Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-17
2002-08-20
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S223000, C540S226000, C540S227000, C540S230000, C540S310000, C540S316000, C540S318000, C540S355000
Reexamination Certificate
active
06437119
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is concerned with an improved process for forming a single composition from two antibiotics, e.g., from Quinolone antibiotics and Beta-lactam antibiotics, as Penicillin and Cephalosporin types, and also with the addition of steps to add a third antibiotic component to the bi-component composition, the third (3
rd
) antibiotic drawn from the group Vancomycin, Erythromycin, Azithromycin, an Aminoglycoside as Gentamycin, A Tetracycline, Clindamycin, and Chloramphenicol.
The value of a composition wherein a trio of individual antibiotics are joined is that the bacterial infective agent will simultaneously be attacked by agents which are known to attack the cell-wall producing enzyme of the bacteria, and inhibit the DNA gyrase enzyme, and inhibit the enzyme that controls bacterial protein synthesis.
The value of this composition of three antibiotic functional types is that it will further be seen that resistant strains will be very unlikely to develop due to the necessity of simultaneously overcoming three attacking agents.
There is evidence for this statement in the present day success of several cocktails—combinations—of drugs which are being utilized to treat AIDS patients, TB patients and other similar examples. In the case of the AIDS virus, a combination of two retroviral inhibitors, as AZT and DDI are being employed plus one of several viral protease inhibitors as invirase. In the case of TB patients a cocktail of four drugs is being utilized successfully to overcome resistant TB strains. Further, White, U.S. Pat. No. 5,281,703, has shown that a composition containing a Cephalosporin and a Quinolone antibiotic is very effective in treating certain pneumonias. Pirie, U.S. Pat. No. 4,351,840, has also shown that the composition of a Penicillin with a Beta-lactam protective inhibitor enhances the value of Penicillin.
In U.S. Pat. No. 5,693,791, whose disclosure is incorporated by reference herein, I have disclosed the process of linking a wide variety of antibiotic moieties, two at a time, using diisocyanates, dianhydrides, diacid chlorides, diepoxides, carbodiiamides and the like as the linking reagents.
There are prior for linking two antibiotics into a single composition, e.g., quinolone antibiotics with the beta-lactam, cephalosporin. However, the processes are complex: the reagents are dangerous; and they are all expensive. They are compared in the following table:
1. White, Norwich Eaton Pharmaceutical, U.S. Pat. No. 5,180,719
A. Links quiniolines and cephalosporins
B. Linking agent-phosgene
C. Synthesis steps—multiple
D. Activity—good, human tests
E. Cost—high
2. Albrecht, Hoffman-LaRoche, U.S. Pat. No. 5,336,768
A. Links quinolones and cephalosporins
B. Linking agent—phosgene
C. Synthesis steps—multiple
D. Activity—good, human tests
E. Cost—high
3. Machida, Eisai (Japan), U.S. Pat. No. 4,546,176
A. Links cephalosporin with substituted quinolone nucleus (not quinolone antibiotic)
B. Linking agent—acid chloride of quinolone
C. Synthesis—multi-step
D. Activity—good
E. Cost—high
4. Arnold, ICI, U.S. Pat. No. 5,232,918
A. Links cephalosporin with substituted quinolone nucleus (not quinolone antibiotic)
B. Linking agent—acid chloride of quiniolone
C. Synthesis—multi-step
D. Activity—good
E. Cost—high
5. Haskell, Warner-Lambert, U.S. Pat. No. 4,404,201
A. Links cephalosporin-quinolone nucleus (not quinolone antibiotic)
B. Linking agent—imidazole
C. Synthesis steps—multiple
D. Activity—good
E. Cost—high
For example, the fluoroquinolone antibiotic inhibits DNA synthesis in the bacteria; Cell wall synthesis is inhibited by the beta lactam antibiotic; and protein synthesis of the bacterial cell is stopped by a wide variety of antibiotics, e.g., tetracyclines, metronidazole, chloramphenicol, clindinomycin, aminoglycosides, erythromycin, azithromycin and vancomycin. The last named, vancomycin, is also a cell wall synthesis inhibitor and has been the antibiotic of choice in attacking staphylococcus infections.
