WO2002056870A2 - Method for treating sleep disorders - Google Patents

Abstract

A method of treating sleep disorders in a mammal by administering to the mammal an effective amount of 1,7,7-trimethylbicyclo[2.2.1]heptane derivative of Formula I wherein R is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.

Description

METHOD FOR TREATING SLEEP DISORDERS

FIELD OF THE INVENTION

The present invention relates in general to a method for treating sleep disorders in a mammal. More particularly, the invention relates to a method for treating sleep disorders in a mammal by administering to the mammal an effective amount of 1,7,7- trimethylbicyclo[2.2.1]heptane derivative of Formula I

wherein R is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.

In addition, the present invention relates to a method for improving the quality of sleep in a mammal by administering to the mammal an effective amount of 1,7,7- trimethylbicyclo[2.2.1]heptane derivative of Formula I, or a pharmaceutically acceptable salt thereof.

Additional objects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention will be realised and attained by means of the elements and combinations particularly pointed out in the appended claims. BACKGROUND OF THE INVENTION

The active ingredients of this invention, (lR,2S,4R)-(-)- 2-phenyl 2- (dimethylaminoethoxy)-l,7,7-trimethyl-bicyclo[2.2.1]heptane, known as deramciclane, and (lR,2S,4R)-(-)- 2-phenyl-2-(methylaminoethoxy)-l,7,7-trimethyl- bicyclo[2.2.1]heptane, known as N-desmethylderamciclane, and their pharmaceutically acceptable acid addition salts with inorganic and organic acids generally used for the purpose, fall within the disclosures of U.S. Patent No. 4,342,762 and International Patent Application No. WO 98/17230, respectively, which are both incorporated herein by reference.

These compounds are selective serotonin 5HT2A- and/or 5HT2C-receptor antagonists. They have shown anxiolytic-like effects in animal test models.

DESCRIPTION OF THE INVENTION

Applicants have surprisingly discovered that the compounds of Formula (I) do provide better quality of sleep by having therapeutic effect on sleep disorders, especially on insomnia, in a mammal. Accordingly, an object of the present invention is a method for treating sleep disorders in a mammal by administering to the mammal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Sleep disorders, such as insomnia, nonrestorative sleep, narcolepsy (with symptoms like excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic hallucinations), sleep apnea, nightmares and night terrors, are often chronic in nature. Insomnia may be divided into difficulty initiating sleep or initial insomnia, difficulty maintaining sleep and early awakening. Sleep disorders may be caused by several reasons, such as various somatic diseases and psychiatric disorders. Psychiatric disorders include but are not limited to affective disorders, such as depression or anxiety disorders, such as Generalized Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), Panic Disorder (PD), Obsessive Compulsive Disorder (OCD), Post-Traumatic Stress Disorder (PTSD), or agoraphobia, hi addition, drugs used for the treatment of psychiatric disorders, such as venlafaxine and SSRIs (selective serotonin reuptake inhibitors) may cause sleep disorders, such as insomnia, as adverse effect. Even hypnotics may cause sleep disorders, such as decreased quality of sleep, as adverse effect.

For the purposes of this disclosure and claims the term "treatment" means treatment in order to cure or alleviate the disease or its symptoms, and to treatment in order to prevent the development or the exacerbation of the disease or its symptoms.

Pharmaceutically acceptable salts of the compound of Formula (I) can be formed with inorganic acids, e.g. hydrohalogenic acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid, or organic acids e.g., tartaric acid, succinic acid, malic acid, maleic acid, fumaric acid, citric acid, or lactic acid. Salt with fumaric acid is preferred.

Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient include the usual oral dosage forms, such as tablets, capsules, and liquid preparations. In oral dosage forms, the active ingredient can be mixed with suitable pharmaceutically acceptable excipients, such as starch, lactose, sucrose and magnesium stearate, in accordance with conventional pharmaceutical practice.

The precise amount of the drug to be administered to a mammal for the treatment of sleep disorders is dependent on numerous factors known to one skilled in the art, such as the compound to be administered, the general condition of the patient, the condition to be treated etc. For example, the usual recommended oral daily dose of deramciclane would be about 5-150 mg/day, or about 10-60 mg/day, or about 30-60 mg/day or about 30 mg/day.

The invention will be further clarified by the following example, which is intended to be purely exemplary of the invention.

EXAMPLE The effects of deramciclane were studied in a randomised placebo-controlled double-blind study. The subjects were randomly assigned to four parallel groups to receive one tablet twice daily (b.i.d) of a placebo, 5mg (=10mg/day), 15mg (=30mg/day), or 30mg (=60mg/day) deramciclane.

The efficacy of deramciclane on insomnia was measured using the Hamilton Anxiety Scale (HAM-A) Insomnia item, hi pairwise comparisons between deramciclane dose levels and placebo, patients treated with deramciclane 15 mg b.i.d experienced less frequent (Mantel-Haenszel model p=0.050) insomnia than those receiving placebo. Further, the patients did not report sedation or sleepiness as adverse effects.

Although the invention has been illustrated by the preceding example, it is not to be construed as being limited to the materials employed therein; rather, the invention is directed to the generic area as herein disclosed. Various modifications and embodiments thereof can be made without departing from the spirit or scope thereof.

Claims

CLAIMS:

1. A method of treating a sleep disorder in a mammal, comprising administering to said mammal an effective amount of at least one compound of Formula (I)

wherein R is hydrogen or methyl, or a pharmaceutically acceptable salt of the compound of Formula (I).

2. The method of claim 1, wherein the sleep disorder is insomnia.

3. The method of claim 1 , wherein the sleep disorder is narcolepsy.

4. The method of claim 1, wherein the sleep disorder is associated with an affective disorder.

5. The method of claim 4, wherein the affective disorder is depression.

6. The method of claim 1, wherein the sleep disorder is associated with an anxiety disorder.

7. The method of claim 6, wherein the anxiety disorder is Generalized Anxiety Disorder.

8. The method of claim 6, wherein the anxiety disorder is Social Anxiety Disorder.

9. The method of claim 6, wherein the anxiety disorder is Panic Disorder.

10. The method of claim 6, wherein the anxiety disorder is agoraphobia.

11. The method of claim 6, wherein the anxiety disorder is Obsessive Compulsive Disorder.

12. The method of claim 6, wherein the anxiety disorder is Post-Traumatic Stress Disorder.

13. The method of claim 1 , wherein the sleep disorder is associated with administration of a drug used for the treatment of a psychiatric disorder.

14. The method of claim 1 , wherein the mammal is human.

15. The method of claim 1, wherein at least one compound is deramciclane or a pharmaceutically acceptable salt thereof.

16. The method of claim 1, wherein about 5 to about 150 mg/day of at least one compound as claimed in claim 1 is administered.

17. The method of claim 16, wherein the amount administered is about 10 to about 60 mg/day.

18. The method of claim 17, wherein the amount admimstered is about 30 mg/day.

19. A method for improving the quality of sleep in a mammal by administering to the mammal an effective amount of at least one compound of Formula I

wherein R is hydrogen or methyl, or a pharmaceutically acceptable salt of the compound of Formula (I).