CN113491680A - Application of catechol and derivatives in preparation of drugs for treating sleep disorders - Google Patents

Application of catechol and derivatives in preparation of drugs for treating sleep disorders Download PDF

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CN113491680A
CN113491680A CN202010257973.9A CN202010257973A CN113491680A CN 113491680 A CN113491680 A CN 113491680A CN 202010257973 A CN202010257973 A CN 202010257973A CN 113491680 A CN113491680 A CN 113491680A
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sleep
prodrug
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acceptable salt
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王汝涛
安龙
赵熠
郭树攀
王惟娇
陈涛
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Xi'an Libangzhao New Biological Technology Co ltd
Xian Libang Zhaoxin Biotechnology Co Ltd
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Abstract

The invention provides application of catechol and derivatives in preparation of drugs for treating sleep disorders. The application is mainly realized by the orexin receptor serving as the medicine. Meanwhile, the invention also discovers that the compound of the invention can simultaneously act on GABAAReceptors, thereby achieving a synergistic effect with the action of orexin receptors; the compound of formula I has the following structure:
Figure DDA0002438160750000011
，R1、R2、R3、R4each independently selected from ethyl, propyl or butyl.

Description

Application of catechol and derivatives in preparation of drugs for treating sleep disorders
Technical Field
The invention relates to the field of medicines, in particular to application of catechol and derivatives in preparation of medicines for treating sleep disorders.
Background
Insomnia is the most common type of sleep disorder in the clinic. The long-term insomnia can have serious negative effects on normal life and work, and even can cause malignant accidents. Epidemiological studies have shown that 45.4% of Chinese have experienced varying degrees of insomnia in the past 1 month. In healthy people, long-term sleep disorders increase the susceptibility to chronic diseases, such as coronary artery disease, diabetes, and the like.
Post-operative sleep disorders (PSD) have become increasingly important in recent years. There are studies reporting that 42% of patients develop sleep disorders after surgery and 23% of patients have a sustainable sleep disorder for 4 days. While approximately 1/4 patients at day 15 post-surgery again reflected insufficient sleep, 24% of which required drug treatment to correct the sleep disorder. PSD not only shows a decrease in sleep quality but also changes in sleep rhythm. Studies show that PSD is related to postoperative paroxysmal hypoxemia, postoperative pain sensitization, postoperative cognitive dysfunction, blood pressure fluctuation caused by sympathetic excitation, arrhythmia and other cardiovascular complications. For postoperative patients, the loss of sleep disturbs individual physiological parameters, which may have negative effects on the treatment and management of patients, such as decreased respiratory muscle compliance, increased blood pressure, decreased wound healing capacity, etc., for ICU patients, sleep disorders increase the risk of secondary complications, prolong the ICU hospitalization days, and increase the infection rate and mortality.
According to the multifunctional sleep record, normal physiological sleep is divided into non-rapid eye movement (NREM) sleep and Rapid Eye Movement (REM) sleep, wherein the NREM and the REM continuously last for about 90-100 min for one time, and 4-6 cycles are performed every night. The NREM is divided into three stages of N1, N2 and N3, and respectively accounts for 2% -5%, 45% -55% and 15% -20% of the total sleeping time. N1, light sleep, refers to the transition from arousal to sleep; n2 for moderate sleep; n3 is deep sleep, and typical electroencephalogram shows high-amplitude low-frequency delta waves (0.5-2.0 Hz). Thus N3 is also known as slow-wave sleep (SWS), the NREM stages 3 and 4 in the Rechtschuffen and Kales sleep systems. NREM is beneficial to physical recovery, removes metabolic waste in brain, and is important for normal physiological function of central nervous system. REM accounts for 20% -25% of the total sleeping time, and electroencephalogram shows that beta waves are mixed among low-amplitude and high-frequency zigzag theta waves, rapid eye movement is accompanied, skeletal muscle tension is lost, and the period is related to dreaming and memory consolidation. Typical manifestations of sleep disorder patients are: the total sleep time is reduced, the sleep-in latent period is increased, the deep sleep is reduced, the light sleep is increased, the SWS and REM are obviously reduced, the wakefulness frequency is increased, and the sleep quality is seriously reduced.
Zolpidem, zopiclone and benzodiazepine drugs (such as midazolam) are currently common hypnotic drugs in clinic and have the common characteristic that the zolpidem, zopiclone and benzodiazepine drugs all act on central inhibitory receptor GABAABy enhancing GABAAReceptor-coupled ion channels are opened, causing cell membrane hyperpolarization and neurons to be inhibited, resulting in sleep-inducing effects. The medicine can obviously shorten the sleep latency, increase the total sleep time and NREM sleep time of a patient, and has the advantages of quick response and strong effect. However, it was found that the compound acts on GABAAThe drugs in the receptors adversely affect the sleep architecture, manifested by inhibition of REM sleep and SWS sleep, loss of SWS sleep impairs memory formation and increases the patient's chances for delirium (delirium), while loss of REM sleep may lead to impaired concentration, altered memory and delirium (delirium). The above conditions limit the effect on GABA aloneAOf the recipient drugThe application of the medicament for resisting insomnia in other clinical applications has respective defects and defects, for example, melatonin receptor agonist and orexin receptor inhibitor (suvorexant) are helpful for improving sleep structure, but have weak sleep induction activity, so that the treatment effect has large individual difference; 5-HT receptor modulators (trazodone) have significant sleep induction, but have many side effects, such as headache, hypotension and cardiovascular risk; some antiepileptic, antidepressant and antipsychotic drugs are being used for sleep induction, but there are insufficient sleep induction research data and there are associated safety risks.
