Macrolide antibiotics

Details Macrolide antibiotics Macrolide antibiotics

2002-07-24

2004-12-28

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200, C536S007400

Reexamination Certificate

active

06835716

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel 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 and disorders related to bacterial infections, such as atherosclerosis and cancer, 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 are bond-spectrum macrolide antibodies that are effective against infections caused by certain gram-positive and gram-negative bacteria as well as protozoa.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula:
or the pharmaceutically acceptable salt thereof; wherein the dashed line between positions 10 and 11 represents an optional double bond;
a is 0 or 1;
R
1
is hydrogen or (C
1
-C
10
)alkyl optionally substituted by fluoro, cyano, R
7
, R
7
O
2
C, R
7
C(O)NH and R
7
S(O)
n
wherein n is 0, 1 or 2 and R
7
is (C
1
-C
8
)alkyl, (C
2
-C
12
)alkenyl, (C
2
-C
12
)alkynyl, (C
3
-C
10
)cycloalkyl(C
1
-C
6
)alkyl, (C
2
-C
9
)heterocycloalkyl(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl or (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three halo, (C
1
-
C
3
)alkoxy, hydroxy, nitro, cyano, (C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryl, R
8
R
9
N, R
8
C(O), R
8
C(O)O, R
8
OC(O), R
8
C(O)NH, R
8
NHC(O), R
8
R
9
NC(O) and R
8
OC(O)
2
wherein R
8
and R
9
are each independently hydrogen, (C
1
-C
6
)alkyl optionally substituted by (C
6
-C
10
)aryl or (C
2
-C
9
)heteroaryl;
R
2
is hydrogen or a hydroxy protecting group;
R
3
is amino, cyano, N
3
, R
10
NH, R
10
C(O)NH, R
10
NHC(O)NH, R
10
NHC(S)NH, R
10
NHNHC(O)NH, R
10
ONHC(O)NH, R
10
O, R
10
OC(O)NH, R
10
S(O)
n
, R
10
phosphoramido, R
10
sulfonamido, SH, R
10
S wherein n is defined above and R
10
is (C
1
-C
6
)alkyl, (C
2
-C
12
)alkenyl, (C
2
-C
12
)alkynyl, (C
3
-C
10
)cycloalkyl(C
1
-C
6
)alkyl, (C
2
-C
9
)heterocycloalkyl(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl or (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents selected independently from halo, (C
1
-C
3
)alkoxy, hydroxy, nitro, cyano, (C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryl, R
8
R
9
N, R
8
C(O), R
8
C(O)O, R
8
OC(O), R
8
C(O)NH, R
8
NHC(O), R
8
R
9
NC(O) and R
8
OC(O)
2
wherein R
8
and R
9
are each independently hydrogen, (C
1
-C
6
)alkyl optionally substituted by (C
8
-C
10
)aryl or (C
2
-C
9
)heteroaryl; or R
3
is R
12
R
13
N wherein R
12
and R
13
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl or (C
2
-C
9
)heteroaryl (C
1
-C
6
)alkyl;
R
4
is hydrogen, methyl optionally substituted by one to two nitro, cyano, R
14
C(O) and R
14
OC(O); or R
4
is N
3
, R
14
O, R
14
NH, R
14
S wherein R
14
is (C
1
-C
6
)alkyl, (C
2
-C
12
)alkenyl, (C
2
-C
12
)alkynyl, (C
3
-C
10
)cycloalkyl(C
1
-C
6
)alkyl, (C
2
-C
9
)heterocycloalkyl(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl,(C
6
-C
10
)aryl(C
1
-C
6
)alkyl or (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C
1
-C
3
)alkoxy, hydroxy, nitro, cyano, (C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryl, R
8
R
9
N, R
8
C(O), R
8
C(O)O, R
8
OC(O), R
8
C(O)NH, R
8
NHC(O), R
8
R
9
NC(O) and R
8
OC(O)
2
, wherein R
8
and R
9
are each independently hydrogen, (C
1
-C
6
)alkyl optionally substituted by (C
