Title: Use of R (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol for the treatment of substance induced insomnia
Abstract: A method of providing symptomatic relief from sleep induced insomnia in a patient comprising administering an effective amount of R-(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
Patent Number: 6,939,879 Issued on 09/06/2005 to Mondadori, et al.
| Inventors:
|
Mondadori; Cesare (Reinach, CH);
Sorensen; Stephen M. (Chester, NJ);
Hitchcock; Janice M. (Fishers, IN)
|
| Assignee:
|
Aventis Pharmaceuticals Inc. (Bridgewater, NJ)
|
| Appl. No.:
|
609751 |
| Filed:
|
June 30, 2003 |
| Current U.S. Class: |
514/317 |
| Intern'l Class: |
A61K 031/44.5 |
| Field of Search: |
514/317
|
References Cited [Referenced By]
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| 4783471 | Nov., 1988 | Carr et al.
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| 4877798 | Oct., 1989 | Sorensen.
| |
| 4908369 | Mar., 1990 | Schechter et al.
| |
| 4912117 | Mar., 1990 | Carr et al.
| |
| 5021428 | Jun., 1991 | Carr et al.
| |
| 5064838 | Nov., 1991 | Carr et al.
| |
| 5106855 | Apr., 1992 | McLees.
| |
| 5134149 | Jul., 1992 | Carr et al.
| |
| 5169096 | Dec., 1992 | Carr et al.
| |
| 5561144 | Oct., 1996 | Carr et al.
| |
| 5618824 | Apr., 1997 | Schmidt et al.
| |
| 5700812 | Dec., 1997 | Carr et al.
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| 5700813 | Dec., 1997 | Carr et al.
| |
| 5721249 | Feb., 1998 | Carr et al.
| |
| Foreign Patent Documents |
| 0317933 | May., 1989 | EP.
| |
| 0319962 | Jun., 1989 | EP.
| |
| 0337136 | Oct., 1989 | EP.
| |
| WO 97/3460/3 | Sep., 1997 | WO.
| |
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|
Primary Examiner: Cook; Rebecca
Attorney, Agent or Firm: Gupta; Balaram
Parent Case Text
CROSS REFERENCE TO RELATED CASES
This application is a continuation of U.S. application Ser. No. 09/886,424,
filed, Jun. 21, 2001 now U.S. Pat. No. 6,613,779, now allowed, which is a continuation
of U.S. application Ser. No. 09/382,932, filed, Aug. 25, 1999, now U.S. Pat. No.
6,277,864 B1, issued Aug. 21, 2001, which claims the benefit of U.S. Provisional
Application No. 60/155,214, filed, Aug. 28, 1998 now abandoned.
Claims
1. A method of providing symptomatic relief from substance induced insomnia in
a patient comprising administering to said patient a therapeutically effective
amount of R-(+)-α-(2,3-dimethoxphenyl)-1-[2-(4-fluoropheyl)ethyl]-4-piperidinemethanol
or a pharmaceutically acceptable salt thereof wherein said substance is selected
from the group consisting of caffeine, alcohol, amphetamine, opioids, sedatives,
hypnotics and anxiolytics.
2. The method of claim 1 wherein the substance is caffeine.
3. The method of claim 1 wherein wherein the substance is alcohol.
4. The method of claim 1 wherein the substance is amphetamine.
5. The method of claim 1 wherein the substance is an opiod.
6. The method of claim 1 wherein the substance is a sedative.
7. The method of claim 1 wherein the substance is a hypnotic.
8. The method of claim 1 wherein the substance is an anxiolytic.
9. A method of providing symptomatic relief from alcohol induced insomnia in
a patient comprising administering to said patient a therapeutically effective
amount of R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 wherein alcohol induced insomnia is caused by effects
of taking alcohol.
11. The method of claim 9 wherein alcohol induced insomnia is caused by effects
of withdrawing from alcohol.
12. A method of providing symptomatic relief from caffeine induced insomnia in
a patient comprising administering to said patient a therapeutically effective
amount of R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
or a pharmaceutically acceptable salt thereof.
13. The method of claim 12 wherein alcohol induced insomnia is caused by effects
of taking caffeine.
14. The method of claim 12 wherein alcohol induced insomnia is caused by effects
of withdrawing from caffeine.
Description
FIELD OF THE INVENTION
The present invention relates to the therapeutic use of a compound for the treatment
of Sleep Disorders (insomnia and obstructive sleep apnea).
BACKGROUND OF THE INVENTION
The compound R-(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
(hereafter referred to as the "COMPOUND") is a 5HT2a antagonist useful in the treatment
of a variety of disorders. U.S. Pat. No. 5,169,096 claimed compounds having a generic
scope which encompassed the COMPOUND and disclosed uses of the treatment of anorexia
nervosa, variant angina, Raynaud's phenomenon, coronary vasospasms, prophylactic
treatment of migraine, cardiovascular diseases such as hypertension, peripheral
vascular disease, thrombotic episodes, cardiopulmonary emergencies and arrythmias,
and has anesthetic properties. See also U.S. Pat. Nos. 4,783,471; 4,912,117; and
5,021,428, which are divisions of U.S. Pat. No. 5,169,096. See also U.S. Pat. No.
