Macrolides

Details Macrolides Macrolides

2000-05-23

2002-10-29

Whisenant, Ethan C. (Department: 1655)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200, C536S007400, C536S124000

Reexamination Certificate

active

06472371

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel erythromycins and azalides that are useful as antibacterial agents and antiprotozoa agents and other applications (e.g., anticancer, atherosclerosis, gastric motility reduction, etc.) 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 and 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 sprectrum 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 serial No. 60/063676, filed Oct. 29, 1997 (Yong-Jin Wu), U.S. application serial No. 60/053161, 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. Latavik, Takushi Kaneko and Bingwel V. Yang), U.S. application serial No. 60/049348, filed Jun. 11, 1997 (Brian S. Bronk, Hengmiao Cheng, E. A. Glaser, Michael A, Letavic, Takushi Kaneko and Bingwei V. Yang), International Application No. PCT/GB97/01810 filed Jul. 4, 1997 (Peter Francis Leadlay, James Staunton, 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. 60/070343, filed Jan. 2, 1998, (Diriam), U.S. application serial No. 60/070358, filed Jan. 2, 1998 (Yong-Jin Wu) 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. 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
or a pharmaceutically acceptable salt thereof, wherein:
Y is H, C
1
-C
10
alkyl, C
2
-
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
m
C
8
-C
10
aryl, —(CH
2
)
m
(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the alkyl, alkenyl, aryl, heteroaryl and alkynyl groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
21
, —OC(O)R
21
, —NR
21
C(O)R
22
, —C(O)NR
21
R
22
, —NR
21
R
22
, hydroxy, C
1
-C
6
alkyl, C
1
-C
8
alkoxy, C
6
-C
10
aryl, and 5-10 membered heteroaryl;
R
1
is an alpha-branched C
3
-C
8
alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C
5
-C
8
cycloalkylalkyl group wherein the alkyl group is an alpha-branched C
2
-C
5
alkyl group; a C
3
-C
8
cycloalkyl or C
5
-C
8
cycloalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C
1
-C
4
alkyl groups or halo atoms: or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C
1
-C
4
alkyl groups or halo atoms;
or R
1
is phenyl which may be optionally substituted with at least one substituent selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy and C
1
-C
4
alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano;
or R
1
may be with a formula (a) as shown below:
 wherein X is O, S or —CH
2
—, a, b, c, and d are each independently an integer ranging from 0 to 2 and a+b+c+d≦5;
or R
1
is CH
2
R
24
, wherein R
24
is H, C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C
3
-C
8
cycloalkyl or C
5
-C
8
cyloalkenyl either or which may be optionally substituted by methyl or one or more C
1
-C
4
alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C
1
-C
4
alkyl groups or halo atoms; or a group of the formula SR
23
wherein R
23
is C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C
1
-C
4
alkyl, C
1
-C
4
alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C
1
-C
4
alkyl groups or halo atoms;
R
2
is H or OH;
R
3
is H, OH, or OCH
3
;
R
4
is H, —C(O)R
9
, —C(O)OR
9
, —C(O)NR
9
R
10
or a hydroxy protecting group;
R
5
is —SR
8
, —(CH
2
)
n
C(O)R
8
wherein n is 0 or 1, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, 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 foregoing R
5
groups are optionally substituted by 1 to 3 R
16
groups;
each R
6
and R
7
is independently H, hydroxy, C
1
-C
6
alkoxy, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
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;
each R
8
is independently H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
q
CR
11
R
12
(CH
2
)
r
NR
13
R
14
wherein q and r are each independently an integer ranging from 0 to 3 except q and r are not both 0, —(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 foregoing R
8
groups except H, are optionally substituted by 1 to 3 R
16
groups;
or where R
8
is as —CH
2
NR
8
R
15
, R
15
and R
8
may be taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and —N(R
8
)—, in addition to the nitrogen to which R
15
and R
8
are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1 to 3 R
15
groups;
each R
9
and R
10
is independently H or C
1
-C
6
alkyl;
each R
11
, R
12
, R
13
and R
14
is independently selected from H, C
1
-C
10
alkyl, —(CH
2
)
m
(C
5
-C
10
aryl), and —(CH
2
)
m
(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R
11
, R
12
, R
13
and R
14
groups, except H, are optionally substituted by 1 to 3 R
16
groups;
or R
11
and R
13
are taken together to form —(CH
2
)
p
— wherein p is an integer ranging from 0 to 3 such that a 4-7 membered saturated ring is formed that optionally includes 1 or 2 carbon-carbon double or triple bonds;
or R
13
and R
14
are taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 6-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and —N(R
8
)—, in addition to the nitrogen to which R
13
and R
14
are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted

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