Title:  Method for treating or preventing sleep disorders

United States Patent:  6,348,485

Assignee:   Takeda Chemical Industries, Ltd. (Osaka, JP)

Filed:  November 14, 2000

PCT NO:  PCT/JP99/03057

102(e) Date:  November 14, 2000

PCT PUB. Date:  December 16, 1999

Foreign Application Priority Data:  Jun 09, 1998[JP] (10-160270)

The present invention provides a pharmaceutical composition for treating or preventing sleep disorders which comprises (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide in combination with at least one active component selected from zolpidem, zopiclone, triazolam and brotizolam.

DISCLOSURE OF THE INVENTION

It is indicated that known hypnotics have many problems such as transient insomnia (rebound insomnia) [Science, Vol.201, pages 1039-1041, 1978], dysmnesia such as anterograde amnesia [Psychopharmacology, Vol.70, pages 231-237, 1980, Neuroscience and Biobehavior Review, Vol.9, Pages 87-94, 1985], ataxia after awaking from sleep and somnolence. Therefore, it is desired to develop a hypnotic without these problems.

The inventors of the present invention made intensive studies and as a result, they found that (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl) ethyl]propionamide (hereinafter referred to as compound A) in combination with at least one active component selected from zolpidem, zopiclone, triazolam and brotizolam (as a pharmaceutical mixture, combination dosage form or concomitant pharmacotherapy) produces clinically beneficial effects as a medication exhibiting remarkable efficacy in the therapy (treating) and prophylaxis (preventing) of sleep disorders with substantially no risk for side effects such as recoil insomnia, dysmnesia, ataxia after awaking from sleep and somnolence and hence is safer than monotherapy using any of the above-mentioned active components. The present invention has been developed on the basis of the above finding.

Namely, the present invention provides a pharmaceutical composition for treating or preventing sleep disorders which comprises compound A in combination with at least one active component selected from zolpidem, zopiclone, triazolam and brotizolam,

a method for reducing amounts and(or) side effects of benzodiazepines administered to a mammal which comprises administering to such mammal an effective amount of melatonin agonists in combination with benzodiazepines,

a method for reducing amounts and(or) side effects of benzodiazepines administered to a mammal which comprises administering to such mammal an effective amount of compound A in combination with benzodiazepines,

a method for reducing amounts and(or) side effects of active component(s) (zolpidem, zopiclone, triazolam and/or brotizolam) administered to a mammal for treating or preventing sleep disorders which comprises administering to such mammal an effective amount of compound A in combination with at least one active component selected from zolpidem, zopiclone, triazolam and brotizolam, and

a pharmaceutical composition for treating or preventing sleep disorders which comprises compound A in combination with at least one active component selected from non-benzodiazepines, etc.

Compound A used in the present invention can be produced by the methods disclosed in Example 11 of WO 97/32871 or analogous methods thereto.

Zolpidem is N,N, 6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide and can be produced by the methods disclosed in Japanese Patent Unexamined Publication No. 8384/1988 (S63) (U.S. Pat. No. 4,794,185) or analogous methods thereto.

Zopiclone is 4-methyl-1-piperazinecarboxylic acid 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b ]pyrazin-5-yl ester and can be produced by the methods disclosed in Japanese Patent Unexamined Publication No. 76892/1973(S48) (U.S. Pat. No. 3,862,149) or analogous methods thereto.

Triazolam (halcion) is 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodi azepine and can be produced by the methods disclosed in Japanese Patent Unexamined Publication No. 76892/1973(S48) (U.S. Pat. No. 3,987,052) or analogous methods thereto.

Brotizolam (lendormin) is 8-bromo-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[3,4c]thieno[2,3e]1,4-dia zepine and can be produced by the methods disclosed in Japanese Patent Unexamined Publication No. 80899/1976(S51) (U.S. Pat. No. 4,094,984) or analogous methods thereto.

The pharmaceutical composition for treating or preventing sleep disorders in the present invention comprises compound A in combination with at least one active component selected from zolpidem, zopiclone, triazolam and brotizolam as active components. This composition can be used orally in the form of a dosage form available for each of the above components or by mixing each of the above components with a pharmacologically acceptable carrier or excipient and then combining them.