4,877,798 (fibromyalgia), U.S. Pat. No. 4,908,369 (insomnia); U.S. Pat. No. 5,106,855
(glaucoma); EP 319 962 (anxiety); EP 337 136 (extrapyramidal symptoms). All of
the foregoing are incorporated herein by reference.
The COMPOUND was then specifically claimed in U.S. Pat. No. 5,134,149 which disclosed
uses of antagonizing serotonin at the 5Ht2 receptor, treating anxiety, variant
angina, anorexia nervosa, Raynaud's phenomenon, intermittent claudication, coronary
or peripheral vasospasms, fibromyalgia, extrapyramidal symptoms, arrythmias, thrombotic
illness, transient ischemic attacks, drug abuse, and psychotic illness such as
schizophrenia and mania. See also U.S. Pat. Nos. 5,561,144; 5,700,812; 5,700,813;
5,721,249—divisionals of U.S. Pat. No. 5,134,149—and also U.S. Pat.
No. 5,618,824 (obsessive compulsive disorder) and PCT/US97/02597 (depressive disorders
including major depressive episode and dysthymia, and bipolar disorder).
The COMPOUND is highly selective in its activity at the 5HT2a receptor compared
to other receptors, and, as such, has reportedly fewer side effects. It has been
shown to have a better CNS safety index relative to the reference compounds haloperiodol,
clozapine, risperiodone, ritanserin, and amperozide in preclinical testing. JPET
277:968-981, 1996, incorporated herein by reference. It has recently been discovered
that this COMPOUND is useful in the treatment of Sleep Disorders such as insomnia
and obstructive sleep apnea.
Chronic insomnia among adults in the United States has been estimated to
be present in ten percent of the adult population, and the annual cost for its
treatment is estimated at $10.9 billion.
JAMA 1997; 278: 2170-2177 at 2170.
Chronic insomniacs report elevated levels of stress, anxiety, depression and medical
illnesses. The most common class of medications for treating insomnia are the benzodiazepines,
but the adverse effect profile of benzodiazepines include daytime sedation, diminished
motor coordination, and cognitive impairments. Furthermore, the National Institutes
of Health Consensus conference on Sleeping Pills and Insomnia in 1984 have developed
guidelines discouraging the use of such sedative-hypnotics beyond 4-6 weeks because
of concerns raised over drug misuse, dependency, withdrawal and rebound insomnia.
JAMA 1997; 278: 2170-2177 at 2170. Therefore, it is desirable to have a
pharmacological agent for the treatment of insomnia which is more effective and/or
has fewer side effects that those currently used.
The prevalence of obstructive sleep apnea is estimated to be approximately 1-10%
in the adult population, but may be higher in elderly individuals. DIAGNOSTIC AND
STATISTICAL MANUAL OF MENTAL DISORDERS 4
th ed., American Psychiatric
Association, Washington D.C. Preliminary evidence suggests that having obstructive
sleep apnea may contribute to increased susceptibility to cardiovascular complications
such as hypertension, cardiac arrhythmias, stroke, and myocardial infarction. Excessive
daytime sleepiness is also a major complication.
Currently, the therapies used to treat obstructive sleep apnea include
weight loss for the obese patient, Nasal-continuous positive Airway Pressure (a
facemask used at night which produces a positive pressure within the upper airway),
pharyngeal surgery and the administration of a variety of pharmacologic agents
which have not been proven to be entirely successful.
Chest 109 (5):1346-1358
(May 1996) entitled Treatment of Obstructive Sleep Apnea, a Review, hereby incorporated
by reference. These agents include Acetazolamide, Medroxyprogesterone, Opioid Antagonists,
Nicotine, Angiotensin-Convertying Enzyme Inhibitors and Psychotropic Agents (including
those that prevent the reuptake of biogenic amines such as norepinephreine, dopamine
and serotonin). Id. At 1353. Many of these pharmacological agents used also have
a ventilatory depressant action (such as benzodiazepines) or other side effects
such as urinary hesitancy and/or impotence in men (Protriptyline) so that a new
agent with fewer side effects is needed for the treatment of obstructive sleep
apnea. Even though serotonin is a sleep-inducing agent and may be a ventilatory
stimulant (Id. At 1354), the COMPOUND of the present invention, which inhibits
serotonin at the 5HT2a receptor, has been found useful in treating obstructive
sleep apnea. See also
Am. J. Respir Crit Care Med (153) pp 776-786 (1996)
where serotonin antagonists exacerbated sleep apnea produced in English bulldogs.
But compare,
Journal of Physiology (466) pp 367-382 (1993), where it is
postulated that an excess of serotonin due to dysfunction of the serotonin biosynthesis
mechanisms might set up conditions which favor obstructive apneas;
European
Journal of Pharmacology (259):71-74 (1994) further work on rat model with 5ht2 antagonist.
Insomnia and Obstructive Sleep Apnea are sometimes found in conjunction
with other conditions and sometimes those conditions are treatable by the COMPOUND,
e.g., patients suffering from fibromyalgia may also have insomnia and/or sleep
apnea.
Am J Med Sci 1998; 315(6):367-376. Having one pharmacological agent
which treats two or more existing or potential conditions, as does the present
invention, is probably more cost effective, leads to better compliance and has
fewer side effects than taking two or more agents.
