CA1263843A - Treatment of sleep disorders - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Sleep disorders in mammals, such as insomnia and narcolepsy, are treated by administering an effective amount of ethyl 4-acetoxybutanoate, or a closely related homolog thereof.
The compounds may also be adlninistered to mammals to cause muscle relaxation and as animal anaesthetics. Moreover the compounds appear to inhibit the release of dopamine in the brain, and are hence useful also in treatment of conditions which are associated with abnormalities of dopamine release and dopamine sensitivities, such as Parkinson's disease schizophrenia and tardive dyskenesia.

Description

This invention relates to chemotherapeutic compounds and compositions, usefuL in the treatment of sLeep disorders and other abnormalities in mammals.
Sleep disorders are a problem in a large portion of the population. Narcolepsy and insomnia are widely occurring.
Safe, non-addictive and Long-lasting drugs that are effective are substantially unavailable. Each class of drug currently used for this purpose has major drawbacks. For example, barbiturates have addictive tendencies, act as depressants on the central nervous system, and can be Le-thal in improper dosages. Benzodiazepines are less effective, and tend to lose their sedative effect with continued use.
hydroxyblltyrate is effective in treatment of narcolepsy, and is a very powerEul muscle relaxant, but is of only short duration of action, e.g. 2-3 hours. This is a major drawback, since tne patient needs to be continualLy re-a~akened foe further dosages.
Laborit et al "Pharmacological Study of Ethyl X-Hydroxybutyrate Glycolate," Agressologie 1974, 15 pp 31-37 attempted to prepare their subject compound, of fo~muLa 12 co . o .CH2 .C~12 C~H2 .co . o .C21~15 by reaction of glycoLic acid and ethyl y -bromobutyrate, to obtain a compound which might possess the muscle relaxant and antitremorine properties of glycolic acid combined with the hypnotic and cerebral dopamine enhancing proper-ties of sodium gamma-hydroxybutyrate (GHB). There is no proper indication in that pubLication that Laborit et aL actually produced their object compound. Attempts to repeat their described synthesis have been unsuccessfuL.

The present invention provides processes, compounds and compositions for use in treatment of sleep disorders such as narcolepsy and insomnia, and for effecting muscle relaxation~ in mammals, animal and human. They act as anaesthetics in animals, especially in small animals. The compounds and compositions are also useful in treatment of Parkinson's Disease, schizophrenia and other dopamine related disorders such as tardive dyskenesia in mammals~ In treatment of sleep disorders, the compounds have su~ficiently long duration of action to overcome the serious disadvantaye associated with ~-hydroxybutyra-te (CHB). The chemical compounds correspond to the general formula:

~ .CO.O.X .CO .O.Rl where ~ is a propylene group (-CH2.CH2.C~12-) or an allylene group (-CH=CH-CH2-), optionally subs-tituted with a fluorine group or a Cl-C6 lower alkyl group, R is selected from lower alkyl groups having 1-6 carbon atoms, aryL and aralkyl groups of 7-L2 carbon atoms, and Rl is selec-ted from lower alkyl groups having 1-6 carbon atoms and benzyl.
Preferred among the active compound ingredients used in the present invention are those of the above general formula in which X represents an unsubstituted C3 methylene chain i.e.
propylene, R is a Cl-C4 lower alkyl or phenyL, and Rl is Cl-C4 Lower alkyl.
Typical and especially preferred among the compounds used in the present invention is ethyl 4-acetoxybutanoate (also referred to as ethyl 4-0-acetyl 4-hydroxy-butanoate) of formula:
Cl13.CO.O.CH2.CH2.CH2.CO.O.C2H5 Accordingly, the invention will be further described with reference to that specific compound.

