6,11-3C-bicyclic 9a-azalide derivatives

Details 6,11-3C-bicyclic 9a-azalide derivatives 6,11-3C-bicyclic 9a-azalide derivatives

2003-03-26

2003-11-11

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400, C536S018500

Reexamination Certificate

active

06645941

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel semisynthetic macrolides having antibacterial activity and useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to 6,11-3C-bridged 9a-azalide derivatives, compositions comprising such compounds, methods for using the same, and processes by which to make such compounds.
BACKGROUND OF THE INVENTION
Macrolide antibacterial agents are widely used to treat and prevent bacterial infections. However, the discovery of bacterial strains which have resistance or insufficient susceptibility to macrolide antibacterial agents has promoted development of compounds with modified or improved profiles of antibiotic activity. One such class of compounds are azalides, which includes azithromycin, described in U.S. Pat. Nos. 4,474,768 and 4,517,359. Azalides are macrolide antibacterial agents with a ring structure similar to the erythronolide A or B, however azalides possess a substituted or unsubstituted nitrogen moiety at the 9a position as illustrated in the following structure:
The potential for azalides to display modified or improved profiles for antibiotic activity has spawned extensive research to identify additional azalide derivatives with enhanced clinical properties. The following are examples of current efforts in azalide research:
PCT Application WO98/56801, published Dec. 17, 1998 discloses a series of 9a-(N-(alkyl))-azalide erythromycin A derivatives and a series of 9a-(N-(alkyl))-azalide 6-O-methylerythromycin A derivatives;
PCT Application WO98/56802, published Dec. 17,1998 discloses a series of 9a-(N-(H))-azalide erythromycin A derivatives and a series of 9a-(N-(H))-azalide 6-O-methylerythromycin A derivatives;
PCT Application WO99/00124, published Jan. 7, 1999 discloses a series of 9a-(N-(R
n
))-azalide 3-thioxoerythromycin A derivatives and a series of 9a-(N7(R
n
))-azalide 6-O-methyl 3-oxoerythromycin A derivatives, wherein R
n
is an optionally substituted alkyl or heteroalkyl;
PCT Application WO99/00125, published Jan. 7, 1999 discloses a series of 9a-(N-(R
n
))-azalide 3-oxoerythromycin A derivatives and a series of 9a-(N-(R
n
))-azalide 6-O-methyl 3-oxoerythromycin A derivatives, wherein R
n
is an optionally substituted alkyl or heteroalkyl; and
U.S. Pat. No. 5,686,587 discloses a synthesis of azithromycin comprising introducing a 9a-(N(H))-moiety to erythromycin A by oxime formation, Beckmann rearrangement, reduction, and methylation.
SUMMARY OF THE INVENTION
The present invention provides a novel class of 6,11-3C-bridged 9a-azalide compounds, or a pharmaceutically-acceptable salt, ester, or prodrug thereof, pharmaceutical compositions comprising at least one compound of the present invention, methods of treating a bacterial infection in a subject by administering said pharmaceutical compositions, and processes of making the compounds of the present invention.
In one embodiment of the present invention there are disclosed compounds of formula I:
as well as the pharmaceutically acceptable salts, esters and prodrugs thereof, wherein:
A is
i) —OH;
ii) —OR
p
, where R
p
is a hydroxy protecting group;
iii) —R
1
, where R
1
is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
iv) —OR
1
, where R
1
is as previously defined;
v) —R
2
, where R
2
is
(a) hydrogen;
(b) halogen;
(c) —C
1
-C
6
alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
(d) —C
2
-C
6
alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or