It is an object of the present invention to provide a therapeutic agent for the
use in treating Sleep Disorders. It is another object of the present invention
to provide one pharmaceutical agent which may be useful in treating two or more
conditions wherein one of the conditions is insomnia or sleep apnea and other Conditions
respond to treatment by the COMPOUND.
Subjective and Objective Determinations of Sleep Disorders
There are a number of ways to determine whether the onset, duration or quality
of sleep (e.g. non-restorative or restorative sleep) is impaired or improved. One
method is a subjective determination of the patient, e.g., do they feel drowsy
or rested upon waking. Other methods involve the observation of the patient by
another during sleep, e.g., how long it takes the patient to fall asleep, how many
times does the patient wake up during the night, how restless is the patient during
sleep, etc. Another method is to objectively measure the stages of sleep.
Polysomnography is the monitoring of multiple electrophysiological
parameters during sleep and generally includes measurement of EEG activity, electroculographic
activity and electromyographic activity, as well as other measurements. These results,
along with observations, can measure not only sleep latency (the amount of time
required to fall asleep), but also sleep continuity (overall balance of sleep and
wakefulness) which may be an indication of the quality of sleep.
There are five distinct sleep stages which can be measured by polysomnogrpahy:
rapid eye movement (REM) sleep and four stages of no-rapid eye movement (NREM)
sleep (stages 1, 2, 3 and 4). Stage 1 NREM sleep is a transition from wakefulness
to sleep and occupies about 5% of time spent asleep in healthy adults. Stage 2
NREM sleep, which is characterized by specific EEG waveforms (sleep spindles and
K complexes), occupies about 50% of time spent asleep. Stages 3 and 4 NREM sleep
(also known collectively as slow-wave sleep) are the deepest levels of sleep and
occupy about 10-20% of sleep time. REM sleep, during which the majority of typical
story like dreams occur, occupies about 20-25% of total sleep.
These sleep stages have a characteristic temporal organization across the night.
NREM stages 3 and 4 tend to occur in the first one-third to one-half of the night
and increase in duration in response to sleep deprivation. REM sleep occurs cyclically
through the night. Alternating with NREM sleep about every 80-100 minutes. REM
sleep periods increase in duration toward the morning. Human sleep also varies
characteristically across the life span. After relative stability with large amounts
of slow-wave sleep in childhood and early adolescence, sleep continuity and depth
deteriorate across the adult age range. This deterioration is reflected by increased
wakefulness and stage 1 sleep and decreased stages 3 and 4 sleep.
SUMMARY OF THE INVENTION
The present invention comprises a method of treating a patient for a Sleep Disorder
by administering to the patient a therapeutically sufficient amount of R-(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
or a pharmaceutically acceptable salt thereof. The Sleep Disorder can be Insomnia
(Primary Insomnia, Insomnia related to another Mental Disorder, or Substance-Induced
Insomnia) or Obstructive Sleep Apnea.
The present invention also comprises monotherapy for treating a Sleep Disorder
and another Condition treatable by administration of R-(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
or a pharmaceutically acceptable salt thereof. Examples of other Conditions treatable
by administration of R-(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
or a pharmaceutically acceptable salt thereof are schizophrenia, fibromyalgia,
obsessive compulsive disorder, coronary vasospams, thrombotic illness, angina,
anorexia nervosa, Raynaud's phenomenon, extrapyramidal symptoms, anxiety, arrythmias,
depressive disorders, and bipolar depression.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following terms have these specified meanings:
- a) the term "patient refers to a warm-blooded animal, such as for example,
rats, mice, dogs, cats, guinea pigs, and primates such as humans;
- b) the term "treat" refers to either preventing, providing symptomatic
relief, or curing the patient's disease, disorder or condition;
- c) the term "administering" comprises administration via any appropriate
route such as oral, sublingual, buccal, transdermal, inhalation, rectal or injection
(including intramuscular, intravenous, subcutaneous, etc.), or any other appropriate
method of providing the COMPOUND to the patient;
- d) The term "therapeutically sufficient amount" means enough of the
COMPOUND which becomes bioavailable through the appropriate route of administration
to treat the patient for the disorder, condition or disease;
- e) The term "pharmaceutically acceptable salt" means either an acid
addition salt or a basic addition salt which is compatible with the treatment of
patients for the intended use. "Pharmaceutically acceptable acid addition salt"
is any non-toxic organic or inorganic acid addition salt of the base compounds
represented by Formula I. Illustrative inorganic acids which form suitable salts
include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal
salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
Illustrative organic acids which form suitable salts include the mono-, di- and
tri-carboxylic acids. Illustrative of such acids are, for example, acetic, glycolic,
lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric,
ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,
salicyclic, 2-phenoxybenzoic, p-toluenesulfonic acid and sulfonic acids such as
methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid
salts can be formed, and such salts can exist in either a hydrated, solvated or
substantially anhydrous form. In general, the acid addition salts of these compounds
are more soluble in water and various hydrophilic organic solvents and which in
comparison to their free base forms, generally demonstrate higher melting points.
