C-4 substituted macrolide antibiotics

Details C-4 substituted macrolide antibiotics C-4 substituted macrolide antibiotics

1999-08-23

2001-10-09

Solola, Taofiq A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400

Reexamination Certificate

active

06300316

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel C-4″ substituted macrolide derivatives 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 sprectrum 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. Like azithromycin and other macrolide antibiotics, the novel macrolide compounds of the present invention possess potent 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 thereof, wherein:
X
1
is —CH(—NR
18
R
19
)—, —C(O)—, —CH
2
NR
9
—, —NR
9
CH
2
—, or —C(═NR
5
)—, wherein the first dash of each of the foregoing X
1
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 compound of formula 1;
R
1
and R
2
are each independently OH;
or R
2
is O and R
1
is X
2
, and they are taken together as follows:
wherein X
2
is O, —N(R
9
)—, or —N(NR
9
R
10
)—;
or R
1
is oxo, OH, or —NR
9
R
10
, R
2
is O and X
1
is —CH(—O)—, and R
2
and X
1
are taken together as follows:
or R
1
is N, R
2
is O, X
1
is —C(═N)— or —CH(—NR
9
)—, and R
1
is taken together with both R
2
and X
1
as follows:
or R
1
is O and X
1
is —C(—NR
9
)—, and they are taken together as follows:
wherein X
3
is H, C
1
-C
6
alkyl, or —(CH
2
)
m
O(C
1
-C
6
alkyl) wherein m is an integer ranging from 1 to 4 and the alkyl moieties of the foregoing X
3
groups are optionally substituted by 1 or 2 substituents independently selected from halo, —NR
9
R
10
and —OR
9
;
R
3
is hydroxy or methoxy;
R
4
is —(CH
2
)
n
NR
8
R
15
wherein n is an integer ranging from 0 to 6 and said R
4
group is optionally substituted by 1 to 3 R
16
groups, with the proviso that n is not 0 where R
8
is —C(O) (C
1
-C
10
alkyl), —C(O)(CH
2
)
t
(C
6
-C
10
aryl), or —C(O)(CH
2
)
t
(4-10 membered hetrocyclic);
R
5
is hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —(CH
2
)
m
(C
6
-C
10
aryl), —(CH
2
)
m
(4-10 membered heterocyclic), or —(CH
2
)
m
O(CH
2
)
z
OR
9
, wherein m is an integer ranging from 0 to 4 and z is an integer ranging from 1 to 6, and the foregoing R
5
groups, except hydroxy, are optionally substituted by 1 to 3 R
16
groups;
each R
6
and R
7
is independently H, —OR
9
, C
1
-C
6
alkyl, —(CH
2
)
m
(C
6
-C
10
aryl), or —(CH
2
)
m
(4-10 membered heterocyclic), wherein m is an integer ranging from 0 to 4, with the proviso that where R
6
and R
7
are both attached to the same nitrogen as —NR
6
R
7
, then R
6
and R
7
are not both —OR
9
;
R
8
is C
1
-C
10
alkyl, —C(O)(C
1
-C
10
alkyl), —(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 4 except that q and r are not both 0, —(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(4-10 membered heterocyclic), —C(O)(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
O(CH
2
)
j
(C
6
-C
10
aryl), —C(O)(CH
2
)
t
(4-10 membered heterocyclic), —SO
2
(CH
2
)
t
(C
6
-C
10
aryl), or —SO
2
(CH
2
)
t
(4-10 membered heterocyclic), wherein j is an integer ranging from 0 to 2, t is an integer ranging from 0 to 5, the —(CH
2
)
t
— moieties of the foregoing R
8
groups optionally include a carbon-carbon double or triple bond where t is an integer between 2 and 5, and the foregoing R
8
groups are optionally substituted by 1 to 3 R
16
groups;
or R
15
and R
8
may be taken together with the nitrogen to which each is attached 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
6
)— in addition to the nitrogen to which R
15
and R
8
are attached, said —N(R
6
)— is optionally ═N— or —N═ where R
15
and R
8
are taken together as said heteroaryl group, said saturated ring optionally may be partially unsaturated by including 1 or 2 carbon-carbon double bonds, and said saturated and heteroaryl rings, including the R
6
group of said —N(R
6
)—, are optionally substituted by 1 to 3 R
16
groups;
or R
15
and R
8
may be taken together with the nitrogen to which each is attached to form a polycyclic moiety of the formula
wherein v is 0 or 1, X
4
is —C(O)—, —CH(OH)—, —(CH
2
)
m
—, —N(R
6
)(CH
2
)
m
—, —(CH
2
)
m
N(R
6
)— or —(CH
2
)
m
O— wherein m is an integer ranging from 0 to 2, and X
6
is —(CH
2
)
w
— wherein w is 1 or 2, —CH
2
O—, —OCH
2
—, —CH
2
N(R
9
)—, or —N(R
9
)CH
2
—;
wherein X
5
is —CH═CH—, —S—, or —N(R
6
)—, and the above groups of formulas 2, 3, and 4, including the Z portions of said groups, 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, C
1
-C
10
alkanoyl, —(CH
2
)
m
(C
6
-C
10
aryl), —C(O)(CH
2
)
m
(C
6
-C
10
aryl), —(CH
2
)
m
(4-10 membered heterocyclic), and —C(O)(CH
2
)
m
(4-10 membered heterocyclic), 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 and r+p equals at least 2, such that a 4-9 membered saturated ring is formed that optionally may be partially unsaturated by including 1 or 2 carbon-carbon double bonds;
or R
13
and R
14
are taken together with the nitrogen to which each is attached 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
6
)—, in addition to the nitrogen to which R
13
and R
14
are attached, said —N(R
6
)— is optionally ═N— or —N═ where R
13
and R
14
are taken together as said heteroaryl group, said saturated ring optionally may be partially unsaturated by including 1 or 2 carbon-carbon double bonds, and said saturated and heteroaryl rings, including the R
6
group of said —N(R
6
)—, are optionally substituted by 1 to 3 R
16
groups;
or R
13
and R
14
are taken together to form ═C(—NR
9
R
6
)NR
10
R
7
;
or R
13
is H and R
14
is —C(═NR
6
)NR
9
R
7
;
R
15
is H or C
1
-C
10
alkyl, wherein the alkyl is optionally substituted by 1 to 3 R
16
groups;
each R
16
is independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
17
, —C(O)OR
17
, —OC(O)R
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, —S(O)
j
(C
1
-C
6
alkyl) wherein j is an integer ranging from 0 to 2, 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, said alkoxy group is optionally substituted by 1 to 3 groups selected from —NR
9
R
10
, halo, and —OR
9
, and said aryl and heteroaryl subsituents are optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
17
, —C(O)OR
17
, —CO(O)R
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, —(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(4-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4;
R
18
and R
19
are

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