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From one aspect ethyl 4-acetoxybutanoate may be regarded as a chemicalLy modified and chemically protec-ted form or ~_hydroxybutyrate ~GHB), with the acid and hydroxyL functions thereof protected. GHB has been demons-trated in clinicaL trials to be a safe, oral drug for treatment of narcolepsy and as a powerful musc'Le relaxant. However, its effects are of too short a duration, due to its lack oE bio-availability. It is possible that, after entry into the cell, the compound ethyl 4-acetoxybutanoate of the invention sLowLy hydrolyses to form GHB or a simi'Lar compound in Sitll, to exercise the therapeutic effects thereof over a longer period of time. In any event, i-t has been found that ethyl 4-acetoxybutanoate has a much longer lasting effec-t, at equivalent dosage levels, than GH~. This makes it a far more effective treatment for narcolepsy than anything heretofore avaiLable. Indeed, the effec-t is so markedly Longer lasting that ethyl 4-acetoxybutanoate shows potential for treatment of patients having conditions or disorders where GHB is of 'little or no use. In cases of chronic insomnia, for example, sufficient dosages of the present compound can be administered to maintain sleep throughout the ni~ht, without incurring the development of tolerance or withdrawal side effects. Current'Ly avaiLabLe cherno~he~apeutic agents will not do this The compound of the present invention constitutes a safe and powerful hypnotic, for administration to a patient each night. ~nimals, especlally small animals, treated with reasonabLe doses of ethyL 4-acetoxybutanoate sleep so deeply that they repose for extended periods of time on their backs. Thus ethyL ~-acetoxybutanoate is usefuL as a veterinary anaesthetic, especialLy for s-mall animals. Upon waking, no ill eEfects are detectable. The compound is also a powerful muscle relaxant Eor us~ in the treatment of a variety of conditions involving muscLe spasticity.
In addition, ethyl ~-acetoxybutanoate appears to inhibit the release of dopamine in the brain, indicating that it is potential-Ly useful in the treatment of conditions which are associated with abnormalities of dopamlne release and dopamine sensitivity, such as schizophrenia and tardive dyskenesia.
Another dopamine related disease for which the compounds of the present invention may be used in treatment is Parkinson's disease, although the basis for its use therein is somewhat different. Parkinson's disease i5 understood to be caused at least in part by degeneration of the dopamine-producing and releasing cells, and is traditionally treated by administration of dopamine to the patient. Administration of ethyl 4-hydroxybu-tanoate, on the other hand/ prior to a night's sleep, temporarily inhibits -the release of dopamine from the dopamine-yenerating cells during the hours ot- sLeep.
Consequently, dopamine is stored in the cells during sleep; and released when the effects of ethyl 4-hydroxybutanoace have worn off, i.e. during the wa~ing hours when control of Parkinson's disease is most needed.
A large dose can have an extremely long duration of action (up to 12 hours) without toxic consequences. The duration of action can be controlled by the size of the dosage.
Ethyl 4-acetoxybutanoate is not a novel compound. It has previously been reported as a trace component in red wine C~3 (Schreier, "Wine Aroma Composition: Identification of Additional Volatile Constituents of Red ~ine", J. Agric. Food Chem., 1980, 28, 926-928) and as an analgesic (French Medicament patent ~7593).
The drug ethyl 4-acetoxybutanoate according to the present invention may be compounded and administered in dosage levels simiLar to those commonly used for GHB (sodium oxybate, sold under the trade names "Anetamine" and "Somsanit"~. Thus it may be orally administered as capsules, in adrnixture with the usual flavorants, excipients, carriers or the like, such as starch, sugar etc. It may be contained as the pure substance in regular gelatin or soft geLatin capsu'les, for oral administration, i.e. with gelatin constituting the carrier, or suspended in a non-reactive medium in a capsule A gelatin capsule, especia~ly a soft gelating ca~sule, of the pure substance is an especial'ly preferred dosage form according to the present invention. It may be taken or~lly as a solution or emulsion. It may be injected intraperitoneally or parenterally as a sterile buEfered solution or emulsion e.g. in water or physiological salineO Amounts of the order of 5-100 mg per kilogram animal body weight, per nightly dosag2, appear suitabLe in humans, with larger doses (up to three tlmes as much) in animal use. A single dosage unit for once-nightly administration is suitably in the range 0.1 -lOg in adult humans, preferabLy 0.25-5 g, and most preferably 250-1000 mg.
In many instances in human uset smaller dosages e.g. from about 0.05 g tO about 0.18 gms are particularly useful, for treatment of sub-acute conditions.