"Pharmaceutically acceptable basic addition salts" means non-toxic organic or inorganic
basic addition salts of the compounds of Formula (I), if it can be made. Examples
are alkali metal or alkaline-earth metal hydroxides such as sodium, potassium,
calcium, magnesium or barium hydroxides; ammonia, and aliphatic, alicyclic, or
aromatic organic amines such as methylamine, trimethylamine and picoline. The selection
of the appropriate salt may be important so that the ester is not hydrolyzed. The
selection criteria for the appropriate salt will be known to one skilled in the art.
- f) The term "Restorative Sleep" means sleep which produces a rested
state upon waking;
- g) the term "Sleep Disorder" means Insomnia and Obstructive Sleep Apnea;
- h) the term "Insomnia" means Primary Insomnia, Insomnia related to another
Mental Disorder, and Substance-Induced Insomnia;
- i) The term "Primary Insomnia" means difficulty in initiating sleep,
in maintaining sleep or having restorative sleep which is not caused by a Mental
Disorder or due to physiological effects of taking or withdrawing from certain
substances (substance-induced). As used herein, it also includes Circadian Rhythm
Insomnia which is insomnia due to a change in the normal sleep-wake schedule (shift
changes, jet lag, etc.);
- j) The term "Insomnia related to another Mental Disorder" means difficulty
in initiating sleep, in maintaining sleep or having restorative sleep which is
caused by an underlying Mental Disorder such as, for example, depression, anxiety
or schizophrenia;
- k) The term "Substance-Induced Insomnia" means difficulty in initiating
sleep, in maintaining sleep or having restorative sleep which is caused by physiological
effects of taking or withdrawing from certain substances such as caffeine, alcohol,
amphetamine, opioids, sedatives, hypnotics and anxiolytics; and
- l) The term "Obstructive Sleep Apnea" means repeated episodes of upper-airway
obstruction during sleep and is normally characterized by loud snores or brief
gasps that alternate with episodes of silence.
The COMPOUND may be synthesized by methods known in the art, such as one previously
described in U.S. Pat. No. 5,134,149, incorporated herein by reference,
##STR1##
##STR2##
In Step A of Reaction Scheme I, an esterification reaction is carried out between
racemic α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
(structure 1) and the (+)-isomer of α-methoxyphenylacetic acid (structure
2). This esterification produces the diastereomeric mixture identified as structure
3. These diastereomers are subjected to silica gel chromatography which separates
the two diastereomers, thereby isolating the (+,+) diastereomer as is depicted
in Step B. In Step C, the (+,+) diastereomer is hydrolyzed which produces the (+)-isomer
of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.
The esterification reaction can be carried out using techniques known in the
art. Typically approximately equivalent amounts of racemic α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
and the (+)-isomer of α-methoxyphenylacetic acid are contacted in an organic
solvent such as methylene chloride, THF, chloroform, toluene and heated to reflux
for a period of time ranging from 5 to 24 hours. The esterification is typically
carried out in the presence of an equivalent amount of dicyclohexylcarbodiimide
and a catalytic amount of 4-dimethylaminopyridine. The resulting diastereomers
can be isolated by filtration of the dicyclohexylurea and evaporation of the filtrate.
The diastereomers are then subjected to silica gel chromatography which separates
the (+,+) and the (-,+) diastereomers. This chromatographic separation may be carried
out as is known in the art. A 1:1 mixture of hexane and ethyl acetate is one suitable eluent.
The resulting (+,+) diastereomer is then subjected to a hydrolysis reaction which
produces the (+)-isomer of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine-methanol.
The hydrolysis is carried out by contacting the diastereomer with an excess of
a base such as potassium carbonate in an aqueous alcoholic solution. The hydrolysis
is carried out at a temperature of about 15 to 30° C. for a period of time
ranging from 2 to 24 hours. The resulting (+)-isomer of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
may then be recovered by dilution with water and extraction with methylene chloride.
It is then purified by recrystallization from a solvent system such as cyclohexane/hexane
or ethyl acetate/hexane.
Methods for producing the starting materials of Reaction Scheme I are known
in the art. For example, U.S. Pat. No. 4,783,471 teaches how to prepare racemic
α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine-methanol.
This patent is hereby incorporated by reference. Examples No. 1 and 2 of this application
also teach suitable methods. Alternatively, racemic α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
can be prepared in the following manner. Initially 4-hydroxypiperidine is subjected
to an N-alkylation reaction with p-fluorophenylethyl bromide which produces 4-hydroxy-1-[2-(4-fluorophenyl)ethyl]-piperidine.
This compound is brominated with Ph
3P.Br
2 which produces
4-bromo-1-[2-(4-fluorophenyl)ethyl]piperidine. This compound is contacted with
Mg thereby forming a Grignard Reagent which is then reacted with 2,3-dimethoxybenzaldehyde
which produces the desired product (±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.
The (+)-isomer of α-methoxyphenylacetic acid is known in the art.
Examples 1, 2 and 3 show one method of making the COMPOUND. Examples 4 and
5 provide data on the method of using the COMPOUND.
EXAMPLE 1
Example 1, Steps A-D, demonstrates the preparation of the starting material
(±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol,
structure 1.
