Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1993-12-01
2002-12-03
Marx, Irene (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S324000, C514S408000, C514S422000
Reexamination Certificate
active
06489355
ABSTRACT:
BACKGROUND OF THE INVENTION
Alzheimer's Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in varied races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. To date, AD has proven to be incurable.
The brains of individuals with AD exhibit neuronal degeneration and characteristic lesions variously referred to as amyloidogenic plaques, vascular amyloid angiopathy, and neurofibrillary tangles. Large numbers of these lesions, particularly amyloidogenic plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restricted anatomical distribution are found in the brains of most aged humans who do not have clinical AD. Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
Several lines of evidence indicate that progressive cerebral deposition of particular amyloidogenic proteins, &bgr;-amyloid proteins, (&bgr;AP), play a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, Selkoe, (1991) Neuron 6:487. Recently, it has been shown that &bgr;AP is released from neuronal cells grown in culture and is present in cerebrospinal fluid (CSF) of both normal individuals and AD patients. See, Seubert et al., (1992) Nature 359:325-327.
In addition to Alzheimer's Disease and other conditions associated with the amyloidogenic peptides &bgr;AP, there exist conditions associated with other amyloidogenic peptides which are structurally similar to &bgr;AP but which share no sequence homology with &bgr;AP. Recent studies have demonstrated the functional interchangeability of many of these amyloidogenic peptides with regard to neurotoxicity. P. C. May, et al.,
Journal of Neurochemistry
, (December 1993); co-pending U.S. patent application Ser. No. 08/109,782, filed Aug. 19, 1993 (Docket X-9342).
Despite the progress that has been made in understanding the underlying mechanisms of AD and other amyloidogenic protein related diseases, there remains a need to develop compositions and methods for treatment of these diseases. Treatment methods could advantageously be based on drugs which are capable of inhibiting the generation or effect of amyloidogenic proteins.
SUMMARY OF THE INVENTION
This invention encompasses methods for the inhibition of a physiological disorder associated with amyloidogenic proteins, which method comprises administering to a human in need thereof an effective amount of a compound of formula I
wherein R
1
and R
3
are independently hydrogen,
or
wherein Ar is optionally substituted phenyl;
R
2
is selected from the group consisting of pyrrolidino, hexamethylenemino, and piperidino; or a pharmaceutically acceptable salt of solvate thereof.
The present invention also provides a method of inhibiting amyloidogenic protein production comprising administering to a human in need thereof an effective amount of a compound of formula 1.
The present invention also provides a method of inhibiting the deposition of amyloid plaque comprising administering to a human in need thereof an effective amount of a compound of formula 1.
The present invention also provides a method of inhibiting Alzheimer's Disease (AD) comprising administering to a human in need thereof an effective amount of a compound of formula 1.
DETAILED DESCRIPTION OF THE INVENTION
The current invention concerns the discovery that a select group of benzothiophenes, those of formula I, are useful for inhibiting the effects of amyloidogenic proteins, and in particular the compounds inhibit amyloidogenic protein formation. The invention encompasses uses practiced by administering to a human in need thereof a dose of a compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof effective to inhibit a physiological disorder associated with amyloidogenic proteins, and preferably &bgr;-amyloid proteins.
The term “inhibit” includes its generally accepted meaning which includes prohibiting, preventing, restraining, and slowing, stopping, or reversing progression, severity, or a resultant symptom. As such, the methods include both therapeutic and prophylactic administration.
The term “physiological disorder associated with an amyloidogenic protein” includes diseases related to the innapropriate or undesirable deposition, such as in the brain, liver, kidney or other organ, of at least one amyloidogenic protein, and as such includes AD (includes familial AD), Down's Syndrome, HCHWA-D, advanced aging of the brain and the like.
The term “effective amount” means the amount of compound necessary to inhibit physiological effects or disorders associated with an amyloidogenic protein, or inhibit amyloidogenic production or deposition, or inhibit Alzheimers disease, as the case may be.
The term “amyloidogenic protein” as used herein refers to those peptides which have the ability to self-associate into higher ordered aggregates and eventually assemble into an amyloid plaque. The preferred target amyloidogenic proteins are &bgr;-amyloid proteins.
Generally, the compound is formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered by the intramuscular or intravenous routes. The compounds can be administered transdermally, and may be formulated as sustained release dosage forms and the like.
The compounds used in the methods of the current invention can be made according to established and analogous procedures, such as those detailed in U.S. Pat. Nos. 4,133,814, 4,418,068, and 4,380,635 all of which are incorporated by reference herein. In general, the process starts with a benzo[b]thiophene having a 6-hydroxyl group and a 2-(4-hydroxyphenyl) group. The starting compound is protected, alkylated, and deprotected to form the formula I compounds. Examples of the preparation of such compounds are provided in the U.S. patents discussed above, and in the examples in this application. Optionally substituted phenyl includes phenyl and phenyl substituted once or twice with C
1
-C
6
alkyl, C
1
-C
4
alkoxy, hydroxy, nitro, chloro, fluoro, or tri(chloro or fluoro)methyl.
Included in this invention is the compound raloxifene, below:
The compounds used in the methods of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of organic and inorganic acids and bases and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoa
Boudreaux William R.
Eli Lilly and Company
Marx Irene
Sales James J.
LandOfFree
Methods of inhibiting the effects of amyloidogenic proteins does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods of inhibiting the effects of amyloidogenic proteins, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods of inhibiting the effects of amyloidogenic proteins will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2980238