DEFINITIONS OF BETA-LACTAMS
There are a number of classes of antibiotics which may be designated “beta-lactams.”
1. Penicillins
2. Cephalosporins
3. Monobactams
4. Carbapenems
All four classes of beta-lactams process several features in common:
1. a 4-membered ring termed a &bgr;-lactam ring. This ring is chemically sensitive to acid and to some bacterial enzymes.
2. Three of the four types have a ring fused to the &bgr;-lactam ring, but not the monobactam type.
3. All possess a carboxyl group pendant to the ring fused to the &bgr;-lactam ring, or a carboxyl group on a side chain pendant to the &bgr;-lactam ring.
4. All possess an amino or hydroxyl group on the pendant side chain of the &bgr;-lactam ring.
From a microbial point of view all four classes of &bgr;-lactams interfere with cell wall synthesis of bacteria.
These four classes of antibiotics have been designated as “beta-lactams” in modern pharmacology books. See, for example, pages 724-737 of Chapter 43 in
“Basic and Clinical Pharmacology,”
B. G. Katzung, Appleton and Lange, 7
th
edition, 1998, Stamford, Conn.
SUMMARY OF THE INVENTION
The general formula for the three antibiotic species is given below
in which Q is a Quinolone antibiotic joined to a Beta-lactam antibiotic B by means of an amide group, or an ester group, and the Beta-lactam antibiotic is then joined by means of a linkage.
in which Z is an oxygen or a nitrogen atom, and A is an antibiotic drawn from the following group:
1. Tetracyclines (all)
2. Metroindazole
3. Chloramphenicol
4. Clindinamycin
5. Aminoglycosides (all)
6. Erythromycin
7. Azithromycin
8. Vancomycin
The initial step in these syntheses is the conversion of the Quinolone to an acid chloride by means of reaction with thionyl chloride. The second step is the reaction of the Quinolone acid chloride with a Beta-lactam type bearing an amino group. The third step is the conversion of the carboxyl group of the Beta-lactam molecule to an acid chloride utilizing the reagent triphenyl phosphine and carbon tetrachloride. The fourth step in the reaction sequence is the reaction of the Beta-lactam acid chloride with the third component drawn from the list of eight antibiotics above, which forms with an amide linkage or an ester linkage.
The three-component antibiotic produced is suitable for the treatment of a wide variety of bacterial infections in man and animals, and will reduce substantially the possibility that antibiotic resistant strains of bacteria will develop.
It will be noted that the chemistry has been selected to avoid structural changes in the components, and chirality is also maintained.
DETAILED DESCRIPTION OF THE INVENTION
I. Composition of Three Antibiotics
The synthesis of the general formula
for the antibiotic composition is detailed below, in which Q—is a quinolone, B—is a Beta-lactam, Z—is an oxygen or nitrogen and A is a third component, an antibiotic.
The initial step is the conversion of a Quinolone to the corresponding acid chloride
in which R is an alkyl group and Y is an amine substituted group without a free amine group
Ofloxacin
and Nalidixic Acid
and Pefloxacin
are example Quinolone antibiotics.
The conversion to the corresponding acid chlorides is straightforward and utilizes SOCl
2
.
There are no isomers resulting from this reaction, the product is a singular one immediately useful in the synthesis sequence.
The reaction with nalidixic acid, or Ofloxacin is analgous to the Pefloxacin reaction, when thionyl chloride is the reagent for conversion to the acid chloride.
The presence of the quinolone component inhibits the DNA gyrase enzyme essential to bacterial multiplication.
The second step in the synthesis sequence is the condensation of the Quinolone acid chloride with the Beta-lactam type antibiotic. The purpose of this component is to cause inhibition of the cell wall synthesis by bacteria.
The following penicillins will be employed:
in which R is:
The following Cephalosporins will be employed:
wherein R
1
and R
2
are as listed,
R
1
R
2
Name
—CH
3.
Cephalexin
—CH
3.
Cephradine
—CH
3.
Cefadroxil
—C
Berch Mark L.
Wolfson Herbert M.
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