A) 1-[2-(4-Fluorophenyl)ethyl]-4-piperidinecarboxamide
A solution of isonipectoamide (10.9 g, 85.0 mmol), 2-(4-fluorophenyl)ethyl Bromide
(15.7g, 77.3 mmol), and K
2CO
3 (2.3 g, 167 mmol) was prepared
in DMF (280 mL) and stirred under argon at 90-95° C. overnight. The cooled
solution was concentrated to a white oily solid. The solid was partitioned between
water and CH
2Cl
2. The layers were separated and the aqueous
layer was extracted with CH
2Cl
2. The combined organic layers
were washed 2× with water, dried (MgSO
4), filtered, and evaporated
to an oily solid. The solid was recrystallized from EtOAc to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxamide
as a white powder, m.p. 177-178° C. (decomp.). Anal. Calcd. for C
14H
19FN
2O:
C, 67.18; H, 7.65: N, 11.19. Found: C, 67.25; H, 7.67; N, 11.13.
B) 4-Cyano-1-[2-(4-fluorophenyl)ethyl]piperidine
To stirred phosphorus oxychloride (25 ml, 41.12 g, 268 mmol) and sodium chloride
(5.1 g, 87.3 mmol) was added 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxamide
(8.9 g, 35.6 mmol) portionwise. After complete addition, the solution was refluxed
for 2 hours. The cooled solution was poured into dilute NH
4OH to destroy
the POCl
3. The aqueous solution was cooled to 0° C., then extracted
2× with CH
2Cl
2. The combined organic layers were dried
(MgSO
4), filtered, and evaporated to afford 8.1 g of an oily solid.
The solid was distilled, (b.p. 150° C., 0.1 mm Hg), to afford a clear, colorless
oil that solidified. This material was crystallized from hexane to afford 4-cyano-1-[2-(4-fluorophenyl)ethyl]piperidine
as white needles, m.p. 47-48° C. Anal. Calcd. for C
14H
17FN
2:
C, 72.39; H, 7.38; N, 12.06. Found: C, 72.62; H, 7.49; N, 12.12.
C) 1-[2-(4-Fluorophenyl)ethyl]-4-piperidinecarboxaldehyde
To a stirred solution of 4-cyano-1-[2-(4-fluorophenyl)-ethyl]piperidine (1.00
g, 4.3 mmol) in THF (20 mL) under argon at 0° C. was added DIBAL-H (4.6 mL
of a 1.0 M solution in THF, 4.6 mmol) via syringe. After stirring overnight at
room temperature, 10% aqueous HCl (25 mL) was added and the solution was stirred
for 3 hours. The entire mixture was then poured into 10% aqueous NaOH (50 mL),
then extracted 2× with ether. The combined organic layers were washed with
brine, dried (MgSO
4), filtered, and evaporated to afford a pale yellow
oil. The oil was chromatographed on silica gel, eluting with EtOAc. The appropriate
fractions were combined and evaporated to afford an oil. This oil was distilled
(b.p. 166° C., 0.05 mm Hg) to afford 1-[2-(4-fluorophenyl)ethyl]-4piperidinecarboxaldehyde,
obtained as a colorless oil. Anal. Calcd. for C
14H
18FNO:
C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08; H, 7.81; N, 5.86.
D) (±)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol
To a stirred solution of veratrole (0.93 g, 6.7 mmol) in THF (20 mL) under argon
at 0° C. was added n-BuLi (2.7 mL of a 2.5 M solution in hexane, 6.75 mmol).
After stirring 2.5 h, the solution was cooled to -78° C. and treated with
1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde (1.30 g, 5.5 mmol) in THF
(25 mL) via an additional funnel. The cooling bath was removed and the solution
was allowed to stir for 2 hours. Water was added, the layers separated, and the
aqueous layer was extracted with EtOAc. The combined organic layers were washed
with brine, dried (MgSO
4), filtered, and chromatographed on silica gel,
eluting with acetone. The appropriate fractions were combined and evaporated to
afford a white solid. The solid was recrystallized from hexane to afford racemic
α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
as shiny white needles, m.p. 126-127° C. Anal. Calcd. for C
22H
28FNO
3:
C, 70.75; H, 7.56; N, 3.75. Found: C, 70.87; H, 7.65; N, 3.68.
EXAMPLE 2
Example 2, Steps A-F, demonstrate an alternative manner of preparing (±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol,
structure 1.
A) 1-(1,1-Dimethylethyl)-1,4-piperidinedicarboxylic Acid
To isonipecotic acid (107.5 g, 832 mmol) stirred in 1N NaOH (40 g NaOH in 900
mL H
2O) and tert-butanol (1800 mL) was added di-tert-butyl dicarbonate
(200 g, 916 mmol) in portions. After stirring overnight, the solution was concentrated
and the resulting water layer was extracted 3× with ether. The combined organic
layers were washed with water, brine, dried (MgSO
4), filtered, and evaporated
to a white solid, which was recrystallized from EtOAc/hexane (300 mL/200 mL) to
afford 1-(1,1-dimethylethyl)-1,4-piperidinedicarboxylic acid as white needles,
m.p. 147-149° C.