In view of the above, the present invention aims to provide a safe and effective new way for treating sleep disorder patients in view of the drawbacks and disadvantages of the existing drugs for treating sleep disorder.
Disclosure of Invention
The invention provides a safe and effective new way for treating sleep disorder patients to overcome the defects of non-ideal drug effect and more adverse reactions of the existing drugs for treating sleep disorder in clinical application. The approach adopts the compound I of the invention to treat the sleep disorder patients and overcomes the defect of acting on GABA aloneAThe medicine for treating sleep disorder of the receptor has the safety problem for patients and has better treatment effect.
To achieve the above objects, in one aspect, the present invention provides a use of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof for preparing a medicament for treating sleep disorders, wherein the compound of formula I has the following structure:
Figure BDA0002438160730000031
R1、R2、R3、R4each independently selected from ethyl, propyl or butyl.
According to some embodiments of the invention, wherein R1、R2、R3、R4Each independently selected from n-propyl or isopropyl.
According to some embodiments of the invention, wherein R1、R2、R3、R4Each independently selected from n-butyl, sec-butyl or tert-butyl.
According to some embodiments of the invention, wherein the compound of formula (I) is selected from the following compounds:
Figure BDA0002438160730000032
Figure BDA0002438160730000041
the prodrug refers to the compound of the invention which can be metabolized in vivo to be converted to have biological activity. Prodrugs of the invention are prepared by modifying the phenolic groups in compounds of the invention, which modifications may be removed by routine manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group.
According to some embodiments of the invention, the prodrug is represented by a compound of formula II:
Figure BDA0002438160730000042
R5is selected from
Figure BDA0002438160730000043
R6Selected from H or R5，
Wherein Y is+Selected from Na+，K+Or H+，R7Is selected from CH3(CH2) n-, n is selected from 0 to 3.
According to some embodiments of the present invention, the pharmaceutically acceptable salt is a salt of compound I with an organic acid, an inorganic acid, or an alkali metal.
According to some embodiments of the invention, wherein the pharmaceutically acceptable salt is selected from the following salts of compound I: a combination of one or more of sulfate, phosphate, hydrochloride, hydrobromide, acetate, oxalate, citrate, succinate, gluconate, tartrate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, benzoate, lactate, maleate, lithium, sodium, potassium and calcium salts.
According to some embodiments of the present invention, the compound I or the pharmaceutically acceptable salt or prodrug thereof is formulated into a pharmaceutical composition, which comprises the compound I or the pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable excipient.
According to some embodiments of the invention, the compound of formula I or the pharmaceutically acceptable salt or prodrug thereof is formulated into a tablet, capsule, injection, emulsion, liposome, lyophilized powder or microsphere formulation containing the same; the capsule is, for example, a soft capsule.
According to some embodiments of the present invention, the compound I or the pharmaceutically acceptable salt or prodrug thereof is formulated into a pharmaceutical composition, which contains the compound I or the pharmaceutically acceptable salt or prodrug thereof and other drugs having activity for treating sleep disorders, wherein the other drugs having activity for treating sleep disorders are selected from benzodiazepines, barbiturates, zolpidem, zopiclone, zaleplon, antihistamines, melatonin receptor agonists, orexin receptor inhibitors or 5-HT receptor modulators.
According to some embodiments of the invention, the sleep disorder comprises insomnia, postoperative sleep disorder, and ICU patient sleep disorder.
According to some embodiments of the present invention, the compound I or a pharmaceutically acceptable salt or prodrug thereof is used for preparing a medicament for inducing, prolonging and/or improving sleep and/or sleep quality.
According to some embodiments of the invention, the improving sleep is achieved by improving sleep architecture.
In addition, the invention also provides a pharmaceutical composition prepared from the compound shown in the formula (I) or the pharmaceutically acceptable salt or prodrug thereof, wherein the pharmaceutical composition contains the compound I or the pharmaceutically acceptable salt or prodrug thereof and pharmaceutical excipients.
The pharmaceutical compositions of the present invention may also be supplemented with one or more pharmaceutically acceptable carriers or excipients, as desired.
In the pharmaceutical composition, the weight percentage of the compound I or the pharmaceutically acceptable salt or prodrug thereof can be 0.1-99.9%, and the balance is a pharmaceutically acceptable carrier.
