Alkyne derivative

Abstract

The present invention addresses the problem of providing: a novel alkyne derivative or a pharmaceutically acceptable salt thereof; and a medicine containing said compound as an active ingredient.　This alkyne derivative or a pharmaceutically acceptable salt thereof exhibited an activity characteristic with respect to an α1 subunit in a GABAAα1β2γ2PAM test, showed, like eszopiclone, a decrease in the awake period and the REM sleep period, an increase in the Non-REM sleep period, and shortening of sleep onset latency, in a sleep test, and showed a weaker bitterness than eszopiclone in a bitterness test. Therefore, this compound has an excellent characteristic in which bitterness is reduced compared to eszopiclone, and is useful as a medicine such as an agent for ameliorating or treating sleep disorders.

Description

Alkyne Derivatives

[0001] The present invention relates to a novel alkyne derivative or a pharmaceutically acceptable salt thereof. The present invention also relates to a pharmaceutical agent, such as an agent for improving or treating a sleep disorder, containing at least one of the novel alkyne derivative and a pharmaceutically acceptable salt thereof as an active ingredient.

[0002] In recent years, numerous sleep studies both in Japan and abroad have provided accumulating evidence that sleep disorders increase the risk of illness and worsen life prognosis. According to epidemiological surveys of the general population, 21.4% of Japanese adults complain of insomnia, and 14.9% suffer from daytime sleepiness. Symptoms of sleep disorders are diverse, including insomnia, hypersomnia, sleep schedule deviations, and abnormal psychosomatic phenomena that occur during sleep. Sleep disorders refer to a variety of disorders related to sleep and wakefulness, including insomnia, periodic limb movement disorder, restless legs syndrome, and sleep apnea syndrome.

[0003] Insomnia is a disease characterized by symptoms such as difficulty falling asleep (difficulty falling asleep), waking up during the night (shallow sleep and waking up multiple times), waking up early in the morning (waking up early in the morning and unable to go back to sleep), and difficulty sleeping soundly (shallow sleep and not feeling like you've had a good night's sleep), which can lead to daytime ailments such as fatigue, loss of motivation, poor concentration, and loss of appetite. While most insomnia cases improve naturally and people are able to fall asleep again, chronic insomnia is said to be difficult to recover from without appropriate treatment. There are many causes of insomnia, including stress, mental or physical illness, and side effects of medication, and treatment must be tailored to the cause.

[0004] 30-40% of the general adult population suffers from some form of insomnia, and it is known that this condition is more prevalent in women. Of those with insomnia, approximately 10% have chronic insomnia, which can be caused by a wide range of factors, including stress, mental illness, neurological disorders, alcohol, and side effects of medication. The number of people who experience insomnia increases with age, with more than half of those over 60 experiencing it.

[0005] Zopiclone, a non-benzodiazepine insomnia treatment, and its S-isomer, eszopiclone, obtained by optical resolution of zopiclone, are characterized by rapid action, low addictive properties, and relatively little next-morning drowsiness, muscle relaxation, or dizziness. Eszopiclone is not designated as a psychotropic drug and is used as one of the first-line medications for insomnia. As disclosed in Non-Patent Document 1, eszopiclone is film-coated to mask its bitter taste upon administration. However, it is known that users experience bitterness even several hours after administration, such as the next morning. This is thought to be due to the extremely strong bitterness of eszopiclone, which is transferred to the bloodstream and affects taste bud cells. In fact, many medical professionals have called for improvement of eszopiclone's bitterness characteristics.

[0006] Insomnia Treatment Drug Eszopiclone Preparation Lunesta Tablets 1mg, 2mg, and 3mg Pharmaceutical Interview Form September 2022 Revised (11th Edition)

[0007] An object of the present invention is to provide a compound that has reduced bitterness and is useful as an active ingredient of a medicine that can be easily used as an agent for improving or treating sleep disorders, and a medicine that contains the compound as an active ingredient.

[0008] As a result of intensive research to solve the above-mentioned problems, the present inventors have found that a novel alkyne derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof has the excellent property of being less bitter than eszopiclone and is highly useful as a pharmaceutical that can be easily used as an agent for improving or treating sleep disorders, etc., and have thus completed the present invention.

[0009] The alkyne derivative or a pharmaceutically acceptable salt thereof of the present invention has little bitterness and can improve the QOL of those who take it, and is therefore highly useful as a medicine for improving or treating sleep disorders.

[0010] The present invention relates to an alkyne derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, which has reduced bitterness and is useful as a pharmaceutical agent for improving or treating sleep disorders. [wherein A and B are the same or different and represent hydrogen, deuterium, or alkyl, or A and B together with the carbons bonding them form a ring to represent cycloalkyl, oxetane, tetrahydrofuran, or tetrahydropyran, or A and B together with the carbons bonding them represent carbonyl; X represents carbon or nitrogen; Y represents hydrogen, deuterium, alkyl, cycloalkyl, or hydroxyalkyl, and when X is nitrogen, Y is unsubstituted; and n represents an integer of 0 to 2.]

[0011] In the substituents of the general formula (I), alkyl preferably represents a linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. Cycloalkyl preferably represents a cyclic cycloalkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0012] A general method for producing the compounds of the present invention is shown below, but a person skilled in the art can make appropriate modifications to the method depending on the chemical structure of a particular compound when producing it.

[0013] The compound of the present invention represented by the above general formula (I) can be produced by the following methods (1) and (2) or (1) and (3).

[0014] (1) Demethylation reaction Compound II can be prepared by demethylating eszopiclone with an appropriate demethylating agent. Examples of demethylating agents include chloroformates. Examples of chloroformates include chloroformates with alkyl, aryl, substituted alkyl, or substituted aryl groups, with 1-chloroethyl chloroformate being preferred. Demethylation can be achieved, for example, by heating 1-chloroethyl chloroformate for 1 to 3 hours to form a carbamate intermediate, followed by cleavage of the carbamate to obtain Compound II. Examples of solvents used for carbamate formation include inert solvents such as acetonitrile, toluene, 1,2-dichloroethane, and 1,2-dichloromethane. Carbamate cleavage can be achieved by refluxing the mixture in an alcohol such as methanol, ethanol, isopropyl alcohol, or butanol for 1 to 3 hours.