3~ 3 In tes~s conducted in animal models, the compound ethyl 4-acetoxybutanoate has evidenced extremeLy low levels of toxicity. In tests conducted with laboratory rats as reported below, doses as high as 3000 mg per kiLogram body weight are required, before a toxic level is reacned.
Methods of synthesis of compounds used in the present invention are known from the prior art. They may be synthesized, for example, from the appropriate lactone, by reaction thereof with the appropriate alcohol, under acid conditions, to form the hydroxy cornpound, which is then reacted with an acid anhydride in pyridine. Thus, for the preparation of ethyl 4-acetoxybutanoa-te, butyrolactone is reacted with ethanol suitably in the presence of sulphuric acid, followed by reaction with acetic annydride in pyridine. Similar procedures empLoying methanoL instead of ethanol yield the methyl ester.
An alternative synthesis involves the ceaction of the appropriate carboxylic acid salt with a 4-halo-es-ter. Thus, by this procedure, ethyl 4-acetoxybutanoate may be prepared by reaction of ethyl 4-chlorobutanoate with potassium acetate in acetic anhydride or acetic acid, folLowing the general procedure of Mereschkowsky (Annalen 431, 231 (1923) and the report by Guest (J.Am. Chem. Soc., 69, 300-302 (1947).
The invention is further described and illustrated in -the following speciEic examples.

Example l - Preparation of Ethyl 4-acetoxybutanoa-te (also named 4-0-acetyl-4-hydroxybutanoate) This is a ~nodification of the methods of ~pencer and ~right (J.Am. Chem. Soc., 63, 128 (l9~1) and Meerwein, Borner, Fuchs, Sasse, Schrodt and Spille (~erichte, 3~, 2060 (1956).
Eighty grams of butyrolactone was dissolved in 500 ml absolute ethanol containing 8 gms 99~ sulEuric acid in a one litre erlenmeyer fLask. After 5 days, with powdered sodium carbonate (added carefully until further additions did not produce foaming)Then 20 g anhydrous sodium sulfate was added to dry the solution. The soLution was fiLtered and t~e filtra~e was concentrated on a rotary evaporator in a two litre round bottom flaskO The concentrated residue was ta~en up in 300 ml water and was extracted with three 200 ml portions of chloroform. 'rhe chLoroform extracts were combined and dried over magnesiuln sulfate, the solution decanted then concentrated by rotary evaporation. Tne concentrate was placed in a l litre flask clamped in an ice bath, and 80 9 acetic anhydride and lO0 mL pyridine were added . After addition was complete, the stoppeced flask was left overnight with the ice allowed to melt. A solution o~ L00 ml concentrated hydrochloric acid (L2M), lO0 ml water and 200 g of ice was prepared and carefully added. I'wo layers formed, and L00 ml chloroform was added. The aqueous layer was extracted with three 100 ml portions oE
chloroform. The nonaqueous layer was taken up in chloroform and combined with the extracts. The eKtract was treated carefully with saturated aqueous sodium bicarbonate in a separatory funnel, followed by shaking~ and the aqueous layer was removed.

.~`.PJ~6 _ 9 The chloroform layer was then extracted with saturated sodium chloride solution then dried over anhydrous magnesium suLfate, and il-tered. The dried solution was concentrated on a rotary eva~orator, then distilLed at 0.1 torr on a 1 cm by 10 cm vacuum jacketed column. The product is collec~ed at 56C, and shown by nmr spectroscopy to be pure ethyl 4-acetoxybutanoate Yield: 35g.

By repeating the above procedure, but substituting methanol for ethanol, methyl 4-acetoxybutanoa~e was similarly prepared.

Example 2 - Preparation of meth~l 4-acetoxybutanoate To a 500 ml round bottom flask, equipped with teflax apparatus, 14.7 g (0.15 ml) oE potassium acetate was dissolved in 185 ml acetic anhydride. 1.87 g potassium iodide (0.0113 mol) was subsequently dissolved into this heterogeneous mixture. After addition of 18.3 ml (0.15 mol) of methyl 4-chlorobu-tanoate, the mixture was refluxed gently for 24 hours. Upon completion of reflux, the apparatus was alLowed to cooL slowLy to room temperature and the precipitate was removed via suction filtration (15 Torr) and washed with ethyl acetate.

