Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-22
2004-02-03
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S230000
Reexamination Certificate
active
06686361
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to methods of treating anxiety and depression using R-6-hydroxy-buspirone and pharmaceutical compositions containing R-6-hydroxy-buspirone.
Buspirone, chemically: 8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione, is approved for the treatment of anxiety disorders and depression by the United States Food and Drug Administration. It is available under the trade name BUSPAR® from Bristol-Myers Squibb Company.
Studies have shown that buspirone is extensively metabolized in the body. (See, for example, Mayol, et al.,
Clin. Pharmacol. Ther.,
37, p. 210, 1985). One of the metabolites is 6-hydroxy-8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione having Formula I. This metabolite is also known as BMS 28674, BMS 442608, or
as 6-hydroxy-buspirone. This compound is believed to be the active metabolite of buspirone and its use in treating anxiety disorders and depression is disclosed in U.S. Pat. No. 6,150,365. The specific stereochemistry of 6-hydroxy-buspirone has not been described previously. Neither racemic 6-hydroxy-buspirone nor its enantiomers are commercially available at the present time.
Preclinical studies demonstrate that 6-hydroxy-buspirone, like buspirone, demonstrates a strong affinity for the human 5-HT1A receptor. In functional testing, 6-hydroxy-buspirone produced a dose-dependent anxiolytic response in the rat pup ultrasonic vocalization test, a sensitive method for assessment of anxiolytic and anxiogenic effects (Winslow and Insel, 1991
, Psychopharmacology,
105:513-520).
Clinical studies in volunteers orally dosed with buspirone demonstrate that 6-hydroxy-buspirone blood plasma levels were not only 30 to 40 times higher but were sustained compared to buspirone blood plasma levels. The time course of 6-hydroxy-buspirone blood plasma levels, unlike buspirone blood plasma levels, correlate more closely with the sustained anxiolytic effect seen following once or twice a day oral dosing with buspirone.
Although buspirone is an effective treatment for anxiety disorders and depression symptomatology in a significant number of patients treated, about a third of patients get little to no relief from their anxiety and responders often require a week or more of buspirone treatment before experiencing relief from their anxiety symptomatology. Further, certain adverse effects are reported across the patient population. The most commonly observed adverse effects associated with the use of buspirone include dizziness, nausea, headache, nervousness, lightheadedness, and excitement. Also, since buspirone can bind to central dopamine receptors, concern has been raised about its potential to cause unwanted changes in dopamine-mediated neurological functions and a syndrome of restlessness, appearing shortly after initiation of oral buspirone treatment, has been reported in small numbers of patients. While buspirone lacks the prominent sedative effects seen in more typical anxiolytics such as the benzodiazepines, patients are nonetheless advised against operating potentially dangerous machinery until they experience how they are affected by buspirone.
It can be seen that it is desirable to find a medicament with buspirone's advantages but which demonstrates more robust anxiolytic potency with a lack of the above described adverse effects.
Formation of 6-hydroxy-buspirone occurs in the liver by action of enzymes of the P450 system, specifically CYP3A4. Many substances such as grapefruit juice and certain other drugs; e.g. erythromycin, ketoconazole, cimetidine, etc., are inhibitors of the CYP3A4 isozyme and may interfere with the formation of this active metabolite from buspirone. For this reason it would be desirable to find a compound with the advantages of buspirone but without the drug—drug interactions when coadministered with agents affecting the activity level of the CYP3A4 isozyme.
SUMMARY OF THE INVENTION
It has now been discovered that the R-isomer of 6-hydroxy-buspirone is an effective treatment for anxiety disorders and depression which should not give rise to the adverse effects associated with buspirone, as well as having an advantage in specificity over racemic 6-hydroxy-buspirone. Therefore, in one aspect, the present invention relates to a method of treating anxiety disorders and depression, comprising administration to a person in need of such therapy a therapeutically effective amount of R-6-hydroxy-buspirone or a pharmaceutically acceptable salt thereof.
It has also been discovered that the R-isomer of 6-hydroxy-buspirone is useful in treating a number of other clinical disorders. Specifically, the present invention relates to methods of treating the following: extrapyramidal motor disorders; panic disorders such as panic attacks; agoraphobia, and phobic anxiety; short-term memory deficit; alcohol abuse and alcoholism symptomatology; nicotine dependence; drug addiction; eating disorders; post traumatic stress disorder; sleep-related respiratory disorders such as sleep apnea and sudden infant death syndrome; childhood autism; pre-menstrual syndrome; sexual dysfunction; agitation; hostility; obsessive-compulsive disorder; nausea and vomiting; incontinence; and acute and chronic pain.
Yet another aspect of the present invention goes to pharmaceutical compositions comprising R-6-hydroxy-buspirone and their administration for treatment of clinical disorders.
And in a further aspect, the invention relates to R-6-hydroxy-buspirone itself, substantially free of the R-enantiomer, or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The active compound of the methods and compositions of the present invention is R-6-hydroxy-buspirone. The compound contains a chiral center that gives rise to the respective R- and S-spatial configurations. Neither enantiomer has been described in the literature. The structure of R-6-hydroxy-buspirone is shown in Formula II.
The R-6-hydroxy-buspirone utilized for the methods and compositions of the present invention is substantially free of the S-stereoisomer of 6-hydroxy-buspirone, S-6-hydroxy-buspirone. The term “substantially free of the S-stereoisomer” as used herein means that the compound and compositions of the present invention contain a significantly greater proportion of the R-isomer of 6-hydroxy-buspirone in relation to the S-isomer of 6-hydroxy-buspirone. In a preferred embodiment of the present invention, the compositions contain at least 90% by weight of R-6-hydroxy-buspirone and 10% by weight or less of S-6-hydroxy-buspirone. More preferably, the compositions contain at least 98% by weight of R-6-hydroxy-buspirone and 2% by weight or less of S-6-hydroxy-buspirone, and in this case, the term “substantially free of the S-isomer” means that the compositions contain at least 98% by weight of R-6-hydroxy-buspirone and 2% by weight or less of S-6-hydroxy-buspirone. These percentages are based upon the total amount of 6-hydroxy-buspirone in the composition. The terms “substantially optically pure R-isomer of 6-hydroxy-buspirone” or “substantially optically pure S-6-hydroxy-buspirone” and “optically pure R-isomer of 6-hydroxy-buspirone” and “optically pure S-6-hydroxy-buspirone” are also encompassed by the above-described amounts.
The present invention also encompasses a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of R-6-hydroxy-buspirone or a pharmaceutically acceptable acid addition salt and/or hydrate thereof. Pharmaceutically acceptable acid addition salts of R-6-hydroxy-buspirone are those in which the anion does not contribute significantly to toxicity or pharmacologic activity of the base form of R-6-hydroxy-buspirone.
Acid addition salts are obtained either by reaction of R-6-hydroxy-buspirone with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed in the literature and available to any practitioner skilled in the art. Exam
Li Jianqing
Mayol Robert F.
Yevich Joseph P.
Yocca Frank
Bernhardt Emily
Bristol--Myers Squibb Company
Ryan Richard P.
LandOfFree
R-6-hydroxy-buspirone does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with R-6-hydroxy-buspirone, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and R-6-hydroxy-buspirone will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3336935