B) 4-(N-methoxy-N-methylcarboxamido)-1-piperidinecarboxylic acid 1,1-dimethylethyl Ester
To a stirred solution of 1-(1,1-dimethylethy)-1,4-piperidinedicarboxylic acid
(50.0 g, 218 mmol) in anhydrous CH
2Cl
2 (500 mL) under N
2
in a 2L flask was added 1,1′-carbonyldiimidazole (38.9 g, 240 mmol)
portionwise. After stirring for 1 hour, N,O-dimethylhydroxylamine hydrochloride
(23.4 g, 240 mmol) was added in one portion. After stirring overnight, the solution
was washed twice with 1N HCl, twice with saturated NaHCO
3, once with
brine, dried (MgSO
4), filtered, and evaporated to an oil. Distillation
afforded 4-(N-methoxy-N-methylcarboxamido)-1-piperidinecarboxylic acid 1,1-dimethylethyl
ester as a clear oil, b.p. 120-140° C., 0.8 mm.
C) 4-(2,3-Dimethoxybenzoyl)-1-piperidinecarboxylic Acid 1,1-dimethylethyl Ester
n-Butyl lithium (14.5 mL of a 2.5 M solution in hexane, 36.3 mmol) was added
via syringe to a stirred solution of veratrole (5.00 g, 36.2 mmol) in THF (50 mL,
anhydrous) under argon at 0° C. The ice bath was removed and the mixture was
allowed to stir for 90 minutes. The mixture was cooled to -78° C. and treated
with 4-(N-methoxy-N-methylcarboxamido)-1-piperidinecarboxylic acid 1,1-dimethylethyl
ester (9.20 g, 33.8 mmol) in THF (50 mL, anhydrous) via syringe. The cooling dry
ice-acetone bath was removed and the mixture was allowed to come to room temperature.
After stirring for 3 hours, saturated aqueous NH
4Cl was added and the
mixture was allowed to stir overnight. The layers were separated and the aqueous
layer was extracted with ether. The combined organic layers were washed with brine,
dried (MgSO
4), filtered, and evaporated to afford an amber oil. The
oil was chromatographed on silica gel, eluting with 20% EtOAc in hexane. The appropriate
fractions were combined and evaporated to an amber oil. The oil was distilled to
afford 4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester
as a colorless oil. (b.p. 225-250° C., 0.05 mm). Anal. Calcd. for C
19H
27NO
5:
C, 65.31; H, 7.79; N, 4.01. Found: C, 65.04; H, 7.92; N, 4.11.
D) 4-(2,3-Dimethoxyphenyl)-4-piperidinylmethanone
4-(2,3-Dimethoxybenzoyl)-1-piperidinecarboxylic
acid 1,1-dimethylethyl ester (7.75 g, 22.2 mmol) was dissolved in trifluoroacetic
acid (50 mL, 650 mmol) and stirred for 45 minutes. The entire solution was poured
into ether (900 mL) and allowed to stand overnight. Filtration yielded 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone
trifluoroacetate as fine white needles, m.p. 123° C. Anal. Calcd. for C
14H
19NO
3.CF
3CO
2H:
C, 52.89; H, 5.55; N, 3.86. Found: C, 52.77; H, 5.62; N, 3.82.
The resulting 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone trifluoroacetate
was dissolved in water, treated with NaOH (10% aqueous) until basic, and extracted
three times with dichloromethane. The combined organic layers were washed with
brine, dried (MgSO
4), filtered and evaporated to afford 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone
as an oil.
E) (2,3-Dimethoxyphenyl)[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]methanone monohydrochloride
A solution of 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone (8.00 g, 32.1 mmol)
and 2-(4fluorophenyl)ethyl bromide (6.52 g, 32.1 mmol) was prepared in DMF (90
mL) treated with K
2CO
3 (7.0 g, 50.7 mmol), then stirred and
heated at 80° C. under argon overnight. The cooled solution was poured into
a partition of 2/1 EtOAc/toluene and water. The layers were separated and the aqueous
layer was extracted with 2/1 EtOAc/toluene. The combined organic layers were washed
2× with water, 1× with brine, dried (MgSO
4), filtered, and
evaporated to afford 11.0 g of an oil. The oil was chromatographed on silica gel,
eluting with EtOAc. The appropriate fractions were combined, concentrated, dissolved
in ethyl acetate and treated with HCl/ethyl acetate. (2,3-dimethoxyphenyl)[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]-methanone
monohydrochloride was obtained as a precipitate, m.p. 225-227° C. (decomp).
Anal. Calcd. for C
22H
26FNO
3.HCl: C, 64.78; H,
6.67; N, 3.43. Found: C, 64.44; H, 6.73; N, 3.41.
F) (±)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
To a stirred solution of (2,3-dimethoxyphenyl)[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]-methanone
(6.0 g, 16.2 mmol) in MeOH (100 mL) at 0° C. was added NaBH
4 (1240
mg, 32.8 mmol) in two portions, over an one hour period. After stirring overnight,
the solution was concentrated to a solid. The solid was partitioned between water
and ether. The layers were separated and the aqueous layer was extracted with ether.
The combined organic layers were washed with brine, dried (MgSO
4), filtered,
and evaporated to a solid. The solid was chromatographed on silica gel, eluting
with acetone. The appropriate fractions were combined and evaporated to afford
a white solid. The solid was recrystallized from cyclohexane to afford (±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol
as white needles, m.p. 126-127° C. Anal. Calcd. for C
22H
28FNO
3:
C, 70.75; H, 7.56; N, 3.75. Found: C, 70.86; H, 7.72; N, 3.93.