6
-C
10
)aryl or (C
2
-C
9
)heteroaryl; or R
4
is R
15
N(C
1
-C
6
)alkyl wherein R
15
is hydrogen, (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl or (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl;
X is oxygen or NOR
16
wherein R
16
is (C
1
-C
6
)alkyl, (C
2
-C
12
)alkenyl, (C
2
-C
12
)alkynyl, (C
3
-C
10
)cycloalkyl(C
1
-C
6
)alkyl, (C
2
-C
9
)heterocycloalkyl(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl or (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C
1
-C
3
)alkoxy, hydroxy, nitro, cyano, (C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryl, R
8
R
9
N, R
8
C(O), R
8
C(O)O, R
8
OC(O), R
8
C(O)NH, R
8
NHC(O), R
8
R
9
NC(O) and R
8
OC(O)
2
, wherein R
8
and R
9
are each independently hydrogen or (C
1
-C
6
)alkyl optionally substituted by (C
6
-C
9
)aryl or (C
2
-C
9
)heteroaryl;
R
5
is hydrogen or methyl;
or R
3
and R
4
may be taken together with the carbons to which they are attached to form:
wherein the dashed line, between the nitrogen and the variable W of formula II, represents an optional double bond;
W is C═O, C═S, SO
2
or C═NR
10
wherein R
10
is as defined above;
Y is oxygen, sulfur or NR
17
wherein R
17
is hydrogen, R
19
, R
19
O or R
19
NH wherein R
19
is hydrogen, (C
1
-C
6
)alkyl, (C
2
-C
12
)alkenyl, (C
2
-C
12
)alkynyl, (C
3
-C
10
)cycloalkyl(C
1
-C
6
)alkyl, (C
2
-C
9
)heterocycloalkyl(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl or (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C
1
-C
3
)alkoxy, hydroxy, nitro, cyano, (C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryl, R
8
R
9
N, R
8
C(O), R
8
C(O)O, R
8
OC(O), R
8
C(O)NH, R
8
NHC(O), R
8
R
9
NC(O) and R
8
OC(O)
2
wherein R
8
and R
9
are each independently hydrogen, (C
1
-C
6
)alkyl optionally substituted by (C
5
-C
10
)aryl or (C
2
-C
9
)heteroaryl;
R
18
is hydrogen, (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl or (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl; wherein the aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C
1
-C
3
)alkoxy, hydroxy, nitro, cyano, (C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryl, R
20
R
21
N, R
20
C(O), R
20
C(O)O, R
20
OC(O), R
20
C(O)NH, R
20
NHC(O), R
20
R
21
NC(O), and R
20
CO
2
wherein R
20
and R
21
are each independently hydrogen, (C
1
-C
6
)alkyl optionally substituted by (C
6
-C
10
)acyl or (C
5
-C
10
)aryl; or (C
2
-C
9
)heteroaryl;
R
6
is hydrogen, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl or (C
1
-C
6
)alkylthio(C
1
-C
6
)alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo; or R
6
is (C
3
-C
10
)cycloalkyl or (C
5
-C
10
)cycloalkenyl optionally substituted by (C
1
-C
6
)alkyl or halo; or R
6
is (C
2
-C
8
)heterocycloalkyl or (C
2
-C
9
)heteroaryl optionally substituted by (C
1
-C
6
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl, (C
3
-C
10
)cycloalkyl, (C
5
-C
10
)cycloalkenyl or aryl wherein the aryl group is optionally substituted by alkyl, (C
1
-C
6
)alkoxy or halo;
with the proviso that at least one of R
17
or R
18
is hydrogen;
with the proviso that when the dashed line between positions 10 and 11 represents a double bond, R
4
is hydrogen; and
with the proviso that when a is zero, R
1
is hydrogen.
The term “alkyl”, as used herein, unless otherwise indicated, includes sat

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