Use of benzodiazepine derivative for treating insomnia comorbid with different diseases

Abstract

Provided in the present invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating (patients with) insomnia comorbid with different diseases.

Description

Benzodiazepines* derivatives are used to treat insomnia complicated by various diseases. Technical Field

[0001] This invention specifically relates to 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][1,4]benzodiazepine 6-one or its pharmaceutically acceptable salts are used to treat insomnia associated with various diseases. Background Technology

[0002] Insomnia is a common type of sleep disorder in clinical practice. Long-term insomnia can have a serious negative impact on normal life and work, and may also lead to other diseases such as hypertension, diabetes, and arrhythmia.

[0003] Clinically, many insomnia patients also suffer from other conditions such as hypertension, diabetes, lipid metabolism disorders, or arrhythmias. While some research has explored the correlation between different diseases and insomnia, this is limited to certain conditions. For example, in patients with both insomnia and hypertension, high blood pressure or the use of antihypertensive medication may affect sleep, and insomnia can worsen hypertension. In patients with both insomnia and diabetes, diabetes can cause nocturnal urination and itchy skin, thus affecting sleep, while insomnia can decrease insulin sensitivity and increase cortisol and adrenaline levels, thereby affecting glucose metabolism and exacerbating diabetes. Furthermore, arrhythmias and insomnia also influence each other to some extent, but the underlying mechanisms of different diseases and insomnia are not fully understood. Currently, there are no drugs on the market specifically for treating insomnia patients with comorbid diseases.

[0004] Insomnia sufferers typically experience several sleep symptoms and sleep disturbances, including prolonged sleep onset latency, increased awakenings during sleep, and reduced total sleep time. Specific sleep patterns can be quantified or monitored using polysomnography (PSG).

[0005] Patent WO2000069858A1 discloses a compound of formula (I), chemically named 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][1,4]benzodiazepine -6-ketone, and discloses the use of compound (I) for non-sedative treatment of insomnia. WO2009024325A2 discloses the use of compound (I) or its pharmaceutical salt in the treatment of various types of insomnia, demonstrating that compound (I) is effective in treating insomnia. However, the above patents do not disclose studies of compound (I) for insomnia (patients) with comorbidities. The chemical structure of compound (I) is shown below: Summary of the Invention

[0006] Insomnia is associated with a variety of diseases such as hypertension, diabetes, and arrhythmia, and is often difficult to predict. This invention studies in detail the application of compound (I) or its pharmaceutically acceptable salt in insomnia complicated with different diseases.

[0007] In this invention, the chemical structural formula of the compound of formula (I) is as follows:

[0008] The present invention provides a method for treating insomnia with comorbidities, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0009] In some specific embodiments, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating insomnia with comorbidities;

[0010] The comorbidities are selected from comorbid respiratory diseases, comorbid hypertension, comorbid glucose metabolism diseases, comorbid arrhythmia diseases, or comorbid lipid metabolism disorders, preferably comorbid lipid metabolism disorders or comorbid arrhythmia diseases.

[0011] In some specific embodiments, the present invention also provides a method for treating insomnia with a need for increased total sleep time, a need for reduced wakefulness after falling asleep, a need for improved sleep efficiency, a need for reduced sustained sleep latency and / or an need for increased N2 sleep, and with comorbidities, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] In some specific embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in the preparation of a medicament for treating insomnia with a need for increased total sleep time, a need for reduced wakefulness after falling asleep, a need for improved sleep efficiency, a need for reduced sustained sleep latency and / or a need for increased N2 sleep, and with comorbidities.

[0013] In some specific embodiments, the present invention also provides a method for treating insomnia with an increased need for total sleep time and comorbidities, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0014] In some specific embodiments, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating insomnia with an increased need for total sleep time and comorbidities;

[0015] In some specific embodiments, the present invention also provides a method for treating insomnia with a reduced need for wakefulness after falling asleep and with comorbidities, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0016] In some specific embodiments, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating insomnia with reduced need for wakefulness after falling asleep and comorbidities;

[0017] In some specific embodiments, the present invention also provides a method for treating insomnia with a need to improve sleep efficiency and comorbidities, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0018] In some specific embodiments, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating insomnia with a need for improved sleep efficiency and comorbidities;

[0019] In some specific embodiments, the present invention also provides a method for treating insomnia with a need for sustained reduction in sleep latency and comorbidities, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0020] In some specific embodiments, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating insomnia with a need for reduced persistent sleep latency and comorbidities;

[0021] In some specific embodiments, the present invention also provides a method for treating insomnia with increased N2 stage sleep demand and comorbidities, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0022] In some specific embodiments, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating insomnia with increased N2 sleep demand and comorbidities;

[0023] In this invention, the diseases in the comorbidity are selected from respiratory diseases, hypertension, glucose metabolism diseases, arrhythmia diseases, or lipid metabolism abnormalities.

