11-C-substituted ketolides

Details 11-C-substituted ketolides 11-C-substituted ketolides

2002-06-25

2004-06-15

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200

Reexamination Certificate

active

06750204

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel macrolides having antibacterial activity and useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to a novel class of 11-C-substituted erythromycin derivatives, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
BACKGROUND OF THE INVENTION
Macrolide antibiotics play a therapeutically important role, particularly with the emergence of new pathogens. Structural differences are related to the size of the lactone ring and to the number and nature (neutral or basic) of the sugars. Macrolides are classified according to the size of the lactone ring (12, 14, 15 or 16 atoms). The macrolide antibiotic family (14-, 15- and 16-membered ring derivatives) shows a wide range of characteristics (antibacterial spectrum, side-effects and bioavailability). Among the commonly used macrolides are erythromycin and clarithromycin.
The search for macrolides active against MLS
B
-resistant strains (MLS
B
=Macrolides-Lincosamides-type B Streptogramines) has become a major goal, together with retaining the overall profile of the macrolides in terms of stability, tolerance and pharmacokinetics.
SUMMARY OF THE INVENTION
The present invention provides a novel class of 11-C-substituted derivatives of erythromycin possessing antibacterial activity toward Gram positive and Gram negative bacteria as well as macrolide-resistant Gram positive bacteria.
In one embodiment, the present invention provides compounds represented by formulae I or II as well as the pharmaceutically acceptable salts, esters and prodrugs thereof.
In formulae I and II above,
A is selected from the group consisting of:
(1) C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl and C
2
-C
6
-alkynyl, optionally substituted with one or more substituents selected from the group consisting of:
i. halogen;
ii. aryl;
iii. substituted aryl;
iv. heterocyclic;
v. substituted heterocyclic;
vi. —O—R
5
, where R
5
is selected from the group consisting of:
a. hydrogen;
b. aryl;
c. substituted aryl;
d. heterocyclic; and
e. substituted heterocyclic;
vii. —O—C
1
-C
6
-alkyl-R
5
, where R
5
is as previously defined;
viii. —O—C
2
-C
6
-alkenyl-R
5
, where R
5
is as previously defined;
ix. —O—C
2
-C
6
-alkynyl-R
5
, where R
5
is as previously defined; and
x. —NR
6
R
7
, where R
6
and R
7
are each independently selected from the group consisting of:
a. hydrogen;
b. C
1
-C
6
-alkyl, optionally substituted with one or more substituents selected from the group consisting of:
(I) halogen;
(II) aryl;
(III) substituted aryl;
(IV) heterocyclic; and
(V) substituted heterocyclic;
c. C
2
-C
6
-alkenyl, optionally substituted with one or more substituents selected from the group consisting of:
(I) halogen;
(II) aryl;
(III) substituted aryl;
(IV) heterocyclic; and
(V) substituted heterocyclic;
d. C
2
-C
6
-alkynyl, optionally substituted with one or more substituents selected from the group consisting of:
(I) halogen;
(II) aryl;
(III) substituted aryl;
(IV) heterocyclic; and
(V) substituted heterocyclic; and
e. R
6
R
7
taken together with the nitrogen atom to which they are connected form a 3- to 7-membered ring which may optionally contain one or more functions selected from the group consisting of:
(I) —O—;
(II) —NH—;
(III) —N(C
1
-C
6
-alkyl)-;
(IV) —N(aryl)-;
(V) —N(heteroaryl)-;
(VI) —S—;
(VII) —S(O)—;
(VII) —S(O)
2
—; and
(IX) —C(O)—;
(2) —C(O)—R
5
, where R
5
is as previously defined;
(3) —C(O)—C
1
-C
6
-alkyl-R
5
, where R
5
is as previously defined;
(4) —C(O)—C
2
-C
6
-alkenyl-R
5
, where R
5
is as previously defined;
(5) —C(O)—C
2
-C
6
-alkynyl-R
5
, where R
5
is as previously defined;
(6) —C
1
-C
6
-alkyl-M—R
5
, where M is —OC(O)—, —OC(O)O—, —OC(O)NR