[0015] (2) Condensation reaction The compound of the present invention (compound of general formula IV) can be produced by the condensation reaction of compound II with a compound of general formula III. L represents a leaving group easily displaceable by a basic nitrogen. Z represents a substituent species attached to the 4-position of the piperazine in the piperazine-1-carboxylate moiety of the alkyne derivative of the present invention represented by general formula (I). Examples of leaving groups for L include halogen, methanesulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, etc. The halogen is preferably chlorine, bromine, or iodine. The reaction is carried out by using equal amounts of compound II and an alkylating agent of general formula III, or an excess of the alkylating agent, in a reaction-inert solvent in the presence of a base at room temperature or under reflux for 1 to 24 hours. Examples of solvents include acetonitrile, ether solvents, halogenated hydrocarbon solvents, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), etc. The solvent can be appropriately selected depending on the type of raw material compound and can be used alone or in combination. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydrogencarbonate, and organic bases such as aniline, pyridine, morpholine, piperidine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, and 4-dimethylaminopyridine. Examples of the catalyst include copper(I) iodide, potassium iodide, and sodium iodide.

[0016] (3) Reductive amination reaction The compound of the present invention (compound of general formula VI) can be produced by reacting compound II with a compound of general formula V and a reducing agent. Z represents the same substituent as in the condensation reaction described above (2). This reductive amination reaction can be carried out by reacting compound II with an equivalent or excess amount of a compound of general formula V and a reducing agent in a reaction-inert solvent in the presence of a base at room temperature for 1 to 24 hours. Examples of reducing agents include sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. Examples of solvents include dichloromethane, 1,2-dichloroethane, tetrahydrofuran, and acetonitrile. Examples of bases include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate, and organic bases such as aniline, pyridine, morpholine, piperidine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, and 4-dimethylaminopyridine.

[0017] The compound of the present invention represented by the general formula (I) includes various pharmaceutically acceptable salts thereof, when such salts exist. Examples thereof include acid addition salts with organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, thiocyanic acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, methanesulfonic acid, oxalic acid, (-)-10-camphorsulfonic acid, maleic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid, and citric acid; salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and metals such as aluminum; and salts with bases such as ammonia and organic amines. These salts can be produced from the respective free compounds by known methods, or can be mutually converted. Furthermore, when the compounds exist in the form of stereoisomers such as cis-trans isomers, optical isomers, conformational isomers, solvates such as hydrates, or metal complex compounds, all of these stereoisomers, solvates, and complex compounds are encompassed in the present invention.

[0018] The compounds of the present invention obtained by the above method are shown below. Hereinafter, when referring to each compound, the following compound number will be used.

[0019] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl)piperazine-1-carboxylate [Compound 1] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl)piperazine-1-carboxylate hydrochloride [Compound 1-1] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(cyanomethyl)piperazine-1-carboxylate [Compound 2] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(3-butyn-1-yl)piperazine-1-carboxylate hydrochloride [Compound 3] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-butyn-1-yl)piperazine-1-carboxylate hydrochloride [Compound 4] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(3-butyn-2-yl)piperazine-1-carboxylate [Compound 5] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-methyl-3-butyn-2-yl)piperazine-1-carboxylate [Compound 6] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(4-hydroxy-2-butyn-1-yl)piperazine-1-carboxylate [Compound 7] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-1,1-d2)piperazine-1-carboxylate [Compound 8] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-1,1-d2) Piperazine-1-carboxylate hydrochloride [Compound 8-1] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-1,1-d2)piperazine-1-carboxylate hydrobromide [Compound 8-2] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-1,1-d2)piperazine-1-carboxylate hemisulfate [Compound 8-3] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-1,1-d2)piperazine-1-carboxylate nitrate [Compound 8-4] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-1,1-d2)piperazine-1-carboxylate phosphate [Compound 8-5] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-Propyn-1-yl-1,1-d2)piperazine-1-carboxylate benzenesulfonate [Compound 8-6] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-Propyn-1-yl-1,1-d2)piperazine-1-carboxylate methanesulfonate [Compound 8-7] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-Propyn-1-yl-1,1-d2)piperazine-1-carboxylate hemioxalate [Compound 8-8] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-1,1-d2)piperazine-1-carboxylate paratoluenesulfonate [Compound 8-9] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-1,1-d2)piperazine-1-carboxylate (-)-10-camphorsulfonate [Compound 8-10] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-1,1-d2)piperazine-1-carboxylate hemimaleate [Compound 8-11] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-1,1-d2)piperazine-1-carboxylate ethanesulfonate [Compound 8-12] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-1,1-d2)piperazine-1-carboxylate 2-hydroxyethanesulfonate [Compound 8-13] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-1,1-d2)piperazine-1-carboxylate citrate [Compound 8-14] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-Propioloylpiperazine-1-carboxylate [Compound 9] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(3-cyclopropyl-2-propyn-1-yl)piperazine-1-carboxylate hydrochloride [Compound 10] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(3-ethynyloxetan-3-yl)piperazine-1-carboxylate [Compound 11] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(3-ethynyloxetan-3-yl)piperazine-1-carboxylate hydrochloride [Compound 11-1] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-pentyn-1-yl)piperazine-1-carboxylate [Compound 12] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-heptyn-1-yl)piperazine-1-carboxylate [Compound 13] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-hexyn-1-yl)piperazine-1-carboxylate [Compound 14] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(4-ethynyltetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate [Compound 15] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(3-ethynyltetrahydrofuran-3-yl)piperazine-1-carboxylate [Compound 16] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(1-ethynylcyclobutyl)piperazine-1-carboxylate [Compound 17] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(1-hexynyl-3-yl)piperazine-1-carboxylate [Compound 18] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(1-heptyn-3-yl)piperazine-1-carboxylate [Compound 19] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(1-pentyn-3-yl)piperazine-1-carboxylate [Compound 20] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-d3)piperazine-1-carboxylate [Compound 21] (S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-(2-propyn-1-yl-3-d)piperazine-1-carboxylate [Compound 22],