[0024] The reduction in wakefulness after falling asleep is preferably a reduction in the duration of wakefulness after falling asleep;

[0025] The increase in N2 stage sleep is preferably N2 stage sleep;

[0026] In this invention, the administration is preferably oral;

[0027] In this invention, the amount or content of the compound of formula (I) or its pharmaceutically acceptable salt is 0.5 mg to 5 mg, preferably 1.0 mg to 4.5 mg, 1.5 mg to 4 mg, 2 mg to 3.5 mg or 2.5 mg to 3 mg, more preferably 0.5 mg, 1.5 mg, 2.5 mg or 3 mg;

[0028] In this invention, pharmaceutically acceptable salts of compounds of formula (I) can be prepared using standard techniques well known to those skilled in the art; specifically, pharmaceutically acceptable salts are acid addition salts, such as salts formed with inorganic or organic acids; examples of such pharmaceutically acceptable salts are hydrochloride, hydrobromide, sulfate, nitrate, citrate, acetate, maleate, fumarate, tartrate, succinate, methanesulfonate, or p-toluenesulfonate, etc.

[0029] In this invention, the drug or pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0030] In this invention, the drug or pharmaceutical composition optionally further includes a pharmaceutically acceptable carrier, diluent, or excipient;

[0031] In this invention, the drug or drug composition may be a tablet, pill, lozenge, capsule, liquid, gel, syrup, ointment or suspension, etc., preferably a tablet or capsule;

[0032] In this invention, the insomnia patient is an adult or an elderly person; the test subject is an adult or an elderly person.

[0033] And / or,

[0034] In this invention, the insomnia patient is male or female; the test subject is male or female;

[0035] And / or,

[0036] In this invention, the insomnia of the insomnia patient can be primary insomnia or secondary insomnia; preferably, it is primary insomnia.

[0037] And / or,

[0038] In this invention, the insomnia of the insomnia patient can be temporary insomnia, short-term insomnia, or long-term insomnia; preferably, it is long-term insomnia.

[0039] And / or,

[0040] In this invention, the insomnia of the insomnia patient can be sleep-onset insomnia, maintenance insomnia, or terminal insomnia; preferably, it is maintenance insomnia or terminal insomnia.

[0041] In this invention, the test subject is a human being;

[0042] In this invention, "adult" refers to a person aged 18 to 65; "elderly" refers to a person aged 65 or older.

[0043] In this invention, "primary insomnia" refers to insomnia not caused by medication, psychological, or environmental factors. The diagnostic criteria for primary insomnia can be found in the *Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition* (DSM-5), which is incorporated herein by reference.

[0044] In this invention, "secondary insomnia" refers to insomnia caused by specific drugs, psychological or environmental conditions;

[0045] In this invention, "temporary insomnia" refers to insomnia that occurs for one to a few days and lasts for less than one week; "short-term insomnia" refers to insomnia that lasts for 1 to 3 weeks; and "long-term insomnia" is generally considered to be an episode that lasts for more than 3 weeks.

[0046] In this invention, "sleep-onset insomnia" or "initiation insomnia" is insomnia characterized by difficulty falling asleep; "maintenance insomnia" is insomnia characterized by difficulty maintaining sleep; and "terminal insomnia" or "offset insomnia" is insomnia characterized by waking up in the morning and being unable to fall back asleep.

[0047] In this invention, Total Sleep Time (TST) is the total sleep time measured within a fixed period (usually 8 hours).

[0048] In this invention, continuous sleep latency (LPS) is the duration of continuous sleep from when the lights are turned off until 10 minutes have passed.

[0049] In this invention, Sleep-on-Sleep Oscillation Time (WASO) is the total amount of sleep-on-sleep waking time measured over a fixed 8-hour bedtime period.

