Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-02-13
2003-07-15
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S007200, C536S007400
Reexamination Certificate
active
06593302
ABSTRACT:
TECHNICAL FIELD
The invention is directed to antibacterial compounds that expand the repertoire of erythromycin-like antibiotics. More particularly, the invention concerns macrolide antibiotics containing an erythronolide nucleus modified at least at the substituent at C-13.
BACKGROUND ART
The increasing number of microbial strains that have acquired resistance to the currently available known antibiotic compounds is recognized as a dangerous threat to public health. As the use of such compounds has proliferated, so too has the need for expanding the options available to treat a wide variety of microbial-based conditions. The need for a larger choice of antimicrobial compounds extends beyond treatment of human infection and to a need to preserve food and other perishable commodities. New antibiotics can also be essential for resistant plants and animals as well as to provide resistance to materials that otherwise are subject to microbially caused corrosion.
Thus, there is a clear need for an expanded armament of compounds which can provide a multifaceted defense against unwanted microbial activity.
WO 98/09978 published Mar. 12, 1998 and incorporated herein by reference discloses modified forms of erythromycin which lack a cladinose residue at the 3-position and which are derivatized in various ways in positions 9-12 of the macrolide ring. Similarly, U.S. Pat. No. 5,750,510, issued May 12, 1998 and incorporated herein by reference, discloses modified erythromycin derivatives.
The naturally occurring erythromycins have the structure
Erythromycin
R′
R″
A
—OH
—CH
3
B
—H
—CH
3
C
—OH
—H
D
—H
—H
wherein R′ can be H or OH and R″ can be H or CH
3
.
All of the compounds disclosed in the above-referenced patent documents contain an ethyl group at position 13 of the macrolide ring. The present inventors have found that alterations in the substituent at position 13 results in a large number of compounds with excellent antibacterial activity.
DISCLOSURE OF THE INVENTION
The invention is directed to erythronolide derivatives that contain modifications from the native structure. All of the compounds of the invention are modified at least at position 13 and have a ring at the 11, 12 position.
Thus, in one aspect, the invention is directed to compounds of the formula
wherein
R
a
is H; substituted or unsubstituted alkyl (1-10C); substituted or unsubstituted alkenyl (2-10C); substituted or unsubstituted alkynyl (2-10C); substituted or unsubstituted aryl (4-14C); substituted or unsubstituted arylalkyl (5-20C); or OR
a
may be replaced by H;
R
b
is H or halogen;
R
c
is H or a protecting group;
R
d
is methyl, unsubstituted alkyl (3-10C); substituted alkyl (1-10C); substituted or unsubstituted alkenyl (2-10C); substituted or unsubstituted alkynyl; substituted or unsubstituted aryl (4-14C); substituted or unsubstituted arylalkyl (5-20C); substituted or unsubstituted arylalkenyl (5-20C); substituted or unsubstituted arylalkyl (5-20C); substituted or unsubstituted amidoarylalkyl (5-20C); substituted or unsubstituted amidoarylalkenyl (5-20C); or substituted or unsubstituted amidoarylalkynyl (5-20C);
R
e
is H or a protecting group;
L is methylene or carbonyl;
T is —O—, —N(R)—, —N(OR)—, —N(NHCOR)—, —N(N═CHR)—, or —N(NHR)— wherein R is H or R
a
as defined above, with the proviso that when L is methylene, T is —O—;
one of Z and Y is H and the other is OH, protected OH, or amino, mono- or dialkylamino, protected amino, or an amino heterocycle or
Z and Y together are ═O, ═NOH or a derivatized oxime;
including any pharmaceutically acceptable salts thereof and any stereoisomeric forms and mixtures of stereoisomeric forms thereof.
In another aspect, the invention is directed to pharmaceutical or preservative compositions containing the compounds of formulas (1)-(3) and to methods to treat infectious diseases by administering these compounds or to preserve materials by providing them.
REFERENCES:
patent: 5141926 (1992-08-01), Weber et al.
patent: 5527780 (1996-06-01), Agouridas et al.
patent: 5635485 (1997-06-01), Agouridas et al.
patent: 5672491 (1997-09-01), Khosla et al.
patent: 5747467 (1998-05-01), Agouridas et al.
patent: 5750510 (1998-05-01), Elliott et al.
patent: 5770579 (1998-06-01), Agouridas et al.
patent: 5866549 (1999-02-01), Or et al.
patent: 6022965 (2000-02-01), Benedetti et al.
patent: 6043226 (2000-03-01), Lundy et al.
patent: 6066721 (2000-05-01), Khosla et al.
patent: 6080555 (2000-06-01), Khosla et al.
patent: 6121432 (2000-09-01), Bonnet et al.
patent: 6124269 (2000-09-01), Phan et al.
patent: 6271255 (2001-08-01), Leadlay et al.
patent: 6274560 (2001-08-01), Khosla et al.
patent: 6274715 (2001-08-01), Or et al.
patent: 2754821 (1998-04-01), None
patent: 97/02358 (1997-01-01), None
patent: 97/42206 (1997-11-01), None
patent: 98/01546 (1998-01-01), None
patent: 98/01571 (1998-01-01), None
patent: 98/09978 (1998-03-01), None
patent: 99/03986 (1999-01-01), None
patent: 99/21871 (1999-05-01), None
patent: 99/35157 (1999-07-01), None
patent: 00/26224 (2000-05-01), None
patent: 00/26349 (2000-05-01), None
patent: 00/34297 (2000-06-01), None
patent: 00/44761 (2000-08-01), None
patent: 00/71557 (2000-11-01), None
U.S. patent application Ser. No. 60/117,631, O'Connell et al., filed Jan. 1999.
Weber J.M. et al. (1991);Science252:114-117.
Ashley Gary
Chu Daniel
Ashley Gary
Favorito Carolyn A.
Kosan Biosciences, Inc.
Lentini David P.
Peselev Elli
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