[0020] Preferred embodiments of the present invention are as follows: (1) An alkyne derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. (2) An alkyne derivative according to (1) above or a pharmaceutically acceptable salt thereof, wherein X is carbon. (3) An alkyne derivative according to (1) or (2) above or a pharmaceutically acceptable salt thereof, wherein Y is hydrogen. (4) An alkyne derivative according to any one of (1) to (3) above or a pharmaceutically acceptable salt thereof, wherein n is 0. (5) An alkyne derivative according to any one of (1) to (4) above or a pharmaceutically acceptable salt thereof, wherein A and B are deuterium. (6) An alkyne derivative according to any one of (1) to (4) above or a pharmaceutically acceptable salt thereof, wherein A and B, together with the carbon atom connecting them, form a ring to form an oxetane. (7) A medicine containing at least one of the alkyne derivatives and pharmaceutically acceptable salts thereof according to any one of (1) to (6) above. (8) The medicament according to (7) above, which is an agent for improving or treating a sleep disorder. (9) The medicament according to (8) above, wherein the sleep disorder is insomnia. (10) The medicament according to (9) above, wherein the insomnia is primary insomnia. (11) The medicament according to (9) above, wherein the insomnia is secondary insomnia. (12) The medicament according to any one of (7) to (11) above, which is an oral preparation. (13) The medicament according to any one of (7) to (11) above, which is an injection. (14) The alkyne derivative or pharmaceutically acceptable salt thereof according to any one of (1) to (6) above, which is used for improving or treating a sleep disorder. (15) The alkyne derivative or pharmaceutically acceptable salt thereof according to (14) above, wherein the sleep disorder is insomnia. (16) The alkyne derivative or pharmaceutically acceptable salt thereof according to (15) above, wherein the insomnia is primary insomnia. (17) The alkyne derivative or pharmaceutically acceptable salt thereof according to (15) above, wherein the insomnia is secondary insomnia. (18) A method for improving or treating a sleep disorder, comprising administering an effective amount of at least one of the alkyne derivatives or pharmaceutically acceptable salts thereof according to any one of (1) to (6) above to a patient having a sleep disorder. (19) The method for improving or treating a sleep disorder according to (18) above, wherein the sleep disorder is insomnia. (20) The method for improving or treating a sleep disorder according to (19) above, wherein the insomnia is primary insomnia. (21) The method for improving or treating a sleep disorder according to (19) above, wherein the insomnia is secondary insomnia.(22) Use of the alkyne derivative or pharmaceutically acceptable salt thereof according to any one of (1) to (6) above in the manufacture of a medicament for improving or treating a sleep disorder. (23) The use according to (22) above, wherein the sleep disorder is insomnia. (24) The use according to (23) above, wherein the insomnia is primary insomnia. (25) The use according to (23) above, wherein the insomnia is secondary insomnia.

[0021] 1 is a graph showing the proportion of wakefulness up to 6 hours after administration of each test solution (control, compound 8, compound 11, and eszopiclone). 2 is a graph showing the proportion of slow-wave sleep (non-REM sleep) up to 6 hours after administration of each test solution (control, compound 8, compound 11, and eszopiclone). 3 is a graph showing the proportion of fast-wave sleep (REM sleep) up to 6 hours after administration of each test solution (control, compound 8, compound 11, and eszopiclone). 4 is a graph showing sleep onset latency following administration of each test solution (control, compound 8, compound 11, and eszopiclone).

[0022] The compound of the present invention can be made into a pharmaceutical composition by combining, as needed, various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants, and diluents appropriate for the dosage form. It can be formulated by any conventional method, and oral preparations can be prepared in dosage forms such as tablets, capsules, powders, granules, liquids, syrups, and sublingual preparations. Parenteral preparations can be formulated into injections for subcutaneous, intramuscular, intra-articular, or intravenous administration, as well as suppositories for rectal administration and inhalants for intranasal administration. When formulated, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, alone or in appropriate combination, or may be combined with other pharmaceutically active ingredients.

[0023] When preparing oral preparations, additives that can be appropriately combined include, for example, conventional excipients such as lactose, mannitol, corn starch, potato starch, etc.; binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch, gelatin, etc.; disintegrants such as corn starch, potato starch, potassium carboxymethylcellulose, etc.; lubricants such as talc, magnesium stearate, etc.; and other fillers, wetting agents, buffers, preservatives, flavorings, etc., and flavoring agents, fragrances, etc. may also be added.

[0024] When preparing a liquid or emulsion, suspension or viscous injection, commonly used solubilizing agents, suspending agents, emulsifying agents, stabilizers, preservatives, isotonic agents, thickening agents and the like may be added as appropriate, and the preparation is usually sterilized.

[0025] The desired dosage of the compound of the present invention may vary depending on the subject (patient's age, weight, etc.), the type and severity of the disease, dosage form, administration method, administration period, etc., but to obtain the desired effect, 0.1 to 100 mg, preferably 0.2 to 50 mg, of the compound of the present invention can generally be orally administered to an adult before bedtime. In the case of parenteral administration, the single dose can be 1 / 10 to 1 / 3 of the above-mentioned respective doses.