[0050] In this invention, sleep efficiency (SE) is the ratio of total sleep time (TST) to total time spent in bed, i.e., the percentage of sleep time. The total time spent in bed is typically 8 hours.

[0051] In this invention, Total Awake Time (TWT) is the total amount of awake time measured over a specific period of time.

[0052] In this invention, the number of awakenings after falling asleep (NAW) is the number of times one returns to a waking state (the number of times an awakening occurs for at least one period of time after the onset of continuous sleep).

[0053] In this invention, DSM-5 refers to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.

[0054] In this invention, respiratory diseases comorbid with insomnia patients may specifically include pulmonary nodules, chronic cough, sleep apnea syndrome, etc.

[0055] In this invention, the glucose metabolism disorders comorbid with insomnia patients may specifically include type 1 diabetes, type 2 diabetes, glucose intolerance, etc.

[0056] In this invention, the arrhythmia comorbid with insomnia patients may specifically include arrhythmia, sinus bradycardia, complete right bundle branch block, etc.

[0057] In this invention, the lipid metabolism abnormalities associated with insomnia patients may specifically include hyperlipidemia, hypercholesterolemia, etc.

[0058] In this invention, for each case, the change in sleep-wake time = sleep-wake time before treatment or its average value - sleep-wake time after treatment or its average value; the average change in sleep-wake time is the average of the "change in sleep-wake time" for all cases or subgroups of cases; when the value is positive, it indicates that the sleep-wake time has decreased after treatment, and when the value is negative, it indicates that the sleep-wake time has increased after treatment.

[0059] In this invention, for each case, the change in total sleep time = total sleep time after treatment or its average value - total sleep time before treatment or its average value; the average change in total sleep time is the average of the "change in total sleep time" for all cases or subgroups of cases; when the value is positive, it indicates that the total sleep time has increased after treatment, and when the value is negative, it indicates that the total sleep time has decreased after treatment.

[0060] In this invention, for each case, the change in sleep efficiency (SE change) = the sleep efficiency after treatment or its average value - the sleep efficiency before treatment or its average value; the average change in sleep efficiency is the average of the "change in sleep efficiency" for all cases or subgroups of cases; when the value is positive, it indicates an increase in sleep efficiency after treatment, and when the value is negative, it indicates a decrease in sleep efficiency after treatment.

[0061] In this invention, for each case, the change in continuous sleep latency = the continuous sleep latency before treatment or its average value - the continuous sleep latency after treatment or its average value; the average change in continuous sleep latency is the average of the "change in continuous sleep latency" for all cases or subgroups of cases; when the value is positive, it indicates that the continuous sleep latency has decreased after treatment, and when the value is negative, it indicates that the continuous sleep latency has increased after treatment;

[0062] In this invention, for each case, the change in N2 stage sleep time = post-treatment N2 stage sleep time or its average value - pre-treatment N2 stage sleep time or its average value; the average change in N2 stage sleep time is the average of the "change in N2 stage sleep time" for all cases or subgroups of cases; a positive value indicates an increase in N2 stage sleep time after treatment, and a negative value indicates a decrease in N2 stage sleep time after treatment. The definitions for N1, N3, and REM sleep are similar.

[0063] This invention confirms that the compound of formula (I) or a pharmaceutically acceptable salt thereof can be used to treat insomnia with comorbidities, increasing total sleep time, reducing wakefulness after falling asleep, improving sleep efficiency, reducing sustained sleep latency, and / or increasing N2 sleep, wherein the comorbidities are selected from comorbid respiratory diseases, comorbid hypertension, comorbid glucose metabolism diseases, comorbid arrhythmia diseases, or comorbid lipid metabolism disorders, especially comorbid lipid metabolism disorders and comorbid arrhythmia diseases. Specific Implementation

[0064] Example 1

[0065] A multicenter, randomized, double-blind, placebo-controlled parallel study was conducted to investigate the efficacy of compound (I) in treating insomnia patients with comorbidities.

[0066] Initial screening criteria: The subjects were patients aged ≥18 years (male or female) who met the DSM-5 diagnostic criteria for insomnia disorder; the subjects' usual bedtime was between 9 p.m. and 1 a.m. the next day, and the subjects spent ≥7 hours in bed each night; the subjects had a sleep onset time >30 minutes or a total subjective sleep time ≤6 hours for at least three nights a week.