The pharmaceutical composition for treating or preventing sleep disorders in the present invention can be provided with compound A in combination with at least one active component selected from zolpidem, zopiclone, triazolam and brotizolam, for example, in the alternative forms prepared by the following procedures. (1) the above components are mixed optionally with a pharmaceutically acceptable excipient or the like by the known pharmaceutical technology to provide one dosage form, (2) the respective components are independently processed, optionally together with a pharmaceutically acceptable excipient or the like, to use in combination with independent dosage forms, at the same time or at staggered times, or (3) the respective components are independently processed, optionally together with a pharmaceutically acceptable excipient or the like, to provide independently prepared dosage forms as a set (kit). In the pharmaceutical composition of the present invention, in the case that the respective components are independently processed to provide independently prepared dosage forms, they can be administered to one patient at the same time or at staggered times, and the numbers of doses of the respective dosage forms may or may not be equal.

The pharmaceutical composition for treating or preventing sleep disorders in the present invention can be provided in one dosage form containing all of the active components or in dosage forms in which the respective active components or part of them are independently prepared. The amount of active components is from about 0.01 to about 100% by weight of the total weight of the composition. This composition can be administered to patients by the oral route, such as tablets, fine granules, capsules and granules, among others. Preferred are tablets, fine granules, and capsules.

The pharmaceutical compositions in the present invention can be formulated in any per se known manner or analogous methods thereof available with pharmaceutically acceptable carriers used in any per se known manner.

The said carriers include any ordinary organic and inorganic carrier substances that are usable in formulating medicines. For example, employable are excipients, lubricants, binders, disintegrators, etc. for formulating solid preparations; and solvents, solubilizers, suspending agents, isotonizing agents, buffers, soothing agents, etc. for formulating liquid preparations. If desired, further employable are other additives such as ordinary preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents, etc.

The excipients include, for example, lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose, light silicic anhydride, etc.

The lubricants include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc.

The binders include, for example, crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose, carboxymethyl cellulose sodium, etc.

The disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, etc.

The solvents include, for example, water for injections, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc.

The solubilizers include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.

The suspending agents include, for example, surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.

The isotonizing agents include, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.

The buffers include, for example, liquid buffers of phosphates, acetates, carbonates, citrates, etc.

The soothing agents include, for example, benzyl alcohol, etc.

The preservatives include, for example, parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.

The antioxidants include, for example, sulfites, ascorbic acid, etc.

The stabilizers for light include, for example, titanium oxide, etc.

The pharmaceutical composition containing compound A used in the present invention can be provided in various dosage forms, for example, as tablets (including sugar-coated tablets, film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained release preparations, plasters and also as chewing gum, etc., in accordance with the per se known methods, for example, the methods disclosed in WO 97/32871 or analogous methods thereto.

The pharmaceutical composition which comprises at least one component selected from zolpidem, zopiclone, triazolam and brotizolam can be prepared in the same manner used in the above pharmaceutical composition containing compound A.

The pharmaceutical composition for treating or preventing sleep disorders which comprises compound A in combination with at least one active component selected from zolpidem, zopiclone, triazolam and brotizolam can reduce the amount (dose) of active component(s) required compared to the case with the monotherapy using any of the above-mentioned active components. Namely, in the present invention, it is preferred to use zolpidem, zopiclone, triazolam and brotizolam in a lower amount than the case with monotherapy using their active components for treating or preventing sleep disorders. In the present invention, for example, a combination of active component(s) in the respective amount of which separately cannot produce beneficial effects exhibits an action for sleep and reduces problematic side effects (e.g. rebound insomnia, dysmnesia, ataxia after awaking from sleep and somnolence). In other words, in the present invention, the amount of zolpidem, zopiclone, triazolam and/or brotizolam can be reduced to an amount which does not produce side effects and an effect for sleep can be produced with the lower amount.

Compound A does not produce side effects in a monotherapy dose.