After rotary evaporation (15 Torr), distillation under vacuum (1.5 Torr) of the orange soLution yielded three fractions:
1) Acetic anhydride, 35-40C;

2) Acetic anhydride -~ product, 41-80C

3) Produc~ 8-L-92C (levelled ot~ at 92C).
Fraction 2 was redistilled and combined with (3) to give 22.96g of methyl 4-acetoxybutanoate (96~ of theoreticaL).

- ~o Example 3 - Preparation of Methyl 4-b nzoyloxybutanoate 21.6 g (0.15 mol) of sodium benzoat~ was added sLowly wich stirring to 240 dimethyl Eormamide in a 500 ml round bottom flask. Upon addition of 1.87 g (0.0113 mol) potassium iodide followed by 18.3 mL (0.15 mol) of methyl 4-chlorobutanoate the mixture was refluxed gently Eor 24 hours. After reflux the reaction vessel was allowed to cool slowly to room temperature and the precipitate was removed via suction fiLtration (15 Torr) and washed with ethyl acetate. AEter rotary evaporation (15 Torr) to remove ethyl acetate distiLlation under vacuum yielded three distinct fractions:
1 ) DL~IF at 35C
2) I~IF at 65-72C
3) Product LL0-150C (levelled otf at 148C).

During the coLlection of the product, the condenser had to be turned oEf in order to avoid cryscaLLization of the product. The yieLd of methyl 4-benzoyloxybutanoate was 26.86 g (80.6~ of theoretical yield) .

Example 4 The preferred compound according to the invention was administered to laboratory rats, and the sLeep oE the animals induced by -the drug was tracked by means oE an electroencephalograph.
Compound ethyl 4-acetoxybutanoate, administered by mouth at a dosage of 250 mg per kilogram body weight induced sleep for 1 hour 28 minutes. At a dosage of 500 mg per kilogram administered in one case by mouth and ln another case intraperitoneally, sleep was induced for 4 hours. In all cases, the limbs and other body joints were ~uite flaccid, indicating a high degree of muscLe reLaxation. Upon waking, none of the animals exhibited ill effects.
The administration to a simiLar laboratory rat, intraperitoneaLly, of a dosage of 500 mg per Icilogram body weight of GHB induced sleep for onLy 1 hour 59 minutes, by contrast.
EXA~LE 5 The eEfects on sleep and righting time of the oraL and intraperitoneal administration of the prior art compound hydroxybutyrate sodium saLt (GHB) and 4-acetoxybutanoate (EAB) according to the invention were determined, using groups of laboratory rats.
In a ~irst experiment, GHB was administered at high dosage level (25 mM/kg or 3gm/kg body weight) orally to three animals. None of the animals slept, confirming literature reports that G~B is ineffective in high doses administered orally. The most Likely reason is that oral GHB is poorLy absorbed.
In a second experiment each o-E GHB and EPB was given to separate groups of twelve and eleven animals respéctively, by oraL administration at the same, lower dosage Level ot lOmM/kg body weight. The results are given in Table 1 below, in which an asterisk indicates that the animaL could be pLaced on its back for the time indicated, AVG 1 is the average time of sleep ~3~

based only on the animals of the group which slept, and AVG 2 is the average sleep time of all the rats, whether they slept or `not. DNS signifies "did not sLeep".

a.;3 _ Drug G~IB _ EAB _ _ ANIl~AL# TIME SLEPT (mins) ANIMALt~_TIME SLEPT (mins) 1 64.70 13 120.30 2 DNS 14 106.10 3 DNS 15 125.75

