Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2000-09-01
2002-05-07
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C514S258100
Reexamination Certificate
active
06384221
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to polymorphs of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-&agr;]-pyrimidin-7-yl}phenyl)acetamide having activity over a wide range of indications, and particularly useful for the treatment of insomnia, and to related processes, 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, Florida, 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 psychomotor function. Chronic insomnia is associated with a higher incidence of morbidity and mortality. Traditionally, the management of insomnia includes treatment 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 is 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
, Rechtschaffen 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 being 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 tartrate), 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 (zaleplon), which is a pyrazolopyrimidine-based compound, recently received 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).
While significant advances have been made in this field, there is still a need in the art for compounds that are effective as sedative or hypnotic agents generally, particularly in the context of treating insomnia. One such class of compound is disclosed in U.S. Pat. Nos. 4,521,422 and 4,900,836. These patents, particularly U.S. Pat. No. 4,521,422, disclose a genus encompassing certain aryl and heteroaryl[7-(aryl and heteroaryl)-pyrazolo[1,5-a]pyrimidin-3-yl]methanones. More specifically, U.S. Pat. No. 4,521,422 discloses that compounds of this genus may be made by reacting an appropriately substituted pyrazole (a) with an appropriately substituted 3-dimethylamino-2-propen-1-one (b).
One particular compound that falls within the genus of U.S. Pat. No. 4,521,422 is N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-&agr;]-pyrimidin-7-yl}phenyl)acetamide, which has the following structure 1 (referred to herein as “Compound 1”):
Compound 1 may be made according to the procedures disclosed in U.S. Pat. No. 4,521,422, which procedure is more specifically disclosed in Example 1. In short, Compound 1 is made by reacting an appropriately substituted pyrazole (a) (i.e., wherein R
2
is hydrogen and R
3
is 2-thienyl) with an appropriately substituted 3-dimethylamino-2-propen-1-one (b) (i.e., wherein R
5
and R
6
are hydrogen and R
7
is 3-N(CH
3
)(COCH
3
)phenyl), followed by recystallization from dichloromethane/hexane. As one skilled in this field will recognize, the dichloromethane has been used to selectively solubilize or extract Compound 1 away from unwanted impurities, while subsequent addition of hexane causes Compound 1 to crystallize or “crash out.” When made in this manner, Compound 1 exists as a mixture of polymorphs.
While Compound 1 has proven particularly promising for the treatment of insomnia, improved forms of this compound are desired, particularly with regard to enhanced solubility, oral bioavailability and/or physical stability. The present invention fulfills this need and provides further related advantages.
SUMMARY OF THE INVENTION
The present invention is directed to substantially pure polymorphs of Compound 1 (referred to herein as “Form I” and “Form II”) which have particularly advantageous properties.
A substantially pure polymorph Form I of Compound 1 exhibits a predominant endotherm at about 196° C. (192-197° C. as measured by a TA 2920 Modulated Differential Scanning Calorimeter (DSC) at a scan rate of 10° C. per minute), and contains less than about 6% by weight of Form II. Specific embodiments of the substantially pure polym
O'Donnell Patrick B.
Thiele William Jay
Neurocrine Biosciences Inc.
Seed Intellectual Property Law Group PLLC
Shah Mukund J.
Truong Tamthom N.
LandOfFree
Polymorphs of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Polymorphs of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Polymorphs of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2864243