Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
1999-06-11
2002-11-19
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C514S017400, C514S018700, C514S019300, C530S330000, C536S023740
Reexamination Certificate
active
06482921
ABSTRACT:
INTRODUCTION
The present invention relates to organic chemistry, medicinal chemistry, biochemistry, pharmacology and medicine. In particular, it relates to uridyl peptide antibiotic (UPA) derivatives, their synthesis and their use in the treatment of bacterial infection.
BACKGROUND OF THE INVENTION
The following is offered as background information only and In is not admitted to be, or to describe, prior art to the present invention.
Despite the emergence of new and potent antibiotics, e.g., beta-lactams, macrolides, quinolones, tetracyclines and aminoglycosides, the incidence of bacterial resistance to antibiotics continues to increase at an alarming rate. Furthermore, cross-resistance, the ability of a bacterium resistant to one antibiotic to resist other different antibiotic(s) is also on the rise. To combat these phenomena, there is a need not merely for new antibiotic compounds but for new classes of antibiotics which are sufficiently different in structure and mode of action from current antibiotics to decrease the rate at which resistance arises and to reduce the chances of cross-resistance.
The uridyl peptide antibiotics (UPAs) appear to be such a class of antibiotic compounds. In the first place, their chemical structures, shown below, are unique among current therapeutic antibiotics:
TABLE 1
Some Pacidamycins, Mureidomycins and Napsamycins
R
a
R
b
R
c
R
d
R
e
Mur A
H
m-HOBn
(CH
2
)
2
SCH
3
m-HOBn
uracil
Mur B
H
m-HOBn
(CH
2
)
2
SCH
3
m-HOBn
dihydrouracil
Mur C
glycyl
m-HOBn
(CH
2
)
2
SCH
3
m-HOBn
uracil
Mur D
glycyl
m-HOBn
(CH
2
)
2
SCH
3
m-HOBn
dihydrouracil
Pac 1
alanyl
m-HOBn
Me
3-CH
2
-indol
uracil
Pac 2
alanyl
m-HOBn
Me
Ph
uracil
Pac 3
alanyl
m-HOBn
Me
m-HOBn
uracil
Pac 4
H
m-HOBn
Me
3-CH
2
-indol
uracil
Pac D
H
Me
Me
3-CH
2
-indol
uracil
Nap
(5-hydroxytetra-
(CH
2
)
2
SCH
3
m-HOBn
uracil
hydroisoquinolin-
3-yl)
Mureidomycin = Mur;
Pacidamycin = Pac;
Napsamycins = Nap
Furthermore, the UPAs share a bacterial cellular target which is likewise unique among current antibiotics. That target is bacterial translocase I (phospho-N-acetylmuramyl-pentapeptide translocase), an enzyme that catalyzes the first reaction in the membrane-bound cycle of reactions in bacterial peptidoglycan biosynthesis, e.g., in
E. coli
the transfer of phospho-MurNAc-L-Ala-&ggr;-D-Glu-m-DAP-D-Ala-D-Ala from UMP to a membrane bound carrier, undecaprenyl phosphate. There are other translocase inhibitors, such as tunicamycin (Compound 1) and amphomycin (Compound 2),
Asp=aspartic acid
Gly=glycine
Val=valine
Pro=proline
Dab
e
=D-erythro-&agr;,&bgr;-diaminobutyric acid
Dab
t
=L-threo-&agr;,&bgr;-diaminobutyric acid
Pip=D-pipecolic acid
however, in addition to inhibiting bacterial translocase, these compounds also inhibit mammalian enzymes that catalyze the formation of lipid-linked saccharides through which membrane and secreted proteins are glycosylated which precludes their use as therapeutic antibiotics. On the other hand, the mureidomycins (and, it would be expected, the structurally similar pacidamycins napsamycins), while inhibiting bacterial translocase I similarly to tunicamycin and amphomycin, do not inhibit either bacterial or mammalian lipid-linked saccharide formation (Inukai, M.,
Antimicrobial Agents and Chemotherapy,
1992, 980-83). The UPAS, then, would appear to be excellent targets for the development of novel therapeutic antibiotics.
SUMMARY OF THE INVENTION
Our own efforts to develop novel therapeutic antibiotics to treat and prevent bacterial infections has resulted in the synthesis of dihydro derivatives of uridyl peptide antibiotics which are active against a variety of bacteria including, significantly, several species which are displaying resistance to current antibiotic therapies.
Thus, in one aspect the present invention relates generally to dihydro derivatives, and their physiologically acceptable salts and prodrugs, of uridyl peptide antibiotics. In addition, the present invention relates to the preparation of pharmaceutical compositions of the dihydro derivatives, and their physiologically acceptable salts and prodrugs, and the use of the compositions for the prevention and treatment of bacterial infections.
As used herein, “uridyl peptide antibiotic” refers to a compound having the core structure:
As used herein, “dihydro uridyl peptide antibiotic” refers to a compound having the core structure:
As used herein, “tetrahydro uridyl peptide antibiotic” refers to a compound having the core structure:
As used herein, “pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or physiologically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically acceptable carriers and/or excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
As used herein, a “physiologically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
An “excipient,” as used herein, refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
A “prodrug” refers to an agent which is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial.
1. Chemistry
A. General structural features.
Thus, in one aspect, this invention relates to a compound having the chemical structure:
R
x
is selected from the group consisting of a first amino acid and a first polypeptide, the first amino acid or the first polypeptide being optionally substituted with one or more groups independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heteroalicyclic.
R
y
is selected from the group consisting of a second amino acid and a second polypeptide, the second amino group or the second polypeptide being optionally substituted with one or more groups independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heteroalicyclic.
The second amino acid or a terminal amino acid of the second polypeptide is linked through its &agr;-amino nitrogen atom to an &agr;-amino nitrogen atom of a third amino acid or a third polypeptide by a carbonyl group, the third amino acid or the third polypeptide being optionally substituted with one or more groups independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heteroalicyclic.
R
4
and R
5
are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heteroalicyclic.
R
8
is uracil or dihydrouracil optionally substituted with a group selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteralicyclic, halo, cyano, nitro and —NRR′.
R
9
and R
10
are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, mercapto, alkylthio, halo, cyano, and —NRR′.
R and R′ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalic
Boojamra Constantine G.
Hecker Scott
Lee Ving J.
Leger Roger
Lemoine Rémy C.
Bingham & McCutchen LLP
Essential Therapeutics, Inc.
Low Christopher S. F.
Lukton David
Rose Bernard F.
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