4 60.80 16 ~43.45 55.30 17 300.20*
6 DNS 18 120.00 7 74.70 19 175.80 8 72.~0 20 331.60*
9 DNS 21 311.50*
DNS 22 317.65*
11 DNS 23 103~90 RANGE 0-74~7 ~ANGE 103~9-331.6 AVG 1 65.76 AVG 1 170.57 _ AVG 2 27.40 These results indicate that a high dose of oral GHB has weak effects. Only Eive out of twelve animals were put to sleep, and none of them could be placed on their backs. A
comparable dose of EAB put all rats to sleep, and four of eleven could be placed on their backs for more than Eive hours, indicating a deep level of sleep, and efEectiveness of the dosage as an animal anaesthetic. This experiment indicates that EAB is effective when given by mouth, and that it is long acting. Moreover, it was observed that the limbs and join-ts of the animals to which EAB had been administered were, during sleep, Loose and flaccid, indicating a high degree of muscle reLaxation. ~o sign of toxicity was observed in the animals treated with EA3, sho~ing that, if the compound shows any toxicity at all, it is at a leveL well above the effective dosage leveLs. Upon waking, none of the animaLs exhibited any ill effects.
_XAMPLE 6 Equivalent doses (5mM/kg body weight) of GHB and EAB
were administered intraperitoneally to 'cwo separate groups of rats, six animals per group, and the ef-fects on sleep and righting time determined. rrhe results are given in Table 2 below, which bears the same legends as Table L.

i3~

. . .
Druq GHB EAB
ANIMAL# (rIl~ SLEPT (mins) ANIl~IAL~ TIME SLEPT (mins) DNS 7 51.70*
2 70.20* ~ 39.30*
3 DNS 9 199.65*
4 55.40* 10 L41.70*
75.20* 11 70.00*
6 87.35* 12 259.00*

R~NGE 0-87.35 RANGE 39.30-259.00 AVG 1 72.04 Ai/G 1 126.89 AVG 2 48.03 ~ _ __ These data indicate that the effects ot EAB are more powerful and longer lastlng, even when given intraperitonealLy.
Thus, the elimination of EAB from the body's system is slower than that of GHB. Again, the anirnals sleeping under the influence of EAB exhibited a high degree of muscle relaxation.
Upon waking, none of them showed any ill effects.

Claims (10)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition in unit dosage form and adapted for administration to human and animal patients for treatment of sleep disorders, for muscle relaxation, for anaesthetic purposes or for treatment of dopamine related disorders, said composition comprising as active ingredient a compound of general formula R.CO.O.X.CO.OR1 in which X is a propylene group or an allylene group optionally substituted with a fluorine group or a C1-C6 lower alkyl group, R is selected from lower alkyl groups having 1-6 carbon atoms, aryl groups and aralkyl groups having 7-12 carbon atoms, and R1 is selected from lower alkyl groups having 1-6 carbon atoms and benzyl, in association with a pharmaceutically acceptable carrier.

2. The composition of claim 1 wherein the active ingredient has the general formula given in claim 1, in which X
represents an unsubstituted C3 methylene chain, R is a C1-C4 lower alkyl or phenyl and R1 is a C1-C4 lower alkyl.

3. The composition of claim 1 wherein the active ingredient compound is selected from ethyl 4-acetoxybutanoate;
methyl 4-acetoxybutanoate; and methyl 4-benzoyloxyblltanoate.

4. The composition of claim 1 wherein the active ingredient compound is ethyl 4-acetoxybutanoate.

5. The composition of claim 2, claim 3 or claim 4 wherein said pharmaceutically acceptable carrier is a gelatin capsule in which the active ingredient is contained.

6. The composition of claim 2, claim 3 or claim 4 wherein said pharmaceutically acceptable carrier is a liquid suspending or dissolving medium.

7. The composition of claim 2, claim 3 or claim 4 wherein the unit dosage amount of active ingredient is in the range 0.1 - 10 g.

8. The composition or claim 2, claim 3 or claim 4 wherein the unit dosage amount of active ingredient is from 0.25 - 5 g.

9. The composition of claim 2, claim 3 or claim 4 wherein the unit dosage amount of active ingredient is from 250-1000 mg.

10. The composition of claim 2, claim 3 or claim 4 wherein the unit dosage amount of active ingredient is from about 0.05 g to about 0.18 g.