C-4″-substituted macrolide derivatives

Details C-4″-substituted macrolide derivatives C-4″-substituted macrolide derivatives

2002-02-26

2003-06-10

Peselev, Elli (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S018500

Reexamination Certificate

active

06576749

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel C-4″ substituted macrolide derivatives 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 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 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. 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 compounds of the formula
and to pharmaceutically acceptable salts thereof, wherein:
X is —CH(NR
9
R
10
)—, —C(O)—, —C(=NOR
9
—, or —N(C
1
-C
8
alkyl)CH
2
— wherein the first dash of each of the foregoing X groups is attached to the C-10 carbon of the compound of formula 1 and the last dash of each group is attached to the C-8 carbon of the of the compound of formula 1;
R
1
is H, hydroxy or methoxy;
R
2
is hydroxy;
R
3
is C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, cyano, —CH
2
S(O)
n
R
8
wherein n is an integer ranging from 0 to 2, —CH
2
OR
8
, —CH
2
N(OR
9
)R
8
, —CH
2
NR
8
R
15
, —(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
3
groups are optionally substituted by 1 to 3 R
16
groups;
or R
2
and R
3
are taken together to form an oxazolyl ring as shown below
R
4
is H, —C(O)R
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 saturated 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
16
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
6
-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 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
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 by 1 to 3 R
16
groups;
R
15
is H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, or C
2
-C
10
alkynyl, wherein the foregoing R
15
groups are optionally substituted by 1 to 3 substituents independently selected from halo and —OR
9
;
each R
16
is independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
17
, —C(O)OR
17
, —C(O)OR
17
, —OC(O)OR
17
, —NR
6
R
7
, —NR
6
R
7
, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein said aryl and heteroaryl substituents are optionally substituted by 1 or 2 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
17
, —C(O)OR
17
, —C(O)OR
17
, —OC(O)OR
17
, —NR
6
C(O)R
7
, —C(O)NR
6
R
7
, —NR
6
R
7
, hydroxy, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
each R
17
is independently selected from 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 m is an integer ranging from 0 to 4;
with the proviso that r
8
is not H where R
3
is —CH
2
S(O)
n
R
8
.
Preferred compounds of formula 1 include those wherein R
1
is hydroxy, R
2
is hydroxy, R
3
is —CH
2
NR
8
R
15
or —CH
2
SR
8
, and R
4
is H.
Other preferred compounds of formula 1 include those wherein R
1
is hydroxy, R
2
is hydroxy, R
3
is —CH
2
NR
8
R
15
, R
4
is H, R
15
and R
8
are each selected from H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, and C
2
-C
10
alkynyl, wherein said R
15
and R
8
groups, except H, are optionally substituted by 1 or 2 substituents independently selected form hydroxy, halo and C
1
-C
6
alkoxy. Specific preferred compounds having the foregoing general structure include those wherein R
15
is either H or is selected from the following groups from which R
8
is also independently selected: methyl, ethyl, allyl, n-butyl, isobutyl, 2-methoxyethyl, cyclopentyl, 3-methoxypropyl, 3-ethoxypropyl, n-propyl, isopropyl, 2-hydroxyethyl, cyclopropyl, 2,2,2-trifluoroethyl, 2-propynyl, sec-butyl, tert-butyl, and n-hexyl.
Other preferred compounds of formula 1 include those wherein R
1
is hydroxy, R
2
is hydroxy, R
3
is —CH
2
NHR
8
, R
4
is H, and R
8
is —(CH
2
)
m
(C
6
-C
10
aryl) wherein m is an integer ranging from 0 to 4. Specific preferred compounds having the foregoing general structure include those wherein R
8
is phenyl or benzyl.
Other preferred compounds of formula 1 include those wherein R
1
is hydroxy, R
2
is hydroxy, R
3
is —CH
2
NR
15
R
8
, R
4
is H, and R
15
and R
8
are taken together to form a saturated ring. Specific preferred compounds having the foregoing general structure include those wherein R
15
and R
8
are taken together to form a piperidino, trimethyleneimino, or morpholino ring.
Other preferred compounds of formula 1 include those wherein R
1
is hydroxy, R
2
is hydroxy, R
3
is —CH
2
NR
15
R
8
, R
4
is H, and R
15
and R
8
are taken together to form a heteroaryl ring optionally substituted by 1 or 2 C
1
-C
6
alkyl groups. Specific preferred compounds having the foregoing general structure include those wherein R
15
and R
8
are taken together to form a pyrrolidino, triazolyl, or imidazolyl ring wherein said heteroaryl groups are optionally substituted by 1 or 2 methyl groups.
Other preferred compounds of formula 1 include

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