Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-12-27
2003-02-04
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S007200, C536S007400
Reexamination Certificate
active
06514944
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. In addition, further modifications are made at positions 9, 11 and 12, or at positions 12 and 13.
In one embodiment, derivatives contain two fused rings at positions 9 and 11, and 11-12 of the erythronolide back bone as in compounds (1)-(3) and (1′)-(3′) of the invention. Specifically, these two fused rings include a fused carbamate ring at the 11-12 position, and a fused diamine ring, which is fused to the erythronolide back bone at positions 9 and 11, and also is fused to the carbamate ring.
In another embodiment, compounds (101)-(103) of the invention contain one fused ring at positions 12-13 of the erythronolide back bone. In this embodiment, the erythronolide back bone initially must be modified at position 13 with a substituent containing a &pgr;-bond in positions &agr;,&bgr; to the ring which is then converted to a fused ring at position 12-13, wherein a 12-hydroxyl group is incorporated into the fused ring, e.g., to form a carbamate ring. Thus, the starter unit for the erythronolide is in one embodiment an &agr;,&bgr;-unsaturated carboxylic acid, which is converted into a thioester, or a diketide thioester having &ggr;,&dgr;-unsaturation.
Thus, in one aspect, the invention is directed to compounds of the formula
wherein
R
a
is substituted or unsubstituted alkyl (1-10C); substituted or unsubstituted alkenyl (2-10C); substituted or unsubstituted alkynyl (2-10C); substituted or unsubstituted aryl (3-20C); or substituted or unsubstituted arylalkyl (4-20C); 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 (2-10C); substituted or unsubstituted aryl (3-20C); substituted or unsubstituted arylalkyl (4-20C); substituted or unsubstituted arylalkenyl (5-20C); substituted or unsubstituted arylalkynyl (5-20C); substituted or unsubstituted amidoarylalkyl (5-20C); substituted or unsubstituted amidoarylalkenyl (5-20C); or substituted or unsubstituted amidoarylalkynyl (5-20C);
R
d
′ is H, substituted or unsubstituted alkyl (1-10C); substituted or unsubstituted alkenyl (2-10C); substituted or unsubstituted alkynyl (2-10C); substituted or unsubstituted aryl (4-20C); substituted or unsubstituted arylalkyl (5-20C); substituted or unsubstituted arylalkenyl (5-20C ); substituted or unsubstituted arylalkynyl; 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;
each of A, B, D and E is independently H, substituted or unsubstituted alkyl (1-10C) wherein any pair of said A, B, D and E forms a 3-7-membered ring optionally containing one or more heteroatoms, with the proviso that at least two of said A, B, D and E must be hydrogen;
L is methylene or carbonyl;
T is —O—, —N(R)—, or —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), (1′)-(3′) or (101)-(103) and to methods to treat infectious diseases by administering these compounds or to preserve materials by providing them.
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Weder J.M. et al. (1991).Science252:114-117.
Favorito Carolyn A.
KOSAN Biosciences, Inc.
Lentini David P.
Peselev Elli
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