[0067] The subjects took the test drug or placebo orally 15-30 minutes before going to bed.

[0068] The test drug is a capsule containing 2.5 mg of compound (I) in powder form.

[0069] The placebo was a capsule that was identical in appearance, color, odor, and packaging to the test drug capsule, but contained no active substance.

[0070] The compound of formula (I) is 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][1,4]benzodiazepine -6-keto.

[0071] Patients who meet the initial screening criteria will undergo polysomnography (PSG) monitoring for two consecutive nights during the introductory period. Patients with a mean total sleep time (TST) of ≥240 minutes and ≤390 minutes will be selected for randomized double-blind treatment.

[0072] Introduction Phase Screening: Initially qualified patients entered a 7-day introduction phase (Day 7 to Day 1). A placebo was administered once daily for 7 consecutive days. From Day 7 to Day 3, patients took the introduction medication (placebo) at home. On Day 2 and Day 1, patients underwent two consecutive nights of polysomnography (PSG) monitoring at the sleep center of each research center, while still receiving the introduction medication (placebo). During the two consecutive nights of PSG monitoring, patients with a mean total sleep time (TST) ≥240 minutes and ≤390 minutes were selected.

[0073] Randomized, double-blind treatment period: Eligible patients entered the randomized, double-blind treatment period (days 1-14). Patients took either the investigational drug or a placebo once daily for 14 days. From day 1 to day 12, patients took the treatment medication at home. On the nights 13 and 14, patients underwent two consecutive nights of PSG monitoring at a sleep center, taking either the investigational drug or a placebo there.

[0074] Each PSG monitoring session should last longer than 480 minutes.

[0075] The average value of all data obtained from PSG monitoring on the two consecutive nights of day -2 and day -1 can be called the average value of all PSG data before treatment;

[0076] The average value of the data obtained from PSG monitoring on the two consecutive nights of day 13 and day 14 can be called the average value of PSG data after treatment.

[0077] The subjects were grouped according to their comorbidities: I: Insomnia patients with respiratory diseases; II: Insomnia patients with glucose metabolism disorders; III: Insomnia patients with arrhythmia; IV: Insomnia patients with hypertension; V: Insomnia patients with lipid metabolism disorders.

[0078] All insomnia patients taking the investigational drug included patients in subgroups I, II, III, IV, and V above, as well as all insomnia patients without comorbidities who took the investigational drug;

[0079] For each case, the change in sleep-onset wake time (WASO) = pre-treatment WASO or its average - post-treatment WASO or its average; the mean change in WASO is the average of the "change in WASO" for all cases or subgroups of cases; a positive value indicates a decrease in WASO after treatment, and a negative value indicates an increase in WASO after treatment.

[0080] For each case, the change in total sleep time = total sleep time after treatment or its average value - total sleep time before treatment or its average value; the average change in total sleep time is the average of the "change in total sleep time" for all cases or subgroups of cases; a positive value indicates an increase in total sleep time after treatment, and a negative value indicates a decrease in total sleep time after treatment.

[0081] For each case, the change in sleep efficiency (SE change) = post-treatment sleep efficiency or its average - pre-treatment sleep efficiency or its average; the average change in sleep efficiency is the average of the "change in sleep efficiency" for all cases or subgroups of cases; a positive value indicates an increase in sleep efficiency after treatment, and a negative value indicates a decrease in sleep efficiency after treatment.

[0082] For each case, the change in continuous sleep latency = the continuous sleep latency before treatment or its average value - the continuous sleep latency after treatment or its average value; the mean change in continuous sleep latency is the average of the "change in continuous sleep latency" for all cases or subgroups of cases; when the value is positive, it indicates that the continuous sleep latency has decreased after treatment, and when the value is negative, it indicates that the continuous sleep latency has increased after treatment.

[0083] For each case, the change in N2 stage sleep time = post-treatment N2 stage sleep time or its average - pre-treatment N2 stage sleep time or its average; the average change in N2 stage sleep time is the average of the "change in N2 stage sleep time" for all cases or subgroups; a positive value indicates an increase in N2 stage sleep time after treatment, and a negative value indicates a decrease in N2 stage sleep time after treatment. The definitions for N1, N3, and REM sleep are similar.