[0026] The present invention will be described in detail below with reference to examples, but is not limited to these. Melting points were measured using a Yamato MP-21 melting point apparatus, with no thermometer correction. NMR spectra were measured using a Bruker AVANCE III 500 nuclear magnetic resonance spectrometer, with tetramethylsilane as the internal standard. Silica gel column chromatography was performed using silica gel PSQ100B or NH-DM1020 (Fuji Silysia Chemical). Thin-layer chromatography was performed using Silica gel F254 (Merck, No. 5715), with detection using a UV lamp and a 5 wt% phosphomolybdic acid-ethanol color reagent. Commercially available reagents and solvents were used as is.

[0027] Example 1. Preparation of (S)-6-(5-chloropyridin-2-yl)-7-oxo-,6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl piperazine-1-carboxylate hydrochloride (hereinafter referred to as LN-M1 hydrochloride). Acetonitrile (450 mL) was added to eszopiclone (30 g, 89 mmol) and the mixture was ice-cooled under an argon atmosphere. 1-Chloroethyl chloroformate (9.7 mL, 77 mmol) was added and the mixture was stirred at 75°C for 3 hours. While heating, methanol (48 mL) was added and the mixture was heated to reflux for 3 hours. After ice-cooling for 1 hour, the precipitate was collected by filtration. The filtrate was concentrated, 100 mL of diethyl ether was added, and the mixture was allowed to stand for 18 hours. The resulting solid was collected by filtration. The collected precipitate and the solid were combined to obtain crude crystals (32.2 g). Ethanol (360 mL) and water (100 mL) were added to the crude crystals and heated to reflux for 1 hour. The mixture was returned to room temperature and allowed to stand for 18 hours, and the precipitated solid was collected by filtration to give 17.4 g (47%) of LN-M1 hydrochloride as the first crystals. The filtrate was concentrated, and ethanol (160 mL) and water (50 mL) were added, followed by heating to reflux for 1 hour. The mixture was returned to room temperature and allowed to stand for 18 hours, and the precipitated solid was collected by filtration to give 2.6 g (7%) of LN-M1 hydrochloride as the second crystals.

[0028] Example 2. Preparation of Compound 1: 2-Propyn-1-yl 4-methylbenzenesulfonate (4.2 g, 20 mmol) was added to acetonitrile (130 mL) and LN-M1 hydrochloride (8.6 g, 21 mmol) at room temperature. N,N-Diisopropylethylamine (6.9 mL, 40 mmol), potassium iodide (330 mg, 2.0 mmol), and cesium carbonate (9.8 g, 30 mmol) were added at room temperature, and the mixture was stirred at 50°C for 18 hours. The reaction mixture was ice-cooled, and the precipitate was collected by filtration. The mixture was then added to a chloroform:methanol (100:1) solution and heated to reflux for 15 minutes. The mixture was allowed to cool to room temperature, and the mixture was suction-filtered using a short pad of silica gel with a chloroform:methanol (100:1) solution. The solvent was removed under reduced pressure to obtain crude crystals (8.0 g). Ethyl acetate (480 mL) was added to the crude crystals, heated to reflux, filtered hot using a glass filter, and recrystallized by cooling to room temperature while stirring at a constant speed (150 rpm) using a stirrer to obtain 4.6 g (56%) of compound 1 as the first crystal. The filtrate was concentrated, ethyl acetate (480 mL) was added, heated to reflux, filtered hot using a glass filter, and recrystallized by cooling to room temperature while stirring at a constant speed (150 rpm) using a stirrer to obtain compound 1 (1.7 g, 21%) as the second crystal.

[0029] Example 3 Preparation of Compound 1-1 To a solution of compound 1 (50 mg, 0.12 mmol) in dichloromethane (5.0 mL) was added 1 mol / L hydrogen chloride-diethyl ether solution (0.40 mL, 0.40 mmol as hydrogen chloride) at room temperature, and the mixture was stirred at room temperature for 10 minutes. The solvent was evaporated under reduced pressure, and petroleum ether was added to the residue. The precipitated crystals were collected by filtration to obtain compound 1-1 (50 mg, 93%).

[0030] Example 4. Preparation of Compound 2: LN-M1 hydrochloride (300 mg, 0.70 mmol) was added with acetonitrile (5.0 mL), N,N-diisopropylethylamine (500 μL, 3.0 mmol), and bromoacetonitrile (200 μL, 2.0 mmol), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (NH-DM1020, chloroform:hexane = 1:1) to give compound 2 (340 mg, 99%) as crystals.

[0031] Example 5. Preparation of Compound 3. Compound 3 (100 mg, 23%) was obtained as an oil from LN-M1 hydrochloride (400 mg, 1.0 mmol), acetonitrile (5.0 mL), N,N-diisopropylethylamine (500 μL, 3.0 mmol), and 4-bromo-1-butyne (200 μL, 1.0 mmol) in the same manner as in Example 4. A 1 mol / L hydrogen chloride-diethyl ether solution (1.0 mL, 1.0 mmol as hydrogen chloride) was added to a dichloromethane (10 mL) solution of compound 3 (100 mg, 0.23 mmol) at room temperature, and the mixture was stirred for 0.5 hours. The solvent was evaporated under reduced pressure, and petroleum ether and diethyl ether were added to the residue. The precipitated crystals were collected by filtration to obtain compound 3 (50 mg, 47%).

[0032] Example 6 Preparation of Compound 5 Compound 5 (110 mg, 26%) was obtained as a crystal from LN-M1 hydrochloride (400 mg, 1.0 mmol), acetonitrile (5.0 mL), N,N-diisopropylethylamine (500 μL, 3.0 mmol), and 3-butynyl-2-mesylate (440 mg, 3.0 mmol) in the same manner as in Example 4.

[0033] Example 7 Preparation of Compound 6 Compound 6 (200 mg, 35%) was obtained as a crystal from LN-M1 hydrochloride (500 mg, 1.2 mmol), tetrahydrofuran (5.0 mL), triethylamine (220 μL, 1.6 mmol), 3-chloro-3-methyl-1-butyne (130 mg, 1.3 mmol), and copper(I) iodide (20 mg, 0.10 mmol) in the same manner as in Example 4.

