9-amino-14-membered macrolides derived from leucomycins

Details 9-amino-14-membered macrolides derived from leucomycins 9-amino-14-membered macrolides derived from leucomycins

2001-04-02

2002-08-20

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S028000, C536S007100, C536S007200, C536S007400

Reexamination Certificate

active

06436906

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 novel 9-amino-14-membered ring analogs, 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. Natural 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). The most commonly used macrolides are erythromycin and josamycin.
Erythromycins A, represented by Formula (Ia),
are well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection. As with other antibacterial agents, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new macrolide compounds which possess one or more properties such as improved antibacterial activity, less potential for developing resistance, desired Gram-negative activity, and unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.
Similarly, 16-membered ring macrolides like josamycin, kitasamycin, or tylosin have been extensively modified. Both josamycin and kitasamycin are members of the Leucomycin series. One group of the Leucomycin series is represented by Formula (Ib) and the various compounds are differentiated by the substituent at C-3 and C4″.
(Ib)

Leucomycin
R2
R4
A1
H
C(O)CH2CHMe2
(Kitasamycin) A5
H
C(O)CH2CH2CH3
A7
H
C(O)CH2CH3
A9
H
C(O)CH3
V(A11)
H
H
(Josamycin) A3
C(O)CH3
C(O)CH2CHMe2
A4
C(O)CH3
C(O)CH2CH2CH3
A6
C(O)CH3
C(O)CH2CH3
A8
C(O)CH3
C(O)CH3
U
C(O)CH3
H
Miokamycin
1
C(O)CH2CH3
C(O)CH2CH2CH3
Rokitamycin
2
H
C(O)CH2CH2CH3
1
9-OAc; 3″-OAc
2
3″-OC(O)CH2CH3; 4″-OC(O)CH2CH2CH3
Typically, one drawback of 16-membered ring macrolides is their weaker antibacterial activity relative to the 14-membered ring macrolides. However, typically the 16-membered ring macrolides show some advantages over the 14-membered ring compounds derived from erythromycin with regard to gastrointestinal tolerance and activity against inducible resistant strain bacteria. Work in the macrolide field has focused primarily on structural modification of the 14-membered ring of erythromycin or the modification of the natural 16-membered ring macrolides.
For example, U.S. Pat. No. 4,048,306 discloses aldehyde-erythromycyclamine condensation products; U.S. Pat. No. 4,526,889 discloses an epimeric azahomoerythromycin A derivative; U.S. Pat. No. 5,075,289 discloses 9-R-azacyclic derivatives of erythromycin; U.S. Pat. No. 5,110,800 discloses 9-N-substituted derivatives of erythromycyclamine and U.S. Pat. No. 5,140,014 discloses certain 9-amino 16-membered tylonide derivatives.
There is a continuing need for novel 14-membered macrolide ring structures which overcome bacterial resistance.
SUMMARY OF THE INVENTION
The present invention provides a novel class of 9-amino- 14-membered macrolide compounds possessing antibacterial activity toward Gram positive and Gram negative bacteria as well as macrolide resistant Gram positives.
In one embodiment, the present invention provides compounds represented by Formulas II or III, or a pharmaceutically acceptable salt, ester or prodrug thereof:
In Formulas II and III:
A is selected from the group consisting of;
(1) —CHO or a protected aldehyde
(2) —CH
2
X, where X is selected from the group consisting of;
a. hydroxy or protected hydroxy,
b. halogen,
c. —NR7R8, wherein R7 and R8 are each independently selected from hydrogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, C1-C6-alkyl, optionally substituted with aryl, substituted aryl, heterocyclic or substituted heterocyclic, C2-C6-alkenyl, optionally substituted with aryl, substituted aryl, heterocyclic or substituted heterocyclic and C2-C6-alkynyl, optionally substituted with aryl, substituted aryl, heterocyclic or substituted heterocyclic; or R7 and R8 taken together with the nitrogen atom to which they are connected form a 3- to 7-membered ring which, may optionally contain a hetero function selected from the group consisting of —O—, —NH—, —N(C1-C6-alkyl)—, —N(aryl)—, —N(heteroaryl)—, —S—, —S(O)— and —S(O)2—,
d. NR7C(O)—R9, where R7 is as previously defined and R9 is selected from the group consisting of,
i. C1-C6-alkyl, optionally substituted with aryl, substituted aryl, heterocyclic or substituted heterocyclic,
ii. aryl,
iii. substituted aryl,
iv. heterocyclic, and
v. substituted heterocyclic
e. —S(O)
n
—(C1-C6-alkyl), optionally substituted with aryl substituted aryl, heterocyclic, or substituted heterocyclic, where n=0, 1 or 2,
f. —S(O)
n
—(C2-C6-alkenyl), optionally substituted with aryl, substituted aryl, heterocyclic or substituted heterocyclic, where n is as previously defined,
g. —S(O)
n
—(C2-C6-alkynyl), optionally substituted with aryl, substituted aryl, heterocyclic or substituted heterocyclic, where n is as previously defined,
h. —S(O)
n
—(aryl or heterocyclic), where n is as previously defined,
i. —O—(aryl or heterocyclic),
(3) substituted or unsubstituted imidazole, arylimidazole or heteroarylimidazole,
(4) substituted or unsubstituted oxazole, aryloxazole or heteroaryloxazole,
(5) substituted or unsubstituted thioxazole, arylthioxazole or heteroarylthioxazole,
(6) substituted or unsubstituted imidazoline, arylimidazoline or heteroarylimidazoline,
(7) substituted or unsubstituted oxazoline, aryloxazoline or heteroaryloxazoline, and
(8) substituted or unsubstituted thioxazoline, arylthioxazoline or heteroarylthioxazoline,
One of R1 and R2 is hydrogen and the other is —NR7R8 where R7 and R8 are as previously defined;
R3, R4 and R5 are each independently selected from the group consisting of,
(1) hydrogen,
(2) a hydroxy protecting group, and
(3) —C(O)—(C1-C12-alkyl), optionally substituted with aryl, substituted aryl, heterocyclic, substituted heterocyclic, —O—R7 or —NR7R8 where R7 and R8 are as previously defined; and
R
p
is hydrogen or a hydroxy protecting group.
The compounds of the invention possess antibacterial activity toward Gram positive and Gram negative bacteria as well as macrolide resistant Gram positives.
DETAILED DESCRIPTION OF THE INVENTION
A first embodiment of the invention is a compound represented by Formula II as described above.
A second embodiment of the invention is a compound represented by Formula III as described above.
Representative compounds of the invention include, but are not limited to, those selected from the group consisting of:
Compound of Formula III: A=CHO, R1=NMe2, R2=H, R3=Ac, R4=C(O)CH2CHMe2, R5=H, R
p
=H
Compound of Formula III: A=CH(OMe)2, R1=NMe2, R2=H, R3=Ac, R4=C(O)CH2CHMe2, R5=H, R
p
=H
Compound of Formula II: A=CH(OMe)2, R1=NH2, R2=H, R3=Ac, R4=C(O)CH2CHMe2, R5=H, R
p
=H.
Compound of Formula II: A=CH(OMe)2, R1=NMe2, R2=H, R3=Ac, R4=C(O)CH2CHMe2, R5=H, R
p
=H
Compound of Formula II: A=CHO, R1=NMe2, R2=H, R3=Ac, R4=C(O)CH2CHMe2, R5=H, R
p
=H
Compound of Formula II: A=CHO, R1=NHMe, R2=H, R3=Ac, R4=C(O)CH2CHMe2, R5=H, R
p
=H
Compound of Formula II: A&equals

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