[0084] Based on PSG monitoring data, the changes in average wake time after sleep onset were analyzed and calculated. The changes in average wake time after sleep onset in each subgroup taking the investigational drug are shown in Table 1 below:

[0085] Table 1. Changes in mean sleep-wake time in each subgroup taking the investigational drug

[0086] Table 1 shows that compound (I) can effectively shorten the wake-up time after falling asleep, especially for insomnia patients with lipid metabolism abnormalities, hypertension, arrhythmia, or respiratory diseases.

[0087] Based on PSG monitoring data, the mean SE change was analyzed and calculated. The mean SE changes in each subgroup of patients taking the investigational drug are shown in Table 2 below:

[0088] Table 2. Changes in mean SE in each subgroup taking the investigational drug

[0089] Table 2 shows that compound (I) can effectively improve sleep efficiency, especially for insomnia patients with lipid metabolism abnormalities and arrhythmia.

[0090] Based on PSG monitoring data, the changes in average total sleep time were analyzed and calculated. The changes in average total sleep time for each subgroup taking the investigational drug are shown in Table 3 below:

[0091] Table 3. Changes in mean total sleep time in each subgroup taking the investigational drug

[0092] Table 3 shows that compound (I) can effectively increase total sleep time, especially for insomnia patients with lipid metabolism abnormalities and arrhythmia.

[0093] Based on PSG monitoring data, the changes in mean continuous sleep latency were analyzed and calculated. The changes in mean continuous sleep latency for each subgroup taking the investigational drug are shown in Table 4 below:

[0094] Table 4. Changes in mean continuous sleep latency in each subgroup taking the investigational drug

[0095] Table 4 shows that compound (I) can effectively shorten the duration of sleep, which is beneficial for insomnia patients to fall asleep, especially for insomnia patients with lipid metabolism abnormalities and arrhythmia.

[0096] Based on PSG monitoring data, the changes in average N2 stage sleep time were analyzed and calculated. The changes in average N2 stage sleep time in each subgroup taking the investigational drug are shown in Table 5 below:

[0097] Table 5. Changes in mean N2 sleep time in each subgroup taking the investigational drug

[0098] Table 5 shows that compound (I) can effectively increase the duration of N2 sleep, especially for insomnia patients with lipid metabolism abnormalities and arrhythmias.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating insomnia with comorbidities; The chemical structural formula of the compound of formula (I) is shown below: The comorbidities are selected from comorbid respiratory diseases, comorbid hypertension, comorbid glucose metabolism diseases, comorbid arrhythmia diseases, or comorbid lipid metabolism disorders, preferably comorbid lipid metabolism disorders or comorbid arrhythmia diseases.

2. The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating insomnia with a need for increased total sleep time, a need for reduced wakefulness after falling asleep, a need for improved sleep efficiency, a need for reduced sustained sleep latency and / or a need for increased N2 sleep, and with comorbidities.

3. The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating insomnia with an increased need for total sleep time and comorbidities, as described in claim 2.

4. The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating insomnia with reduced need for wakefulness after falling asleep and comorbidities, as described in claim 2.

5. The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating insomnia in patients with a need for improved sleep efficiency and comorbidities, as described in claim 2.

6. The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating insomnia with a need for reduced sustained sleep latency and comorbidities, as described in claim 2.

7. The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating insomnia with increased N2 sleep demand and comorbidities, as described in claim 2.

8. The use according to any one of claims 1-7, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 0.5 mg to 5 mg, preferably 1.0 mg to 4.5 mg, 1.5 mg to 4 mg, 2 mg to 3.5 mg or 2.5 mg to 3 mg, more preferably 0.5 mg, 1.5 mg, 2.5 mg or 3 mg.

9. The use according to any one of claims 1-8, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride, hydrobromide, sulfate, nitrate, citrate, acetate, maleate, fumarate, tartrate, succinate, methanesulfonate or p-toluenesulfonate.

10. The use according to any one of claims 1-9, wherein the insomnia of the insomnia patient is primary insomnia or secondary insomnia; preferably primary insomnia; And / or, The insomnia of the insomnia patients is temporary, short-term, or long-term; preferably long-term insomnia.

11. The use according to any one of claims 1-10, wherein the insomnia of the insomnia patient is sleep-onset insomnia, maintenance insomnia, or terminal insomnia; preferably maintenance insomnia or terminal insomnia.

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