[0034] Example 8 Preparation of Compound 7 Compound 7 (170 mg, 38%) was obtained as a crystal from LN-M1 hydrochloride (400 mg, 1.0 mmol), acetonitrile (5.0 mL), N,N-diisopropylethylamine (500 μL, 3.0 mmol), 4-chloro-2-butyn-1-ol (100 μL, 1.0 mmol), and potassium iodide (20 mg, 0.10 mmol) in the same manner as in Example 4.

[0035] Example 9 Preparation of Compound 10 Compound 10 (0.15 g, 54%) was obtained from LN-M1 hydrochloride (500 mg, 1.2 mmol), acetonitrile (20 mL), N,N-diisopropylethylamine (0.27 mL, 2.4 mmol), and (3-bromo-1-propynyl)cyclopropane (0.27 mL, 2.4 mmol) in the same manner as in Example 5.

[0036] Example 10 Preparation of Compound 12 Compound 12 (580 mg, 55%) was obtained as a crystal from LN-M1 hydrochloride (1.0 g, 2.4 mmol), acetonitrile (10 mL), N,N-diisopropylethylamine (830 μL, 4.8 mmol), 1-bromo-2-pentyne (430 mg, 2.9 mmol), potassium iodide (30 mg, 0.20 mmol), and cesium carbonate (1.2 g, 3.6 mmol) in the same manner as in Example 4.

[0037] Example 11 Preparation of Compound 15 Compound 15 (1.0 g, 31%) was obtained as a crystal from LN-M1 hydrochloride (2.7 g, 6.6 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (2.8 mL, 17 mmol), 4-ethynyltetrahydro-2H-4-pyranyl methanesulfonate (1.5 g, 7.3 mmol), and copper(I) iodide (110 mg, 0.6 mmol) in the same manner as in Example 4.

[0038] Example 12 Preparation of Compound 16 Compound 16 (1.0 g, 21%) was obtained as a crystal from LN-M1 hydrochloride (4.0 g, 10 mmol), tetrahydrofuran (15 mL), N,N-diisopropylethylamine (4.5 mL, 26 mmol), 3-ethynyltetrahydro-3-furanyl methanesulfonate (1.8 g, 9.4 mmol), and copper(I) iodide (190 mg, 1.0 mmol) in the same manner as in Example 4.

[0039] Example 13 Preparation of Compound 17 Compound 17 (1.0 g, 30%) was obtained as a crystal from LN-M1 hydrochloride (3.0 g, 7.3 mmol), tetrahydrofuran (10 mL), N,N-diisopropylethylamine (3.2 mL, 18 mmol), 3-ethynylcyclobutyl methanesulfonate (1.4 g, 8.0 mmol), and copper(I) iodide (130 mg, 0.70 mmol) in the same manner as in Example 4.

[0040] Example 14 Preparation of Compound 18 Compound 18 (1.6 g, 46%) was obtained as a crystal from LN-M1 hydrochloride (3.1 g, 7.7 mmol), tetrahydrofuran (30 mL), N,N-diisopropylethylamine (3.3 mL, 19 mmol), 1-hexynyl-3-methanesulfonate (1.5 g, 8.5 mmol), and copper(I) iodide (130 mg, 0.70 mmol) in the same manner as in Example 4.

[0041] Example 15 Preparation of Compound 19 Compound 19 (2.2 g, 96%) was obtained as a crystal from LN-M1 hydrochloride (2.0 g, 4.9 mmol), tetrahydrofuran (30 mL), N,N-diisopropylethylamine (2.1 mL, 12 mmol), 1-heptynyl-3-methanesulfonate (1.0 g, 5.4 mmol), and copper(I) iodide (100 mg, 0.50 mmol) in the same manner as in Example 4.

[0042] Example 16 Preparation of Compound 20 Compound 20 (800 mg, 25%) was obtained as a crystal from LN-M1 hydrochloride (3.0 g, 7.3 mmol), tetrahydrofuran (30 mL), N,N-diisopropylethylamine (3.2 mL, 18 mmol), 1-pentynyl-3-methanesulfonate (1.3 g, 8.0 mmol), and copper(I) iodide (130 mg, 0.70 mmol) in the same manner as in Example 4.

[0043] Example 17 Preparation of Compound 21 Compound 21 (2.3 g, 54%) was obtained as crystals from 2-propyn-1-yl-d3 4-methylbenzenesulfonate (2.1 g, 9.8 mmol), acetonitrile (30 mL), LN-M1 hydrochloride (4.2 g, 10 mmol), N,N-diisopropylethylamine (3.4 mL, 20 mmol), and potassium iodide (160 mg, 1.0 mmol) in the same manner as in Example 2.

[0044] Example 18 Preparation of Compound 22 Compound 22 (2.7 g, 69%) was obtained from 2-propyn-1-yl-3-d 4-methylbenzenesulfonate (2.0 g, 9.5 mmol), acetonitrile (30 mL), LN-M1 hydrochloride (4.1 g, 10 mmol), N,N-diisopropylethylamine (3.3 mL, 19 mmol), and potassium iodide (170 mg, 1.0 mmol) in the same manner as in Example 2.

[0045] Example 19 Preparation of 2-propyn-1-yl-1,1-d2 4-methylbenzenesulfonate: Deuterated paraformaldehyde (1.0 g, 31 mmol) was added to tetrahydrofuran (50 mL), and a 0.5 mol / L ethynylmagnesium bromide tetrahydrofuran solution (100 mL, 50 mmol) was added dropwise under ice cooling, followed by stirring at 50° C. for 18 hours. The reaction mixture was returned to room temperature, saturated aqueous ammonium chloride (8.0 mL) and dichloromethane (25 mL) were added, and the mixture was stirred for 5 minutes. The mixture was filtered through Celite, and the filtrate was concentrated to quantitatively obtain 2-propyn-1,1-d2-1-ol as an oil. The resulting 2-propyn-1,1-d2-1-ol was mixed with cyclopentyl methyl ether (50 mL) and tosyl chloride (7.0 g, 37 mmol) and cooled to -10°C. Potassium hydroxide (8.4 g, 150 mmol) was added and the mixture was stirred while gradually warming to room temperature. The reaction mixture was suction filtered using glass fiber filter paper, and water was added to the filtrate, followed by extraction with ethyl acetate. The mixture was suction filtered through a short silica gel column using a heptane:ethyl acetate (10:1) solution, and the solvent was evaporated under reduced pressure to give the title compound (4.4 g, 66%) as an oil.

