C
2
-C
20
alkynyl or —PO
4
2−
;
R
8
is hydrogen or methyl;
R
9
is
or 4″-oxocladinosyl; and
R
12
is C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, cyano, —CH
2
S(O)
p
C
10
-C
10
alkyl, —CH
2
S(O)
p
C
2
-C
10
alkenyl, —CH
2
S(O)
p
C
2
-C
10
alkynyl, wherein p is an integer ranging from 0 to 2, —CH
2
O(C
1
-C
10
alkyl), —CH
2
O(C
2
-C
10
alkenyl), —CH
2
O(C
2
-C
10
alkynyl), —CH
2
N(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl)(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl), —(CH
2
)
m
(C
6
-C
10
aryl) or —(CH
2
)
m
(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the foregoing are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)C
1
-C
10
alkyl, —C(O)C
2
-C
10
alkenyl, —C(O)C
2
-C
10
alkynyl, —OC(O)C
1
-C
10
alkyl, —OC(O)C
2
-C
10
alkenyl, —OC(O)C
2
-C
10
alkynyl, —N(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl)C(O)(C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl), —C(O)N(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl)(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl), —N(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl)(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl), C
1
-C
10
alkoxy, C
6
-C
10
aryl or 5-10 membered heterocyclic, hydroxy, C
1
-C
6
alkyl, C
2
-C
6
alkoxy, C
6
-C
10
aryl and 5-10 membered heteroaryl.
The present invention further relates to a compound of the formula 15
or a pharmaceutically acceptable salt thereof, wherein:
acetyl, 3-N,N-dimethylamino-2-propenoyl,
1-N-methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N-(3-hydroxybenzyl)-3-pyrazolyl, 3-isoxazolyl,
R
2
is hydrogen or C
1
-C
4
alkyl;
R
3
is hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
m
(C
6
-C
10
aryl), —(CH
2
)
m
(C
6
-C
10
heterocyclic) or aryl, each, other than hydrogen, being optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, —C(O)C
1
-C
10
alkyl, —C(O)C
2
-C
10
alkenyl, —C(O)C
2
-C
10
alkynyl, —OC(O)C
1
-C
10
alkyl, —OC(O)C
2
-C
10
alkenyl, —OC(O)C
2
-C
10
alkynyl, —N(hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
2
-C
10
alkynyl)C(

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