Methods of making macrolides

Details Methods of making macrolides Methods of making macrolides

2002-08-23

2004-04-27

Peselev, Elli (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S018500

Reexamination Certificate

active

06727352

ABSTRACT:

FIELD OF THE INVENTION
The invention is directed to novel macrolide derivatives, pharmaceutical compositions comprising them, and methods of using them in the treatment or prevention of, for example, bacterial or protozoa infections in mammals, fish, or birds.
BACKGROUND OF THE INVENTION
Macrolide antibiotics that can be used in the treatment or prevention of bacterial or protozoa infections in mammals, fish, or birds 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. Examples of additional macrolides are disclosed in: U.S. patent application Ser. No. 09/424,104, filed May 29, 1998 (Brian S. Bronk, Michael A. Letavic, Takushi Kaneko, Bingwei V. Yang, E. A. Glazer, and Hengmiao Cheng); WO 98/01571 (Peter Francis Leadlay, James Staunton, Jesus Cortes and Michael Stephen Pacey); WO 98/01546 (Peter Francis Leadlay, James Staunton, and Jesus Cortes); U.S. patent application Ser. No. 09/554,988, filed Dec. 21, 1998 (John P. Dirlam); U.S. Pat. No. 6,043,227, issued Mar. 28, 2000; and WO 98/09978, all of which are incorporated herein by reference.
SUMMARY OF THE INVENTION
This invention is directed to novel compounds of Formula 1:
and to pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein:
X is —CH
2
NR
7
— or —NR
7
CHR
6
—, wherein the first dash of each of the foregoing X groups is attached to Y and the last dash of each of the foregoing X groups is attached to the C-8 carbon;
Y is —CH(CH
3
)—;
or X, Y, and R
3
can be taken together to form the moiety of Formula a
Z is selected from the group consisting of —C(O)—, —CH(—OR
8
)—, and the moiety of Formula b
R
1
is H or a hydroxy protecting group;
R
2
is —OR
13
, or R
2
and R
3
are taken together to form the moiety of Formula c
or if X is —NR
7
CHR
6
—, R
2
and R
6
can be taken together to form the moiety of Formula d
R
3
is —OC(O)R
14
, or R
3
, X, and Y are taken together to form the moiety of Formula a, or R
3
and R
2
are taken together to form the moiety of Formula c;
R
4
is —OR
15
;
R
5
is an alpha-branched C
2
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, C
2
-C
8
alkoxyalkyl, or C
2
-C
8
alkylthioalkyl group optionally substituted with at least one hydroxyl group; an alpha-branched C
2
-C
5
alkyl group attached to a C
5
-C
8
cycloalkyl group; a C
3
-C
8
cycloalkyl or cycloalkenyl group optionally substituted with at least one moiety selected from the group consisting of methyl, hydroxyl, halo, and C
1
-C
4
alkyl groups; or a 3-6 membered saturated, or fully or partially unsaturated, heterocycle comprising at least one atom of oxygen or sulphur and optionally substituted with one or more C
1
-C
4
alkyl groups or halogen atoms;
R
6
is H, or if X is —NR
7
CHR
6
—, R
6
and R
2
can be taken together to form the moiety of Formula d;
R
7
is selected from the group consisting of H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(5-10 membered heteroaryl), wherein the alkyl, alkenyl, aryl, heteroaryl, and alkynyl moieties of the foregoing R
7
groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
11
, —OC(O)R
11
, —NR
11
C(O)R
12
, —C(O)NR
11
R
12
, —NR
11
R
12
, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
6
-C
10
aryl, and 5-10 membered heteroaryl;
R
8
is selected from the group consisting of H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —C(O)R
17
, —C(O)NR
17
R
18
, —(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, aryl, and heteroaryl moieties of the foregoing R
8
groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
11
, —OC(O)R
11
, —NR
11
C(O)R
12
, —C(O)NR
11
R
12
, —NR
11
R
12
, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
6
-C
10
aryl, and 5-10 membered heteroaryl;
R
9
is hydroxy;
R
10
is selected from the group consisting of H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, cyano, —CH
2
S(O)
n
R
11
, —CH
2
OR
11
, —CH
2
NR
11
R
12
, —(CH
2
)
m
(C
6
-C
8
aryl), and —(CH
2
)
m
(5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, aryl, and heteroaryl moieties of the foregoing R
10
groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
11
, —OC(O)R
11
, —NR
11
C(O)R
12
, —C(O)NR
11
R
12
, —NR
11
R
12
, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
6
-C
10
aryl, and 5-10 membered heteroaryl;
each R
1
and R
12
is independently selected from the group consisting of H, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, (CH
2
)
m
(C
6
-C
10
aryl), (CH
2
)
m
(5-10 membered heteroaryl), and C
2
-C
10
alkynyl, wherein the alkyl, alkenyl, aryl, heteroaryl, and alkynyl moieties of the foregoing R
11
and R
12
groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
R
13
is selected from the group consisting of H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —R
16
(C
6
-C
10
aryl), and —R
16
(5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, aryl, and heteroaryl moieties of the foregoing R
13
groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
11
, —OC(O)R
11
, —NR
11
C(O)R
12
, —C(O)NR
11
R
12
, —NR
11
R
12
, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
6
-C
10
aryl, and 5-10 membered heteroaryl;
R
14
is selected from the group consisting of C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(5-10 membered heteroaryl), wherein the alkyl, alkenyl, aryl, heteroaryl, and alkynyl moieties of the foregoing R
14
groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
11
, —OC(O)R
11
, —NR
11
C(O)R
12
, —C(O)NR
11
R
12
, —NR
11
R
12
, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
6
-C
10
aryl, and 5-10 membered heteroaryl;
each R
15
is independently selected from the group consisting of H, C
1
-C
10
alkyl, C
2
-C
10
-alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, aryl, and heteroaryl moieties of the foregoing R
15
groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
11
—OC(O)R
11
, —NR
11
C(O)R
12
, —C(O)NR
11
R
12
, —NR
11
R
12
, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
6
-C
10
aryl, and 5-10 membered heteroaryl;
R
16
is selected from the group consisting of C
1
-C
6
alkyl, C
3
-C
6
alkenyl, and C
3
-C
6
alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the foregoing R
16
groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
11
, —OC(O)R
11
, —NR
11
C(O)R
12
, —C(O)NR
11
R
12
, —NR
11
R
12
, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
6
-C
10
aryl, and 5-10 membered heteroaryl, and wherein at least one carbon atom of each of the foregoing R
16
groups can optionally be replaced with 1 to 3 atoms or moieties independently selected from group consisting of O, N(R
15
), and S;
each of R
17
and R
18
is independently selected from the group consisting of H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, aryl, and heteroaryl moieties of the foregoing R
17
and R
18
groups are optionally subs

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