[0046] Example 20 Preparation of Compound 8 Compound 8 (20.0 g, 61%) was obtained as a crystal from 2-propyn-1-yl-1,1-d2 4-methylbenzenesulfonate (16.0 g, 75 mmol), acetonitrile (240 mL), LN-M1 hydrochloride (32.4 g, 79 mmol), N,N-diisopropylethylamine (26 mL, 150 mmol), potassium iodide (1.3 mg, 8 mmol), and cesium carbonate (37.0 g, 113 mmol) in the same manner as in Example 2.

[0047] Example 21 Preparation of 3-ethynyl-3-oxetan-3-yl methanesulfonate The title compound (24.5 g, 139 mmol) was obtained as an oil from 3-oxetanone (10.0 g, 139 mmol), tetrahydrofuran (40 mL), a 0.5 mol / L ethynylmagnesium bromide tetrahydrofuran solution (300 mL, 150 mmol), dichloromethane (180 mL), triethylamine (19 mL, 138 mmol), and mesyl chloride (9.3 mL, 121 mmol) in the same manner as in Example 19.

[0048] Example 22 Preparation of Compound 11 Compound 11 (26.4 g, 48%) was obtained as crystals from LN-M1 hydrochloride (47.0 g, 114 mmol), tetrahydrofuran (700 mL), N,N-diisopropylethylamine (52 mL, 300 mmol), 3-ethynyl-3-oxetanyl methanesulfonate (23.2 g, 132 mmol), and copper(I) iodide (2.3 g, 12 mmol) in the same manner as in Example 2.

[0049] Example 23. Preparation of Compound 4. LN-M1 hydrochloride (400 mg, 1.0 mmol) was added with dichloroethane (5.0 mL) and N,N-diisopropylethylamine (170 μL, 1.1 mmol) at room temperature and stirred for 15 minutes. 2-Butynal (200 mg, 3.0 mmol) was added at room temperature and stirred for 10 minutes. Sodium triacetoxyborohydride (110 mg, 1.5 mmol) and acetic acid (120 μL, 2.0 mmol) were then added at room temperature and stirred for 18 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (NH-DM1020, chloroform:hexane = 1:1) to obtain the free form of compound 4 (120 mg, 28%) as an oil. To a solution of the free compound 4 (120 mg, 0.28 mmol) in dichloromethane (10 mL) was added a 1 mol / L hydrogen chloride-diethyl ether solution (1.0 mL, 1.0 mmol as hydrogen chloride) at room temperature, and the mixture was stirred for 0.5 hours. The solvent was evaporated under reduced pressure, and petroleum ether and diethyl ether were added to the residue. The precipitated crystals were collected by filtration to give compound 4 (70 mg, 54%) as crystals.

[0050] Example 24 Preparation of Compound 13 LN-M1 hydrochloride (1.7 g, 4.1 mmol), dichloromethane (10 mL), N,N-diisopropylethylamine (790 μL, 4.6 mmol), and 2-heptynal (700 mg, 6.3 mmol) were added, and the mixture was stirred with sodium triacetoxyborohydride (1.8 g, 8.4 mmol) and acetic acid (480 μL, 8.4 mmol) in the same manner as in Example 23 to obtain compound 13 (1.0 g, 51%) as crystals.

[0051] Example 25 Preparation of Compound 14 LN-M1 hydrochloride (2.2 g, 5.3 mmol), dichloromethane (10 mL), N,N-diisopropylethylamine (1.1 mL, 4.6 mmol), and 2-hexynal (800 mg, 8.3 mmol) were added, and the mixture was stirred with sodium borohydride (2.3 g, 11 mmol) and acetic acid (630 μL, 11 mmol) in the same manner as in Example 23 to obtain compound 14 (800 mg, 32%) as crystals.

[0052] Example 26. Preparation of Compound 9: To a suspension of LN-M1 hydrochloride (1.0 g, 2.4 mmol) in dichloromethane (30 mL), N,N-diisopropylethylamine (0.44 mL, 2.5 mmol) was added at room temperature and stirred for 15 minutes. Propiolic acid (0.18 mL, 2.9 mmol) and water-soluble carbodiimide hydrochloride (0.56 g, 2.9 mmol) were added under ice cooling and stirred at room temperature for 4 hours. The reaction mixture was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PSQ100B, chloroform:methanol = 60:1) to give compound 9 (0.56 g, 54%) as crystals.

[0053] Example 27 Preparation of Compound 8-1 To a solution of compound 8 (1.5 g, 3.6 mmol) in dichloromethane (55 mL) was added a 1 mol / L hydrogen chloride-diethyl ether solution (11 mL, 11 mmol as hydrogen chloride) at room temperature, and the mixture was stirred for 0.5 hours. The solvent was evaporated under reduced pressure, and diethyl ether was added to the residue. The precipitated crystals were collected by filtration to obtain compound 8-1 (1.4 g, 89%).

[0054] Example 28 Preparation of Compound 8-2 Compound 8 (0.30 g, 0.72 mmol) was suspended in tetrahydrofuran (THF, 15 mL) and dissolved at 40 °C. 48% hydrobromic acid (0.10 mL, 0.93 mmol as hydrogen bromide) was added at room temperature, and the mixture was stirred for 3 hours. The precipitated crystals were collected by filtration and washed with THF to obtain compound 8-2 (0.27 g, 71%).

