Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-12
2003-02-04
Raymond, Richard L. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S411000, C514S224500, C514S229800, C514S250000, C514S347000, C544S031000, C544S095000, C544S101000, C544S250000, C544S346000, C546S087000, C548S428000, C548S430000, C548S432000, C548S441000, C548S448000
Reexamination Certificate
active
06514984
ABSTRACT:
BACKGROUND OF THE INVENTION
Alzheimer's disease is a degenerative disorder of the human brain. Clinically, it appears as a progressive dementia. Its histopathology is characterized by degeneration of neurons, gliosis, and the abnormal deposition of proteins in the brain. Pathological hallmarks include neurofibrillary tangles (paired helical filaments) and amyloid deposits within the parenchyma and cerebral vasculature.
Recent studies indicate that a major component of the pathology of Alzheimer's disease is chronic inflammation. See, J. Schnabel,
Science
, 260:1719-1720 (1993).
Administration of nonsteroidal anti-inflammatory drugs appears to slow the advance of Alzheimer's disease. Understanding this inflammatory component of Alzheimer's disease may lead to advances in methods of treating patients suffering from this disease.
The structure and physical properties of human non-pancreatic secretory phospholipase A
2
(hereinafter called, “sPLA
2
”) has been described in two articles, namely, “Cloning and Recombinant Expression of Phospholipase A
2
Present in Rheumatoid Arthritic Synovial Fluid” by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.;
The Journal of Biological Chemistry
, Vol. 264, No. 10, Issue of Apr. 5, 1989; pp. 5335-5338, and “Structure and Properties of a Human Nonpancreatic Phospholipase A
2
” by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake;
The Journal of Biological Chemistry
, Vol. 264, No. 10, Issue of Apr. 5, 1989; pp. 5768-5775, the disclosures of which are incorporated herein by reference.
It is believed that sPLA
2
is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids.
The scientific literature suggests NSAIDs may be beneficial in the treatment of Alzheimer's Disease. Moreover, COX-2 inhibitors are currently being tested for treatment of Alzheimer's.
PLA
2
inhibitors have been proposed as treatment for Alzheimer's disease (see, U.S. Pat. Nos. 5,478,857 and 5,563,164), but typically these have been cytosolic phospholipase A
2
inhibitors.
Because of the debilitating effects of Alzheimer's disease there continues to exist a need for effective treatments. This invention provides methods for the treatment of Alzheimer's disease in mammals.
SUMMARY OF THE INVENTION
This invention is a method of treating a mammal, including a human, susceptible to having Alzheimer's disease, to prevent or delay the onset of Alzheimer's disease; said method comprising administering to said mammal a prophylactically effective amount of substituted tricyclic sPLA
2
inhibitor or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof.
This invention is also a method of treating a mammal, including a human, already afflicted with Alzheimer's disease to prevent or diminish the rate of further deterioration; said method comprising administering to said mammal a therapeutically effective amount substituted tricyclic sPLA
2
inhibitor compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
All temperatures stated herein are in degrees Celsius (° C.). All units of measurement employed herein are in weight units except for liquids which are in volume units.
General Definitions
The term “prophylactically effective amount” is the quantity of substituted tricyclic sPlA
2
inhibitor required to prevent or significantly delay the onset of Alzheimer's disease in a mammal susceptible (by reason of age, family history, etc.) to contracting Alzheimer's disease.
The term “therapeutically effective amount” is the quantity of substituted tricyclic sPLA
2
inhibitor sufficient to prevent or retard the progress of Alzheimer's disease in a mammal already afflicted with Alzheimer's disease.
The term “parenteral” means not through the alimentary canal but by some other route such as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, or intravenous.
The term “active compound” means one or more substituted tricyclic sPLA
2
inhibitors used in the method of the invention as further described in Formula III or named below.
As used herein, the term, “alkyl” by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl tert butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and the like. The term “alkyl” includes —(C
1
-C
2
)alkyl, —(C
1
-C
4
)alkyl, —(C
1
-C
6
)alkyl, —(C
5
-C
14
)alkyl, and —(C
1
-C
10
)alkyl.
The term “alkenyl” as used herein represents an olefinically unsaturated branched or linear group having at least one double bond. Examples of such groups include radicals such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl as well as dienes and trienes of straight and branched chains.
The term “alkynyl” denotes such radicals as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl as well as di- and tri-ynes.
The term “halo” means chloro, fluoro, bromo or iodo.
The term “—(C
1
-C
4
)alkoxy”, as used herein, denotes a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups, attached to the remainder of the molecule by the oxygen atom.
The term “phenyl(C
1
-C
4
)alkyl” refers to a straight or branched chain alkyl group having from one to four carbon atoms attached to a phenyl ring which chain is attached to the remainder of the molecule. Typical phenylalkyl groups include benzyl, phenylethyl, phenylpropyl, phenylisopropyl, and phenylbutyl.
The term “—(C
1
-C
4
)alkylthio” defines a straight or branched alkyl chain having one to four carbon atoms attached to the remainder of the molecule by a sulfur atom. Typical —(C
1
-C
4
)alkylthio groups include methylthio, ethylthio, propylthio, butylthio and the like.
The term “—(C
3
-C
14
)cycloalkyl” includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl and the like. The term “—(C
3
-C
14
)cycloalkyl” includes and —(C
3
-C
7
)cycloalkyl.
The term, “heterocyclic radical”, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pryidinyl, dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, and quinoxalinyl.
The term “carbocyclic radical” refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms. Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexeyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb),
where n is an integer from 1 to 8.
The term, “non-interfering substituent”, refers to rad
Benjamin Roger S.
Eli Lilly and Company
Raymond Richard L.
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