(e) —C
2
-C
6
alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
vi) —OR
2
, where R
2
is previously defined;
vii) —S(O)
n
R
11
, where n=0, 1 or 2, and R
11
is R
1
or R
2
, where R
1
and R
2
are as previously defined;
viii) —NHC(O)R
11
, where R
11
is as previously defined;
ix) —NHC(O)NHR
11
, where R
11
is as previously defined;
x) —NHS(O)
2
R
11
, where R
11
is as previously defined;
xi) —NR
14
R
15
, where R
14
and R
15
are each independently R
11
, where R
11
is as previously defined; or
xii) —NHR
3
, where R
3
is an amino protecting group;
B is
i) hydrogen;
ii) deuterium;
iii) halogen;
iv) —OH;
v) —R
1
, where R
1
is as previously defined;
vi) —R
2
, where R
2
is as previously defined; or
vii) —OR
p
, where R
p
is as previously defined, provided that when B is halogen, —OH or OR
p
, A is R
1
or R
2
, where R
1
and R
2
are previously defined;
or, alternatively, A and B taken together with the carbon atom to which they are attached are
i) C═O;
ii) C(OR
2
)
2
, where R
2
is as previously defined;
iii) C(SR
2
)
2
, where R
2
is as previously defined;
iv) C[—O(CH
2
)
m
]
2
, where m=2 or 3;
v) C[—S(CH
2
)
m
]
2
, where m is as previously defined;
vi) C═CHR
11
, where R
11
is as previously defined;
vii) C═N—O—R
11
, where R
11
is as previously defined;
viii) C═NNHR
11
, where R
11
is as previously defined;
ix) C═NNHC(O)R
11
, where R
11
is as previously defined;
x) C═NNHC(O)NHR
11
, where R
11
, is as previously defined;
xi) C═NNHS(O)
2
R
11
, where R
11
is as previously defined;
xii) C═NNHR
3
, where R
3
is as previously defined; or
xiii) C═NR
11
, where R
11
is as previously defined;
L is
i) —CH
3
;
ii) —CH
2
CH
3
;
iii) —CH(OH)CH
3
;
iv) —C
1
-C
6
alkyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
v) —C
2
-C
6
alkenyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or
vi) —C
2
-C
6
alkynyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
D is —N(Q)CH
2
—, —N(R′)C(O)—, or —N═C(OR′)—, wherein R′ is R
11
as previously defined;
Q is
i) hydrogen;
ii) —C
1
-C
12
-alkyl, C
3
-C
12
-alkenyl, or C
3
-C
12
-alkynyl, all optionally substituted with one, two or three substituents independently selected from:
(a) halogen;
(b) —OR
6
, wherein R
6
is selected from:
1. hydrogen;
2. —C
1
-C
12
-alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one, two, or three substituents independently selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
3. aryl;
4. substituted aryl;
5. heteroaryl; and
6. substituted heteroaryl;
(c) —NR
4
R
5
, where R
4
and R
5
are each independently R
6
, where R
6
is as previously defined, or in the alternative R
4
and R
5
, together with the atom to which they are attached, form a heterocycloalkyl or substituted heterocycloalkyl moiety;
(d) —N—O—R
6
, where R
6
is as previously defined;
(e) —R
1
, where R
1
, is as previously defined;
(f) —C
3
-C
8
-cycloalkyl;
(g) substituted —C
3
-C
8
-cycloalkyl;
(h) heterocycloalkyl;
(i) substituted heterocycloalkyl;
(j) —NHC(O)R
6
, where R
6
is as previously defined;
(k) —NHC(O)OR
7
, where R
7
is selected from:
1. —C
1
-C
12
-alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one, two, or three substituents independently selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
2. aryl;
3. substituted aryl;
4. heteroaryl; or
5. substituted heteroaryl;
(l) —NHC(O)NR
4
R
5
, where R
4
and R
5
are as previously defined;
(m) —OC(O)NR
4
R
5
, where R
4
and R
5
are as previously defined;
(n) —OC(O)R
7
, where R
7
is as previously defined;
(o) —OC(O)OR
7
, where R
7
is as previously defined;
(p) —OC(O)NR
4
R
5
, where R
4
and R
5
are as previously defined,
(q) —C(O)R
6
, where R
6
is as previously defined,
(r) —CO
2
R

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