Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-23
2002-09-10
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S272000, C514S274000, C544S276000, C544S277000, C544S312000, C544S321000
Reexamination Certificate
active
06448256
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to antibiotic prodrugs and organic chemistry.
BACKGROUND OF THE INVENTION
The management of life-threatening diseases caused by multi-antibiotic-resistant (MAR) bacteria has become a major clinical and public health problem. One approach to solving this problem is the identification of new antibiotic targets and the development of target-selective “bullets.”
Gram-positive bacterial DNA polymerase III, an enzyme essential for replication of the bacterial chromosome, is an attractive target. A number of N3-substituted 6-anilinouracils and 6-benzylaminouracils have been shown to inhibit the activity of this enzyme. These compounds base-pair with an unopposed template cytosine in the enzyme's DNA template and insert the anilino group into a specific “receptor” within the enzyme's dNTP-binding site. The base-pairing and receptor binding create a non-productive ternary complex of enzyme, inhibitor, and primer-template, thereby inhibiting replication of the bacterial chromosome and thus presenting bacterial reproduction, thereby inhibiting replication of the bacterial chromosome and thus preventing bacterial reproduction.
SUMMARY OF THE INVENTION
The invention is based on the discovery that certain prodrugs of ring N-substituted derivatives of 6-aminouracils, 6-aminoisocytosines, guanines, and 2-aminoadenines have advantageous properties, such as greater water solubility or greater oral bioavailability, than the ultimate drugs. The N-linked substituents generally include esters, such as amino acid esters and dicarboxylic acid esters. Upon administration into an animal, the prodrugs are converted into bioactive drugs by cleavage of the ester bond, e.g., via endogenous esterases. The prodrugs can therefore be formulated into compositions for treating Gram-positive bacterial infections.
The invention features compounds having the formulas:
where R
1
is —(CH
2
)
a
—(CHOH)
b
—(CH
2
)
c
—O—C(═O)—(CH
2
)d-CHR
5
-R
6
, where a is 1-4; b is 0 or 1; c is 1-5; d is 0-4; n is 0 or 1; R
5
is the side chain of an amino acid; R
6
is —COOH —COO
−
M
+
, or —NH
2
; each of R
2
and R
3
is, independently, linear C
1-6
alkyl, branched C
3-6
alkyl, linear C
1-6
haloalkyl, branched C
3-6
haloalkyl, halo, or R
2
and R
3
together are a bivalent moiety having the formula —(CH
2
)
3
—; M
+
is a pharmaceutically acceptable counter-ion, such as Na
+
; R
9
is a moiety containing an aryl group; and R
4
is =0 or —NH
2
, or a pharmaceutically acceptable salt thereof. For example, R
2
can be ethyl or iodo, and R
3
can be methyl. Upon administration of the prodrug into a subject, e.g., a mammal such as a human, R
1
of the compound is cleaved at the ester group to produce the drug.
The dotted lines representing chemical bonds in the structures described herein denote changes in valency when, e.g., R
4
is ═O versus —NH
2
in the structures described above.
In certain embodiments, R
5
is the side chain of a naturally-occurring amino acid, e.g., an amino acid of animal, plant, fungal or bacterial origin. For example, when d=0, R
5
can be the side chain of glycine, alanine, valine, leucine, isoleucine, glutamic acid, glutamine, aspartic acid, asparagine, lysine, phenylalanine, serine, proline, or ornithine. When d=1, R
5
can be the side chain of beta-alanine. When d=2, R
5
can be the side chain of gamma-aminobutyric acid. In other embodiments, a is 1, b is 0, c is 3, d is 0 or 1-4, and n is 0. The stereochemical configuration of any chiral carbon atom, including the carbon bonded to R
4
, can be S or R. R
5
can also be the side chain of synthetic non-naturally occurring amino acids.
The invention also features a pharmaceutical composition containing a compound of the invention (e.g., a racemic mixture thereof) and a pharmaceutically acceptable carrier. Also featured is a method of treating a Gram-positive bacterial infection in a subject (e.g., a mammal such as a human) by administering to the animal a therapeutically effective amount of a compound of the invention.
In another aspect, the invention includes a method of producing a compound by combining an amino acid or an amino acid anhydride with a compound having the formula
where R
7
is —(CH
2
)
a
—(CHOH)
b
—(CH
2
)
c
—R
8
, where a is 1-4; b is 0 or 1; c is 1-5; n each of R
2
and R
3
is, independently, linear C
1-6
alkyl, branched C
3-6
alkyl, linear C
1-6
haloalkyl, branched C
3-6
haloalkyl, halo, or R
2
and R
3
together are a bivalent moiety having the formula —(CH
2
)
3
—; R
8
is, e.g., —OH, -halo, —OSO
2
CH
3
, —OSO
2
CF
3
, or OSO
2
(p-tolyl); R
9
is a moiety containing an aryl group; and R
4
is ═O or —NH
2
.
The term halo includes any of F, Cl, Br and I. The term haloalkyl includes any of mono-, poly- and per-haloalkyl groups.
A pharmaceutically acceptable counter-ion is any positive or negative ion that is suitable in pharmaceutical formulations, including, without limitation, sodium, potassium, ammonium, phosphate, and chloride ions.
A therapeutically effective amount is an amount sufficient to decrease by 90% or less (e.g., 90, 95, 99, 99.9, or 99.99% or less) the number of bacteria in a subject, e.g., a mammal, as determined by standard assays and compared to a control number (e.g., the number of bacteria in a placebo-infected control subject). For example, a volume of a body fluid (e.g., blood, serum, cerebral spinal fluid, seminal fluid, or urine) can be obtained from the animal after administration of a compound of the invention. The number of bacteria can then be determined by diluting the fluid, plating on appropriate solid media, and comparing to a control number of bacteria (e.g., the number of bacteria in a fluid of a placebo-treated subject). If a therapeutically effective amount of the compound was administered, the number of bacteria after administration should be less than the control number. Alternatively, a solid or semi-solid tissue of a body (e.g., fecal matter) can be suspended in a fluid, and the fluid assayed for bacteria as described immediately above.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Prodrugs have many useful properties. For example, a prodrug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A prodrug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue. The use of prodrugs therefore enables the rapid development of effective, easily-administered antibiotic formulations for use in human patients suspected of having a bacterial infection or human patients in which prevention or amelioration of a subsequent bacterial infection is desired.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
REFERENCES:
patent: 4957924 (1990-09-01), Beauchamp
patent: 5516905 (1996-05-01), Brown et al.
patent: 5646155 (1997-07-01), Wright
patent: WO 96/06614 (1996-03-01), None
Colla et al., “Synthesis and Antiviral Activity of . . . ”, J. Med. Chem., 26:602-604, 1983.
Wright et al., “DNA polymerase III: A new . . . ,” Current Opinion in Anti-infective Investigational Drugs, 1(1):45-48, 1999.
Beauchamp et al., “Amino acid ester . . . ,” Antiviral Chemistry & Chemot
Brown Neal C.
Wright George E.
Zhi Chengxin
Shah Mukund J.
Truong Tamthom N.
University of Massachusetts
LandOfFree
Antibiotic prodrugs does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Antibiotic prodrugs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antibiotic prodrugs will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2891401