Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-24
2001-06-26
Kight, John (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S374000, C514S365000, C514S277000, C514S400000
Reexamination Certificate
active
06251898
ABSTRACT:
RELATED APPLICATION
This application is being filed simultaneously with a related application entitled, “Fluorenone Compounds with Modified 7-Position Substituents for Treating and Preventing Brain and Spinal Injury”, application Ser. No. 09/379,816. It describes and claims various fluorenone derivatives with ether, ester, or amide groups bonded to the 7-position of the fluorenone structure. The contents of that application are incorporated herein by reference, as though fully set forth herein.
BACKGROUND OF THE INVENTION
This invention is in the fields of neurology and pharmacology, and relates to drugs that can minimize brain injury due to various causes, such as traumatic head injury or crises such as stroke, cardiac arrest, or asphyxiation.
The compounds disclosed herein (referred to as “fluorenone” drugs) are all within a class of compounds that were first discovered, and recognized to be potentially useful for reducing brain damage, in the 1970's. A great deal of time, effort, and expense were devoted to these drugs, and they were extensively patented and studied by one of the world's largest pharmaceutical companies, Merck & Company, Inc.
However, these drugs were never commercialized in any way, at any time, by Merck or any other company. The primary discoverer and inventor, Dr. Edward Cragoe, Jr., retired from Merck years ago, without ever getting to see any of these drugs provide the much-needed public service of offering a treatment to reduce or prevent brain injury. The patents on these fluorenone drugs have either expired, or were deliberately allowed to lapse due to intentional non-payment of the maintenance fees. The expired or lapsed patents in this field which cover fluorenone compounds include U.S. Pat. Nos. 4,316,043 (issued in February 1982); 4,317,922 (March 1982); 4,337,354 (June 1982); 4,356,313 and 4,356,314 (both in October 1982); 4,604,396 (August 1986); 4,675,341 (June 1987); 4,731,471 and 4,731,472 (both in March 1988); 4,782,073 (November 1988); 4,797,391 (January 1989); and 4,835,313 (May 1989).
Other lapsed and abandoned US patents which disclose and claim methods of synthesizing such compounds include U.S. Pat. Nos. 4,605,760 and 4,605,761 (both issued in August 1986).
Still other lapsed and abandoned US patents which disclose fluorenone-type compounds that are not as closely related to the subject matter of this invention include U.S. Pat. Nos. 4,731,470 (March 1988); 4,769,370 (September 1988); and 4,777,281 (October 1988).
Not a single one of the “fluorenone” compounds covered in any of the patents listed above has ever been commercialized or made available to the public. As mentioned above, all of the patents listed above were allowed to lapse and expire, due to nonpayment of their maintenance fees.
Fluorenone Compounds
The compounds disclosed in the most relevant prior art belong to a class of compounds that are analogs (mostly in the form of ether or ester analogs) of R-(+)-(5,6-dichloro-2,3,9,9a-tetrahydro-7-hydroxy-9a-hydrocarbyl-1H-fluoren-3-one compounds. Their general chemical structure is:
where R, X, and Y
1
and Y
2
are various organic moieties as specified in the prior art patents.
These compounds are sometimes called “fluorene” compounds or derivatives, because they are contain a tri-cyclic structure called fluorene, which is shown in the Merck Index and in various articles cited therein which date back to the 1920's. The illustration of fluorene analog L-644,711, shown at the top of
FIG. 1
herein, shows the conventional numbering used for the carbon atoms in the three-ring structure of fluorene.
It should be noted that fluorene has no relation to fluorine (the halogen atom), even though both words are pronounced the same. To avoid confusion, a fluorene compound which bears a double-bonded oxygen attached to one of the three ring structures can be called a “fluorenone” compound. All of the drugs discussed herein are fluorenone compounds, since they bear a double-bonded oxygen attached to the 3-carbon atom, as shown in FIG.
1
.
Cragoe et al 1986 and Cragoe 1987, which are review articles, provide additional information on prior art fluorenone compounds. Briefly, Cragoe and his coworkers initially began working with compounds known as “indanones”, which were demonstrated to have diuretic activity (i.e., they caused the excretion of large quantities of body fluids, via urine); see Woltersdorf et al 1977 and deSolms et al 1978. By systemically reducing body fluids via increased urine output, some of these drugs were shown to help reduce edema inside the brain after a traumatic brain injury. This reduction of edema inside the brain helped restore blood flow in an injured brain, as discussed in Cragoe et al 1986.
It was subsequently discovered and shown that some indanone compounds (which are bi-cyclic) could be further cyclized to generate tri-cyclic fluorenone compounds, which had increased activity in reducing brain edema without the unwanted systemic side effects produced on body tissues by diuretic agents; this was discussed in Cragoe 1987.
Accordingly, subsequent research by the Merck scientists focused on the tri-cyclic fluorenone compounds as potential neuroprotective drugs. That research in the late 1980's eventually settled on the L-644,711 compound as Merck's lead compound for in vitro and in vivo testing, since it was one of the most desirably active, effective, and selective compounds known at that time. In that particular compound, the “X” group attached to the 9a-position is a propyl group in the R(+) orientation, and the “R” group attached to the 7-carbon atom is a carboxymethyl group (HOOCCH
2
—). The complete chemical name of compound L-644,711 is R(+)-[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren-7-yl)oxy]acetic acid, and it is shown as a starting reagent at the top of FIG.
1
. It is also shown as compound (+)-5c in Cragoe et al 1986 (which summarizes the steps used to synthesize the entire series of fluorenone compounds), and as compound B-3(+) in Cragoe 1987 (which discusses the biological activities of various fluorenone compounds).
Samples of L-644,711 were provided by the Merck company to various researchers at medical schools and elsewhere, who tested it and reported on its potential for preventing brain damage (see, e.g., Kimelberg et al 1987 and 1989; Barron et al 1988; Trachtman et al 1989; Bednar et al 1992; and Kohut et al 1992).
However, as noted above, that line of research was abandoned within a few years. It did not lead to any commercialized compounds, and all of the US patents listed above were allowed to lapse and expire, due to non-payment of their maintenance fees.
L-644,711 was used as a “benchmark” compound in the new research disclosed herein. This new research, which was sponsored and funded by Cypros Pharmaceutical Corporation (Carlsbad, Calif.), identified a number of compounds that are markedly better than L-644,711 as a neuroprotective drug, as measured by appropriate biological assays.
Accordingly, the new compounds disclosed herein should be regarded as highly improved fluorenone compounds which perform markedly better than any of the prior art compounds disclosed in any of the patents cited above, or in any other publications that are known to the Inventors herein.
Background on Glial Cells and Traumatic Brain Edema
Inside the mammalian central nervous system (CNS, which includes the brain and spinal cord), cells are divided into two major categories: neurons, and glial cells. Neurons are cells which actually receive and transmit nerve signals. By contrast, the term “glial cells” includes a variety of supporting cells which help nourish and protect neurons, but which do not and cannot receive and transmit nerve signals. Glial cells are subdivided into various cell types, including: (1) astrocytes, which have cell shapes that resemble a star in certain respects, with a main central portion having various arms projecting outwardly from the central portion; (2) oligodendrocytes, which have several long proje
Cragoe, Jr. Edward J.
Marangos Paul J.
Weimann Torsten R.
Kight John
Pennie & Edmonds LLP
Questcor Pharmaceuticals, Inc.
Robinson Binta
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