The pharmaceutical composition for treating or preventing sleep disorders which comprises compound A in combination with at least one active component selected from zolpidem, zopiclone, triazolam and brotizolam is useful for treating and/or preventing, for example, sleep disorders [e.g., primary insomnia, sleep-awake rhythm disorders (e.g., work-shift syndrome, time-zone syndrome (jet-lag)), seasonal melancholia, genital disorder, neuroendocrine disorder, senile dementia, Alzheimer's disease, various disorders accompanied by aging, cerebrovascular disorders (e.g. cerebral hemorrhage, etc.), cranial injury, spinal injury, epilepsy, anxiety, depression, manic-depressive psychosis, schizophrenia, alcoholism, Parkinson's disease, hypertension, arteriosclerosis, arrhythmia, premenstrual tension syndrome, glaucoma, cancer, AIDS and diabetes in mammals (e.g. human, cat, dog, monkey, etc.). In addition, it is also effective for protection against aging, immunoregulation, and ovulatory regulation (e.g., contraception). Compound A is independently useful for treating and/or preventing, for example, sleep disorders (e.g., primary insomnia), sleep-awake rhythm disorders (e.g. work-shift syndrome, time-zone syndrome (jet-lag)), seasonal melancholia, genital disorder, neuroendocrine disorder, senile dementia, Alzheirner's disease, various disorders accompanied by aging, cerebrovascular disorders (e.g. cerebral hemorrhage, etc.), cranial injury, spinal injury, epilepsy, anxiety, depression, manic-depressive psychosis, schizophrenia, alcoholism, Parkinson's disease, hypertension, arteriosclerosis, arrhythmia, premenstrual tension syndrome, glaucoma, cancer, AIDS and diabetes in mammals (e.g. human, cat, dog, monkey, etc.). In addition, it is also effective for protection against aging, immunoregulation, and ovulatory regulation (e.g., contraception).

The pharmaceutical composition for treating or preventing sleep disorders in the present invention is of low toxicity and can be used safely for human with oral administration.

Though the dose of the pharmaceutical composition of the present invention varies, depending on the subject to which the composition is administered, the administration route employed, the disorder of the subject, the kinds of active components used, etc., for example, as the respective active components dose for adults (body weight about 60 kg) with sleep disorders, the following amount may be administered once or several times a day, at the same time or at an interval of 30 minutes or 3 hours.

The dose of compound A may be from about 0.05 to about 10 mg preferably from about 0.1 to about 3 mg for one administration.

The dose of zolpidem may be from about 0.2 to about 10 mg preferably from about 0.5 to about 5 mg for one administration.

The dose of zopiclone may be from about 0.2 to about 10 mg of, preferably from about 0.5 to about 5 mg of for one administration.

The dose of triazolam may be from about 0.01 to about 0.5 mg, preferably from about 0.02 to about 0.3 mg for one administration.

The dose of brotizolam may be from about 0.01 to about 1 mg preferably from about 0.05 to about 0.3 mg for one administration.

In the pharmaceutical composition for treating or preventing sleep disorders in the present invention, the ratio in combination of compound A with at least one selected from zolpidem, zopiclone, triazolam and brotizolam (relative dosage) is 0.1 to 30 part by weight per 1 part by weight of compound A.

The pharmaceutical composition for treating or preventing sleep disorders in the present invention may be used with other active components (e.g., benzodiazepine-type medicines comprising benzodiazepine compounds such as diazepam, alprazolam, estazolam, etc.; agents for regulating sleep rhythm comprising fatty acid derivatives such as butoctamide and its salt, etc.; sleep reducing substances comprising cis-9,10-octadecenamide, etc. Such other active components and the compound A and at least one active component selected from zolpidem, zopiclone, triazolam and brotizolam may be mixed by means of per se known methods to give pharmaceutical compositions (e.g., tablets, powders, granules, capsules including soft capsules, liquids, injections, suppositories, sustained release preparations, etc.); or they may be separately formulated into different preparations, which may be administered to one and the same subject either simultaneously or at different times.

Claim 1 of 2 Claims

What is claimed is:

1. A method for treating sleep disorders in a mammal comprising administering to a mammal in need thereof a combination of

a first component, (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamde,

wherein the amount of said first component is an amount ineffective for inducing sleep when administered alone; and

a second component, at least one active component selected from the group consisting of zolpidem, zopiclone, brotizolam and triazolam,

wherein the amount of said second component is an amount ineffective for inducing sleep when administered alone; such that said combination induces sleep.

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