EXAMPLE 3
This example demonstrates the preparation of the compound of Formula-I.
Preparation of (+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
A) Preparation of Diastereomers
A solution of 3.90 g (10.4 mmol) of (±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol,
1.74 g (10.4 mmol) of S-(+)-α-methoxyphenylacetic acid, 2.15 g (10.4 mmol)
of 1,3-dicyclohexylcarbodiimide and 0.1 g of 4-dimethylaminopyridine in chloroform
(75 mL) was refluxed for 17 hours, allowing to cool to room temperature and filtered.
The filtrate was concentrated and chromatographed on a silica gel column eluting
with ethyl acetate/hexane (1:1) to afford two diastereomers, Rf=0.1 and 0.2 (TLC
EtOAc/hexane, 1:1). Intermediate fractions were re-chromatographed to give additional
material. Those fractions with Rf=0.2 were combined to give a single diastereomeric
ester, (+,+)-(2,3-dimethoxyphenyl)[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]methyl-α-methoxybenzene-acetate.
B) Preparation of (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
To a stirred solution of 0.97 g (1.9 mmol) of the above mentioned diastereomeric
ester, Rf=0.2, in 25 mL of methanol was added 0.5 g (3.6 mmol) of potassium carbonate
and 5.0 mL of water. After stirring 17 hours at room temperature the reaction mixture
was diluted with water and extracted twice with methylene chloride. The combined
extracts were washed with water, brine and dried over MgSO
4. After filtering,
the filtrate was concentrated to an oil and crystallized from 40 mL of cyclohexane/hexane
(1:1) to give (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol,
m.p. 112-113° C., [α]
D20=+13.9°.
The COMPOUND can be formulated into pharmaceutical dosage forms using techniques
well known in the art. For oral administration, the compound can be formulated
into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts,
powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of
the ordinary gelatin type containing, for example, surfactants, lubricants and
inert fillers such as lactose, sucrose, and cornstarch or they can be sustained
release preparations. In another embodiment, the compound can be tableted with
conventional tablet bases such as lactose, sucrose, and cornstarch in combination
with binders, such as acacia, cornstarch, or gelatin, disintegrating agents, such
as potato starch or algenic acid, and a lubricant such as stearic acid or magnesium
stearate. Liquid preparations are prepared by dissolving the active ingredient
in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also
contain suspending agents, sweetening agents, flavoring agents, and preservative
agents as are known in the art.
For parenteral administration, the compound or its salts may be dissolved in
a physiologically acceptable pharmaceutical carrier and administered as either
a solution or a suspension. Illustrative of suitable pharmaceutical carriers are
water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal,
vegetable, or synthetic origin. The pharmaceutical carrier may also contain preservatives,
buffers, etc. as are known in the art.
The dosage range at which the COMPOUND exhibits its ability to treat Sleep Disorders,
including each specific type of Sleep Disorder, can vary depending upon the specific
disorder, its severity, the patient, any underlying disease states that the patient
is suffering from, and other medications that may be concurrently administered
to the patient. Generally though, this COMPOUND will exhibit its ability to treat
Sleep Disorders at a range of 0.001 mg/kg/day to about 100 mg/kg/day. It may be
delivered by any appropriate means, such as orally, sublingually, buccally, transdermally,
rectal via suppository, inhalation or injection.
EXAMPLE 4
A) In five healthy subjects received a single 10 mg dose of the COMPOUND and
seven
subjects received a single 20 mg dose of the COMPOUND administered orally. Forty
percent of the subjects receiving the 20 mg dose (2 out of 5) and sixty percent
of the subjects receiving the 10 mg dose (3 out of 5) experienced mild to moderate sedation.
B) Forty-nine patients diagnosed with schizophrenia received either 10 mg of the
COMPOUND (5 mg twice daily), 20 mg of the COMPOUND (10 mg twice daily), 40 mg of
the COMPOUND (20 mg twice daily) or placebo orally twice daily. The following was reported:
| |
| |
Placebo |
10 mg |
20 mg |
40 mg |
Total |
| |
| |
| Insomnia |
N = 1; |
N = 0; 0% |
N = 3: |
N = 3; |
N = 7; |
| |
14.3% |
|
21.4% |
23.1% |
14.3% |
| Somnolence |
N = 0; 0% |
N = 3; 20% |
N = 1; |
N = 2; |
N = 6; |
| |
|
|
15.4% |
15.4% |
12.2% |
The milligram (mg) amounts refer to the amount of the COMPOUND orally administered
to the subjects and "n" refers to the number of subjects that reported the effect.
This chart shows that although some insomnia was reported by some subjects having
schizophrenia, some subjects also reported somnolence.