6
—, —C(O)NR
6
, —NR
6
C(O), —NR
6
C(O)O—, —NR
6
C(O)NR
7
—, —NR
6
C(N)NR
7
— or S(O)
n
—, where n=0, 1 or 2, and where R
5
, R
6
, R
7
are as previously defined;
(7) —C
2
-C
6
-alkenyl-M—R
5
, where M and R
5
are as previously defined; and
(8) —C
2
-C
6
-alkynyl-M—R
5
, where M and R
5
are as previously defined;
B, C, and D may be present singly or in combination and are each independently selected from the group consisting of:
(1) hydrogen;
(2) halogen
(3) C
1
-C
6
-alkyl;
(4) aryl;
(5) substituted aryl;
(6) heterocyclic;
(7) substituted heterocyclic;
(8) O—R
5
, where R
5
is as previously defined;
(9) B and C taken together are ═O;
(10) B and C taken together are ═N—O—R
5
, where R
5
is as previously defined;
(11) B and C taken together are ═N—N—R
6
R
7
, where R
6
and R
7
are as previously defined;
(12) B and D taken together are —O—;
(13) B and D taken together are —S—;
(14) B and D taken together are —N(R
6
), where R
6
is as previously defined; and
(15) B and D taken together with the carbon atoms to which they are attached form a 4- to 8-membered ring which may optionally contain one or more functions selected from the group consisting of:
i. —O—;
ii. —NH—;
iii. —N(C
1
-C
6
-alkyl)-;
iv. —N(aryl)-;
v. —N(heteroaryl)-;
vi. —S—;
vii. —S(O)—;
viii. —S(O)
2
—; and
ix. —C(O)—;
R
1
is selected from the group consisting of:
(1) halogen;
(2) R
3
, where R
3
is C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl or C
2
-C
6
-alkynyl, optionally substituted with one or more substituents selected from the group consisting of:
i. halogen;
ii. aryl;
iii. substituted-aryl;
iv. heterocyclic;
v. substituted-heterocyclic;
vi. —O—C
1
-C
6
-alkyl-R
5
, where R
5
is as previously defined; and
vii. —N—R
6
R
7
, where R
6
and R
7
are as previously defined;
(3) —C(O)—R
4
, where R
4
is as previously defined;
(4) —C(O)O—R
3
, where R
3
is as previously defined; and
(5) —C(O)N—R
6
R
7
, where R
6
and R
7
are as previously defined;
W is selected from the group consisting of:
(1) hydrogen;
(2) halogen;
(3) C
1
-C
6
-alkyl;
(4) C
2
-C
6
-alkenyl; and
(5) C
2
-C
6
-alkynyl; and
Rp
1
is hydrogen or a hydroxy protecting group.
In other embodiments, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier and treatment of bacterial infections with such compositions. Suitable carriers and methods of formulation are disclosed. Also provided are processes for preparing the compounds represented by formulae I and II.
DETAILED DESCRIPTION OF THE INVENTION
A first embodiment of the invention is a compound represented by formula I as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof.
A second embodiment of the invention is a compound represented by formula II as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof.
Preferred embodiments of the invention are: compounds of formula I wherein R
1
is hydrogen, W is hydrogen or halogen, and A and Rp
1
are as previously defined; and compounds of formula II wherein R
1
is hydrogen, W is hydrogen or halogen, and A, B, C, D and Rp
1
are as previously defined.
Representative compounds of the invention are those selected from the group consisting of:
Compound of formula I: A═CHO, R
1
═H, W═H and Rp
1
═H;
Compound of formula I: A═CH
2
OH, R
1
═H, W═H and Rp
1
═H;
Compound of formula I: A═CH
2
OCO-[3-quinolyl], R
1
═H, W═H and Rp
1
═H;
Compound of formula I: A═CH
2
OCO-[4-quinolyl], R
1
═H, W═H and Rp
1
═H;
Compound of formula I: A═CH═CH-phenyl, R
1
═H, W═H and Rp
1
═H;
Compound of formula I: A═CH
2
NH-benzyl, R
1
═H, W═H and Rp
1
═H;
Compound of formula I: A═CH
2
NH-allyl, R
1
═H, W═H and Rp
1
═H;
Compound of formula II: A═CHO, B═H, C═H, D═H, R
1
═H, W═H and Rp
1
═H;
Compound of formula II: A═CHO, B and D taken together ═—O—, C═H, R
1
═H, W═H and Rp
1
═H;
Compound of formula II: A═CHO, B and C taken together are ═O, D═H, R
1
═H, W═H and Rp
1
═H;
Compound of f

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