[0055] Example 29 Preparation of Compound 8-3 Compound 8-3 (0.12 g, 55%) was obtained as crystals from compound 8 (0.20 g, 0.48 mmol), THF (10 mL), and 1 mol / L sulfuric acid (0.53 mL, 0.53 mmol as sulfuric acid) in the same manner as in Example 28.

[0056] Example 30 Preparation of Compound 8-4 Compound 8-4 (0.27 g, 79%) was obtained as crystals from compound 8 (0.30 g, 0.72 mmol), THF (16 mL), and 60% nitric acid (0.08 mL, 0.79 mmol as nitric acid) in the same manner as in Example 28.

[0057] Example 31 Preparation of Compound 8-5 Compound 8-5 (0.05 g, 14%) was obtained as a crystal from compound 8 (0.30 g, 0.72 mmol), THF (15 mL), and phosphoric acid (0.04 mL, 0.72 mmol as phosphoric acid) in the same manner as in Example 28.

[0058] Example 32 Preparation of Compound 8-6 Compound 8-6 (0.31 g, 76%) was obtained as a crystal from compound 8 (0.30 g, 0.72 mmol), THF (19 mL), and benzenesulfonic acid monohydrate (0.15 g, 0.86 mmol) in the same manner as in Example 28.

[0059] Example 33 Preparation of Compound 8-7 Compound 8-7 (0.30 g, 81%) was obtained as a crystal from compound 8 (0.30 g, 0.72 mmol), THF (19 mL), and methanesulfonic acid (0.06 mL, 0.86 mmol) in the same manner as in Example 27.

[0060] Example 34 Preparation of Compound 8-8 Compound 8-8 (0.16 g, 48%) was obtained as crystals from compound 8 (0.30 g, 0.72 mmol), THF (16 mL), oxalic acid (0.11 g, 0.86 mmol), and water (3.0 mL) in the same manner as in Example 27.

[0061] Example 35 Preparation of Compound 8-9 Compound 8-9 (0.31 g, 74%) was obtained as a crystal from compound 8 (0.30 g, 0.72 mmol), THF (21 mL), and p-toluenesulfonic acid monohydrate (0.16 g, 0.86 mmol) in the same manner as in Example 27.

[0062] Example 36 Preparation of Compound 8-10 Compound 8-10 (0.39 g, 84%) was obtained as a crystal from compound 8 (0.30 g, 0.72 mmol), THF (21 mL), and (-)-10-camphorsulfonic acid (0.20 g, 0.86 mmol) in the same manner as in Example 28.

[0063] Example 37 Preparation of Compound 8-11 Compound 8-11 (0.24 g, 63%) was obtained as crystals from compound 8 (0.30 g, 0.72 mmol), THF (19 mL), and maleic acid (0.09 g, 0.76 mmol) in the same manner as in Example 27.

[0064] Example 38 Preparation of Compound 8-12 Compound 8-12 (200 mg, 53%) was obtained as a crystal from compound 8 (0.30 g, 0.72 mmol), THF (19 mL), and ethanesulfonic acid (65 μL, 0.79 mmol) in the same manner as in Example 27.

[0065] Example 39 Preparation of Compound 8-13 Compound 8-13 (200 mg, 51%) was obtained as a crystal from compound 8 (0.30 g, 0.72 mmol), THF (19 mL), and 2-hydroxyethanesulfonic acid (100 μL, 0.79 mmol) in the same manner as in Example 27.

[0066] Example 40 Preparation of Compound 8-14 Compound 8-14 (200 mg, 55%) was obtained as a crystal from compound 8 (0.25 g, 0.60 mmol), THF (15 mL), and citric acid (100 μL, 0.79 mmol) in the same manner as in Example 27.

[0067] Example 41 Preparation of Compound 11-1 Compound 11-1 (1.45 g, 90%) was obtained as crystals from compound 11 (1.5 g, 3.3 mmol), THF (140 mL), and 35% hydrochloric acid (2.8 mL, 33 mmol as hydrogen chloride) in the same manner as in Example 28.

[0068] The physical property data of the compounds of the present invention obtained by the production in the above examples are shown in Tables 1 to 6.

[0069]

[0070]

[0071]

[0072]

[0073]

[0074] Test Example 1: GABA A α1β2γ2PAM test (In vitro) GABA A The receptor is a pentamer consisting of five subunits, with the α subunit playing an important role. The α subunits are further classified into α1 to α6, with α1 being involved in sedative and hypnotic effects. The compound of the present invention was expressed in HEK293 cells (human embryonic kidney cells 293) and composed of α1β2γ2 subunits. A The PAM (Positive Allosteric Modulator) activity against the receptor was evaluated using an IonFlux HT (automated patch clamp system) under a voltage clamp of -60 mV. The chloride ion flux induced by GABA was defined as 100%, and the concentration at which the chloride ion flux increased to 150% by adding each compound of the present invention and eszopiclone as a control substance was defined as the EC 150% The value was EC 150% The values ​​were calculated by repeated linear regression using the statistical analysis tool Stat Preclinica 2.2. An example of the results is shown in Table 7.

[0075]

[0076] As shown in Table 7, the compounds of the present invention exhibited activity against the α1 subunit. Compounds 4 and 7 had a higher EC than eszopiclone. 150% Although it shows low values, it has been shown to have activity against the α1 subunit, and can be said to have sedative and hypnotic effects.

