9a-azalides with antibacterial activity

Details 9a-azalides with antibacterial activity 9a-azalides with antibacterial activity

2000-07-25

2004-07-20

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C540S467000, C540S468000, C514S375000, C514S450000, C536S007400

Reexamination Certificate

active

06764996

ABSTRACT:

TECHNICAL FIELD
The instant invention relates to 9a-azalides which are antibacterial agents, compositions containing the compounds, processes for making the compounds, synthetic intermediates employed in the processes, and methods for treatment and prevention of bacterial infections.
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 such as azithromycin, referred to in U.S. Pat. Nos. 4,474,768 and 4,517,359. Azalides are macrolide antibacterial agents with a core ring structurally similar to the erythronolide A or B ring except for the presence of a substituted or unsubstituted nitrogen moiety at the 9a position. Because of the potential for azalides to display modified or improved profiles of antibiotic activity, they are the subject of current research for their clinical potential.
PCT Application WO 98/56801, 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 WO 98/56802, 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 WO 99/00124, published Jan. 7, 1999, discloses a series of 9a-(N(R
n
))-azalide 3-thioxoerythromycin 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.
PCT Application WO 99/00125, 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.
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, Beckman rearrangement, reduction, and methylation.
SUMMARY OF THE INVENTION
In one embodiment of the present invention are disclosed compounds of formula (I)
compounds of formula (II)
compounds of formula (III)
and
compounds of formula (IV)
or pharmaceutically acceptable salts or prodrugs thereof, wherein, in formulas (I)-(IV), R
1
and R
6
are independently selected from the group consisting of
(1) hydrogen,
(2) —C
1
-C
12
-alkyl,
(3) —C
3
-C
12
-alkenyl, and
(4) —C
3
-C
12
-alkynyl,
wherein (2)-(4) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
(a) halogen,
(b) —OR
9
, wherein R
9
is selected from the group consisting of
(i) hydrogen,
(ii) —C
1
-C
12
-alkyl,
(iii) —C
2
-C
12
-heteroalkyl,
wherein (ii) and (iii) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
(1′) aryl,
(2′) substituted aryl,
(3′) heteroaryl,
and
(4′) substituted heteroaryl,
(iv) aryl,
(v) substituted aryl,
(vi) heteroaryl,
and
(vii) substituted heteroaryl,
(c) —NR
11
R
12
, wherein R
11
and R
12
are independently selected from the group consisting of
(i) hydrogen,
(ii) —C
1
-C
12
-alkyl,
(iii) —C
2
-C
12
-heteroalkyl,
wherein (ii) and (iii) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
(1′) aryl,
(2′) substituted aryl,
(3′) heteroaryl,
and
(4′) substituted heteroaryl,
(iv) aryl,
(v) substituted aryl,
(vi) heteroaryl,
and
(vii) substituted heteroaryl,
or
R
11
and R
12
, together with the atom to which they are attached, form a heterocycloalkyl ring, wherein the heterocycloalkyl ring can be optionally substituted,
(d) ═N—O—R
9
, wherein R
9
is defined above,
(e) aryl,
(f) substituted aryl,
(g) heteroaryl,
(h) substituted heteroaryl,
(i) —C
3
-C
8
-cycloalkyl,
(j) substituted —C
3
-C
8
-cycloalkyl,
(k) heterocycloalkyl,
(l) substituted heterocycloalkyl,
(m) —NHC(O)R
9
, wherein R
9
is defined above,
(n) —NHC(O)OR
10
, wherein R
10
is selected from the group consisting of
(i) —C
1
-C
12
-alkyl,
(ii) —C
1
-C
12
-heteroalkyl,
wherein (i) and (ii) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
(1′) aryl,
(2′) substituted aryl,
(3′) heteroaryl,
and
(4′) substituted heteroaryl,
(iii) aryl,
(iv) substituted aryl,
(v) heteroaryl,
and
(vi) substituted heteroaryl,
(o) —NHC(O)NR
11
R
12
, wherein R
11
and R
12
are defined above,
(p) —OC(O)R
10
, wherein R
10
is defined above,
(q) —OC(O)OR
10
, wherein R
10
is defined above,
(r) —OC(O)NR
11
R
12
, wherein R
11
and R
12
are defined above,
(s) —C(O)R
9
, wherein R
9
is defined above,
(t) —CO
2
R
9
, wherein R
9
is defined above,
and
(u) —C(O)NR
11
R
12
, wherein R
11
and R
12
are defined above;
R
2
is hydrogen;
R
3
is —OR
13
, wherein R
13
is selected from the group consisting of
(1) hydrogen,
(2) —C(O)R
9
, wherein R
9
is defined above,
(3) —CO
2
R
10
, wherein R
10
is defined above,
and
(4) —C(O)NR
11
R
12
, wherein R
11
and R
12
are defined above;
or
R
2
and R
3
together are oxo;
R
4
and R
5
are hydrogen;
or
R
4
and R
5
together are —C(O)— or —CH
2
)
x
—, wherein x is one, two, or three;
or
R
5
and R
6
together are —C(O)— or —CH
2
)
x
—, wherein x is defined above;
R
7
is selected from the group consisting of
(1) hydrogen,
(2) —C
1
-C
12
-alkyl,
(3) —C
3
-C
12
-alkenyl,
(4) —C
3
-C
12
-alkynyl,
(5) —C
2
-C
12
-heteroalkyl,
(6) —C
4
-C
12
-heteroalkenyl,
(7) —C
4
-C
12
-heteroalkynyl,
wherein (2)-(7) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
(a) halo,
(b) hydroxy,
(c) —NR
11
R
12
, wherein R
11
and R
12
are defined above,
(d) aryl,
(e) substituted aryl,
(f) heteroaryl,
and
(g) substituted heteroaryl,
(8) —C(O)R
9
, wherein R
9
is defined above,
(9) —CO
2
R
9
, wherein R
9
is defined above,
and
(11) —C(O)NR
11
R
12
, wherein R
11
and R
12
are defined above;
and
R
8
is hydrogen or a hydroxy protecting group;
with the proviso that when R
2
and R
3
together are oxo, R
1
is other than hydrogen or unsubstituted methyl.
In another embodiment of the present invention are disclosed pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds in combination with a pharmaceutically acceptable carrier.
In still another embodiment of the present invention are disclosed methods of treating a bacterial infection in a mammal in need of such treatment which comprises administering to the mammal a therapeutically effective amount of the compounds.
In still yet another embodiment of the present invention is disclosed a method for preparing the compounds,
the method comprising
(a) reacting compounds of formula (Ia)
or compounds of formula (Ib)
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
7
, and R
1
are defined above, with an oxime activating agent;
(b) optionally reacting the product from step (a) with a reducing agent;
(c) optionally alkylating the product from step (b);
and
(d) optionally deprotecting the product from step (c).
DETAILED DESCRIPTION OF THE INVENTION
The term “alkenyl,” as used herein, refers to a monovalent straight or branched chain group containing at least one carbon-carbon double bond. The alkenyl groups of this invention can be optionally substituted.
The term “alkyl,” as used herein, refers to saturated, straight or branched chain hydrocarbon radicals. Examples of alkyl radicals include methyl, ethyl, propyl, iso-propyl, n-butyl, tert-butyl, neo-pentyl, and n-hexyl. The alkyl groups of this invention can be optionally substituted.
The term “—C
1
-C
3
-alkylamino,” as used herein, refers to a amino group, as defined herein wherein one hydrogen atom is replaced by a —C
1
-C
3
-alkyl gr

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