C) Doses of 36 mg, 72 mg, 108 mg and 138 mg of the COMPOUND and placebo were orally
administered to healthy subjects. The following data were reported.
| |
| |
|
|
18 |
36 |
72 |
108 |
138 |
| |
Placebo |
9 mg |
mg |
mg |
mg |
mg |
mg |
| |
| |
| |
n = 6 |
n = 4 |
n = 4 |
n = 4 |
n = 4 |
n = 4 |
n = 4 |
| Drowsiness |
33% |
50% |
100% |
100% |
75% |
100% |
100% |
| |
n = 3 |
n = 2 |
n = 4 |
n = 4 |
n = 3 |
n = 4 |
n = 4 |
The drowsiness was rated as mild or moderate at doses below 72 mg and moderate
to severe at 72 mg and above.
D) In healthy subjects, the COMPOUND was administered in 3 mg (n=4), 9 mg (n=4),
18 mg (n=4), 36 mg (n=4) and 72 mg (n=4) doses along with the placebo (n=5) wherein
"n" is the number of subjects. Only the group receiving the 72 mg dose reported
drowsiness (n=3).
EXAMPLE 5
Intraperitoneal application of L-Tryptophan (10 mg/kg) and Pargyline
(50 mg/kg) to anaesthetized newborn rats depressed the amplitude of the inspiratory
discharges of the genioglossal muscle and induced obstructive apneas (OA). The
following shows that the COMPOUND is efficient in preventing these effects and
compares its efficiency to theophylline.
Experiments were carried out on newborn Sprague Dawley rats from Iffa
Credo breeding center. The animals were anaesthetized by intraperitoneal injection
of low doses of sodium pentobarbitone (7-10 mg/kg), kept lying (dorsal cubitus)
on a warming blanket and were spontaneously ventilating.
The EMG activity of the genioglossal muscles and the diaphragm were recorded
with fine insulated wires (bipolar recordings) inserted within the muscles, filtered
(100-3,000 Hz), amplified (×5-10,000) and integrated (time constant 50 ms).
The rib cage movements were recorded via a captor gently touching the lower ribs
and/or the abdominal wall. The air flow changes resulting from the respiratory
chest movements were recorded via a facial mask and a highly sensitive pressure recorder.
Effects of Compound on Depression of Genioglossal EMG Induced by L-Tryptophan
and Pargyline
Ten to fifteen minutes after induction of anesthesia, the animals received first
an intraperitoneal injection of the COMPOUND, and a control recording was taken
to define the mean amplitude of the integrated EMGs. Then, the animal received
an intraperitoneal injection of L-Tryptophan plus Pargyline ("L-Trp+Parg") 10 mg/kg
and 50 mg/kg, respectively, and the changes in EMG amplitudes were checked every
10 minutes and were expressed as % of control values.
In ten animals, the pre-treatment with MDL 100,907 at 0.1 mg/kg did not prevent
the depression of genioglossal (GG) discharge induced by injection of L-Trp+Parg.
L-Trp+Parg injection significantly depressed by 30-50% the mean GG discharge for
about 30 minutes. A larger dose of the COMPOUND (1 mg/kg) was applied in ten other
newborn rats and this pre-treatment was now efficient in preventing the GG depression.
Finally, ten more animals received the largest dose used of the COMPOUND (3 mg/kg)
and confirmed the efficiency of the COMPOUND.
Effects of the Compound Pretreatment on the Occurrence of Obstructive Apnea Induced
by L-Tryptophan and Pargyline Injection
The respiratory movements and resulting air flow changes were measured in 30
newborn rats which received first a pre-treatment with the COMPOUND at either 0.1,
1 or 3 mg/kg and 10 min later L-Trp+Parg injection. L-Trp+Parg injection induced
OAs in 9 of 10 newborn rats which received the COMPOUND at 0.1 mg/kg, and 4 of
the 10 animals eventually died of respiratory distress, similar to animals from
previous studies which received L-Trp+Prg alone.
Five out of ten newborn rats which received the COMPOUND at 1 mg/kg did not
present short lasting OAs at all after L-Trp+Parg injection. Among the 5 of 10
newborn rats which displayed OAs, 2 animals had infrequent OAs (less than 5 short
lasting OAs in 60 minutes). The mean curve calculated for the 1 mg/kg sample revealed
a peak frequency of occurrence of short lasting OAs between 20-40 min after the
injection (range 4 OAs per 10 minute period) which was significantly less than
that observed in the 0.1 mg/kg sample. After 1 mg/kg pre-treatment with the COMPOUND,
long lasting OAs were observed in only one newborn rat and all animals survived
to L-Trp+Parg injection. Applying the largest dose of the COMPOUND (3 mg/kg) confirmed
the COMPOUND efficiency in preventing OAs. Only 2 of 10 treated rats presented
frequent short lasting Oas, 3 of 10 had a total of less than 3 short lasting Oas,
and 5 of 10 showed no short lasting Oas. None of the 10 animals displayed long
lasting OAs and all survived.
Effects of Theophylline Pre-Treatment on the Occurrence of Obstructive Apneas
Induced by L-Tryptophan and Pargyline Injection
Five newborn rats received theophylline at 10 mg/kg and 5 other animals received
theophylline at 30 mg/kg. In both cases, L-Trp+Prg injection depressed the amplitude
of GG inspiratory discharges and this effect was not prevented by either dose of
theophylline. In a second set of experiments, induction of OAs after L-Trp+Prg
injection also was not prevented by theophylline at 10 or 30 mg/kg.
*