[0077] Test Example 2: Sleep Analysis Test The sleep-inducing effects of the compounds of the present invention were evaluated by analyzing sleep stages using rat electroencephalograms and electromyograms as indicators. Electrodes were implanted in the frontal cortex and hippocampus of rats to measure electroencephalograms, and leads were implanted in the neck to measure electromyograms. After surgery, rats were allowed to recover for at least 5 days, and healthy rats were used for the study. Each group consisted of 8 rats: a control group, a compound 8 (30 mg / kg) treatment group, a compound 11 (30 mg / kg) treatment group, and an eszopiclone (30 mg / kg) treatment group. The control group received a 1% w / v methylcellulose solution, and each compound was suspended in the same solution. Each compound solution was orally administered simultaneously with the onset of the dark period, and electroencephalograms and electromyograms were continuously recorded for up to 6 hours after administration. The recorded electroencephalograms were analyzed using a sleep analysis research program (Sleep Sign, Kissei Comtec Co., Ltd.). Sleep stages were classified into wakefulness, slow-wave sleep (non-REM sleep), and fast-wave sleep (REM sleep) using EEG and EMG as indices. Sleep onset latency was defined as the latency period until a sleep period consisting of continuous non-REM and REM sleep lasting a total of 120 seconds or more. Significant differences were determined using a Dunnett test, with "*" indicating a significant difference at p<0.05 and "**" indicating a significant difference at p<0.01. Examples of sleep stage results are shown in Figures 1-3, and an example of sleep onset latency results is shown in Figure 4.

[0078] As shown in Figures 1 to 4, in a sleep analysis test using rats after a single oral administration, the compounds of the present invention, like eszopiclone, decreased the wakefulness period and REM sleep period, increased the non-REM sleep period, and shortened the sleep onset latency in the sleep-wake cycle.

[0079] Test Example 3: Bitterness Intensity Test Using a Taste Recognition Device Bitterness was evaluated using the taste sensor of a taste recognition device (TS-5000Z, manufactured by Intelligent Sensor Technology Co., Ltd.). An example of a method for measuring bitterness using a taste sensor is as follows. First, the taste sensor is immersed in a reference solution to obtain a membrane potential Vr. Next, the test solution is immersed in the taste sensor to obtain a membrane potential Vs. The membrane potential change obtained here (Vs - Vr) is called a relative value and corresponds to a first taste such as sourness, bitterness, astringency, umami, saltiness, or sweetness. After that, the taste sensor is washed with the reference solution, and then the taste sensor is immersed in the reference solution again to obtain a membrane potential Vr'. The membrane potential change (Vr'-Vr) obtained here is called the CPA (Change of Membrane Potential caused by Adsorption) value, and corresponds to aftertastes such as bitterness, astringency, and rich umami. In particular, the CPA value responds specifically to bitterness. Meanwhile, the relative values ​​of BT0 and AN0 of the sensor measuring bitterness respond to bitterness and saltiness, and the values ​​responding to each are added together. However, since there is a positive correlation between the relative value responding to saltiness and the conductivity (logarithm) of the solution, by measuring the conductivity and subtracting the relative value responding to saltiness, it is possible to specifically evaluate the intensity of bitterness even in relative values.

[0080] However, the CPA values ​​of eszopiclone and the compounds of the present invention at the concentrations at which they were dissolved were small, making it difficult to evaluate the intensity of bitterness using the CPA values. Therefore, the conductivity of each sample solution was measured, and the bitterness intensity was evaluated as a relative value corrected for conductivity.

[0081] Evaluation of Bitterness Intensity: Using 0.015 mg / mL, 0.037 mg / mL, and 0.094 mg / mL quinine sulfate solutions as reference solutions, the relative bitterness (mV) of 0.5 mg / mL eszopiclone and 0.5 mg / mL compounds of the present invention (Compounds 1, 7, 8, 9, and 11) was measured using the bitterness sensor (BT0 sensor) of the taste recognition device. Since it was not possible to simultaneously measure all of the compounds of the present invention, the test was conducted twice. Examples of the results are shown in Tables 8 and 9.

[0082]

[0083]

[0084] As is clear from Tables 8 and 9, in the bitterness evaluation test using the bitterness sensor, the output values ​​(relative values) of quinine sulfate solutions (0.015 mg / mL, 0.037 mg / mL, and 0.094 mg / mL) increased depending on the intensity of bitterness. Compared with 0.5 mg / mL of eszopiclone, the output values ​​(relative values) of Compounds 1, 7, 8, 9, and 11 at 0.5 mg / mL were all lower, indicating that the compounds of the present invention have a weaker bitterness than eszopiclone.

[0085] As shown in Table 7, the compounds of the present invention exhibited in vitro GABAergic activity. A In the α1β2γ2PAM test, the compounds exhibited activity against the α1 subunit. As shown in Figures 1 to 4, in a sleep analysis test using a single oral dose of the compounds in rats, the compounds decreased the wakefulness and REM sleep periods, increased the non-REM sleep period, and shortened the sleep onset latency, similar to eszopiclone. Furthermore, as shown in Tables 8 and 9, in a bitterness intensity test, the compounds of the present invention were found to be less bitter than eszopiclone. Therefore, the compounds of the present invention have a reduced bitterness compared to eszopiclone and improve the QOL of patients taking them, making them highly useful as pharmaceuticals for improving or treating sleep disorders.

Claims

1. An alkyne derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: [wherein A and B are the same or different and represent hydrogen, deuterium, or alkyl, or A and B together with the carbons bonding them form a ring to represent cycloalkyl, oxetane, tetrahydrofuran, or tetrahydropyran, or A and B together with the carbons bonding them represent carbonyl; X represents carbon or nitrogen; Y represents hydrogen, deuterium, alkyl, cycloalkyl, or hydroxyalkyl, and when X is nitrogen, Y is unsubstituted; and n represents an integer of 0 to 2.] 2. The alkyne derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is carbon.

3. The alkyne derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Y is hydrogen.

4. The alkyne derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein n is 0.

5. The alkyne derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein A and B are deuterium.

6. The alkyne derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein A and B together with the carbons to which they are bonded form a ring to form an oxetane.

7. A medicine containing at least one of the alkyne derivatives and pharmaceutically acceptable salts thereof according to any one of claims 1 to 6.

8. The pharmaceutical composition according to claim 7, which is an agent for improving or treating sleep disorders.

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