Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-09
2002-06-04
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S281000
Reexamination Certificate
active
06399621
ABSTRACT:
TECHNICAL FIELD
This invention is directed to N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-&agr;]-pyrimidin-7-yl}phenyl)acetamide which has utility as a sedative or hypnotic agent, as well related compositions and methods.
BACKGROUND OF THE INVENTION
The term “insomnia” is used to describe all conditions related to the perception of inadequate or non-restful sleep by the patient (Dement,
International Pharmacopsychiatry
17:3-38, 1982). Insomnia is the most frequent complaint, being reported by 32% of the adult population surveyed in the Los Angeles area (Bixler et al,
Amer. Journal of Psychiatry
136:1257-1262, 1979), and 13% of the population surveyed in San Marino, Italy (Lugaresi et al.,
Psychiatric Annals
17:446-453, 1987). Fully 45% of the surveyed adult population of Alachua County, Fla., reported trouble getting to sleep or staying asleep (Karacan et al.,
Social Science and Medicine
10:239-244, 1976). The prevalence of insomnia has also been shown to be related to the age and sex of the individuals, being higher in older individuals and in females.
Insomnia, if left untreated, may result in disturbances in metabolism and overall body function. Reduced productivity and significant changes in mood, behavior and pyschomotor function. Chronic insomnia is associated with a higher incidence of morbidity and mortality. Traditionally, the management of insomnia includes treatment and/or and/or mitigation of the etiological factors, improving sleep hygiene and the administration of hypnotic agents. The early hypnotic agents, such as barbiturates, while effective, elicited a spectrum of unwanted side effects and longer-term complications. For example, barbiturates have the potential to result in lethargy, confusion, depression and a variety of other residual effects many hours post dosing, as well as having a potential for being highly addictive.
During the 1980's, the pharmaceutical treatment of insomnia shifted away from barbiturates and other CNS depressants toward the benzodiazepine class of sedative-hypnotics. This class of sedative-hypnotic agents showed substantial effectiveness in producing a calming effect which results in sleep-like states in man and animals (Gee et al.,
Drugs in Central Nervous Systems
, Horwell (ed.), New York, Marcel Dekker, Inc., 1985, p. 123-147) and had a greater safety margin than prior hypnotics, barbiturates or chloral hydrate (Cook and Sepinwall,
Mechanism of Action of Benzodiazepines
, Costa and Greengard (eds.), New York, Raven Press, 1975, p. 1-28). The therapeutic action of benzodiazepines are believed to be mediated by binding to a specific receptor on benzodiazepine GABA complexes in the brain. As a result of this binding, synaptic transmission is altered at neurons containing the benzodiazepine GABA complex (Clody et al.,
Benzodiazepines II
, Rechtschaffen and Kales (eds.), New York, Springer-Verlag, 1989, p. 341-354). The clinical usefulness of different benzodiazepine hypnotics relates largely to their pharmacokinetic differences with regard to this binding and, in particular, to the half-lives of the parent compound and its active metabolites (Finkle,
Benzodiazepines II
, Rechtschaffen and Kales (eds.), New York, Springer-Verlag, 1989, p. 619-628).
As with barbiturates, however, many benzodiazepines also possess side effects that limit their usefulness in certain patient populations. These problems include synergy with other CNS depressants (especially alcohol), the development of tolerance upon repeat dosing, rebound insomnia following discontinuation of dosing, hangover effects the next day, and impairment of psychomotor performance and memory (Cook and Sepinwall, supra; Hartman,
Benzodiazepines II
, Rechtschaffen and Kales (eds.), New York, Springer-Verlag, 1989, p. 187-198; Linnoila and Ellinwood,
Benzodiazepines II
, Rechtschaffen and Kales (eds.), New York, Springer-Verlag, 1989, p. 601-618). Memory impairment, which can include amnesia for events occurring prior to and after drug administration, is of particular concern in the elderly whose cognitive function may already be impaired by the aging process (Ayd,
Benzodiazepines II
, Rechtschatfen and Kales (eds.), New York, Springer-Verlag, 1989, p. 593-600; Finkle, supra; Linnoila and Ellinwood, supra).
More recently, a new class of agents have undergone development. These agents are non-benzodiazepine compounds, which bind selectively to a specific receptor subtype of the benzodiazepine receptor. This receptor selectivity is thought to be the mechanism by which these compounds are able to exert a robust hypnotic effect, while also demonstrating an improved safety profile relative to the non-selective, benzodiazepine class of agents. The first of these agents to be approved by the United States Food and Drug Administration (FDA) for marketing in the United States was Ambien (zolpidem tatrate), which is based on the imidazopyridine backbone (see U.S. Pat. Nos. 4,382,938 and 4,460,592). In addition to Ambien, another compound known as Sonata (zelaphon), which is a pyrazolopyrimidine-based compound, is currently awaiting FDA approval (see U.S. Pat. No. 4,626,538). Other non-benzodiazepine compounds and/or methods for making or using the same have also been reported (see, e.g., U.S. Pat. Nos. 4,794,185, 4,808,594, 4,847,256, 5,714,607, 4,654,347; 5,891,891; 5,538,977).
While significant advances have been made in this field, there is still a need in the art for compounds which are effective as sedative or hypnotic agents generally, particularly in the context of treating insomnia. Such compounds preferably have superior PK profiles in adults and the elderly, a preferable metabolism and excretion pathway, a lower propensity to tolerance, less hangover effects, no additive effects with alcohol and other CNS depressant drugs, and/or a lower propensity for abuse. The present invention fulfills this need and provides further related advantages.
SUMMARY OF THE INVENTION
In brief, the present invention is directed to a compound and the use of the same as a sedative or hypnotic agent. More specifically, the compound of this invention is N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-&agr;]-pyrimidin-7-yl}phenyl)acetamide, which compound has the following structure 1 (referred to herein as “Compound 1” or “1”), including pharmaceutically acceptable salts thereof:
The present invention is also directed to methods for treating a variety of conditions by administering an effective amount of Compound 1 to an animal or subject in need thereof (referred to herein as a “patient”), typically a warm-blooded animal (including a human). Prior to administration, Compound 1 is preferably formulated as a pharmaceutical composition which contains an effective dosage amount of Compound 1 in combination with one (or more) pharmaceutically acceptable carrier(s). Conditions that may be treated by Compound 1, or a pharmaceutical composition containing Compound 1, include any condition which may benefit from administration of agents which possess anxiolytic, anti-anoxic, sleep-inducing, hypnotic, anticonvulsant, and/or skeletal muscle relaxant properties. Such conditions include insomnia specifically, as well as sleep disorders generally and other neurological and psychiatric complaints, anxiety states, vigilance disorders, such as for combating behavioral disorders attributable to cerebral vascular damage and to the cerebral sclerosis encountered in geriatrics, epileptic vertigo attributable to cranial trauma, and for metabolic encephalopathies.
These and other aspects of this invention will be apparent upon reference to the following detailed description. To that end, certain patent and other documents are cited herein to more specifically set forth various aspects of this invention. Each of these documents are hereby incorporated by reference in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, the present invention is directed to N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,
Albright Jay D.
Beer Bernard
Dusza John P.
Tomcufcik Andrew S.
American Cyanamid Company
Ford John M.
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