The pharmaceutical composition of the present invention can be prepared into any pharmaceutically acceptable dosage forms, including: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, pills, powders, ointments, pellets, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches. The preparation of the invention is preferably a tablet, a capsule, an injection, an emulsion, a liposome, freeze-dried powder or a microsphere preparation; the capsule is, for example, a soft capsule.
The pharmaceutical composition of the present invention, its preparation for oral administration, may contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents, and the tablet may be coated if necessary.
Suitable fillers include cellulose, mannitol, lactose and other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
The solid oral compositions can be prepared by conventional methods of mixing, filling, tabletting and the like. Repeated mixing can distribute the active throughout those compositions that use large amounts of filler.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles, preservatives and the like, and, if desired, conventional flavoring or coloring agents. Such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel and/or hydrogenated edible fats; such as lecithin, sorbitan monooleate and/or acacia; such non-aqueous carriers (which may include edible oils) are for example almond oil, fractionated coconut oil, oily esters such as esters of glycerol, propylene glycol and/or ethyl alcohol; such preservatives are, for example, p-hydroxybenzyl esters or propyl p-hydroxybenzoate and/or sorbic acid.
For injections, liquid unit dosage forms are prepared containing the active substance of the invention (i.e., 3',5,5' -tetraisopropyl-4, 4' -biphenylol and pharmaceutically acceptable salts, esters, or solvates thereof as described herein) and a sterile carrier. Depending on the carrier and concentration, the compound may be suspended or dissolved. Solutions are generally prepared by dissolving the active substance in a carrier, filter sterilising before filling it into a suitable vial or ampoule and then sealing. Adjuvants such as a local anaesthetic, preservatives and buffering agents may also be dissolved in the vehicle. To improve its stability, the composition can be frozen after filling into vials and the water removed under vacuum.
The pharmaceutical composition of the present invention, when being prepared into a medicament, can be optionally added with a suitable pharmaceutically acceptable carrier selected from the group consisting of: mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, EDTA disodium, calcium sodium EDTA, monovalent alkali metal carbonates, acetates, phosphates or aqueous solutions thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and derivatives thereof, alginates, gelatin, polyvinylpyrrolidone, glycerol, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid-based materials, kaolin, talc, calcium stearate and/or magnesium stearate, and the like.
Preferably, the pharmaceutical excipients of the invention may include polyethylene glycol, phospholipids, vegetable oil, vitamin E and/or glycerol;
the phospholipid can be one or more selected from soybean phospholipid, egg yolk lecithin and hydrogenated phospholipid;
the vegetable oil may be one or more selected from soybean oil, olive oil and safflower oil.
Wherein, the compound of formula I or the pharmaceutically acceptable salt or prodrug thereof is prepared into tablets, capsules, injections, emulsions, liposomes, lyophilized powder or microsphere preparations containing the compound of formula I or the pharmaceutically acceptable salt or prodrug thereof; the capsule is, for example, a soft capsule.
Wherein the compound I or the pharmaceutically acceptable salt or the prodrug thereof is prepared into a pharmaceutical composition which contains the compound I or the pharmaceutically acceptable salt or the prodrug thereof and other medicaments with the activity of treating the sleep disorder, and the other medicaments with the activity of treating the sleep disorder are selected from benzodiazepine medicaments, zolpidem, zopiclone, zaleplon, antihistamines, melatonin, orexin receptor inhibitors or 5-HT receptor inhibitors.
Wherein the benzodiazepine drug can be selected from diazepam, lorazepam, oxazepam, midazolam, triazolam and estazolam;
the barbiturates may be selected from barbiturates, phenobarbital, amobarbital and secobarbital;
said antihistamine can be selected from diphenhydramine, chlorpheniramine, and promethazine;
the orexin receptor inhibitor is suvorexant;
the 5-HT receptor modulator is trazodone;
preferably, the sleep disorders include insomnia, postoperative sleep disorders and ICU patient sleep disorders.
The invention also provides application of the compound I or pharmaceutically acceptable salt or prodrug thereof in preparing a medicament for inducing, prolonging and/or improving sleep and/or sleep quality.
According to some embodiments of the invention, the improving sleep is achieved by improving sleep architecture.
The application is mainly realized by the orexin receptor serving as the medicine. Meanwhile, the invention also discovers that the compound of the invention can simultaneously act on GABAAReceptors, thereby achieving a synergistic effect with the action of orexin receptors.
In the examples of the present invention, in vitro receptor target assays indicate that compound (I) has significant inhibitory effects on Orexin (OX) receptors. Orexin receptors have recently been found to be sleep-related, exhibiting a somnolence effect when inhibited, and the potential of OX receptors for the treatment of insomnia and sleep disorders has been found to currently include GABAAWhile standard treatments including receptor modulators vary greatly, these treatments generally lack selectivity for sleep/wake mechanism control, the OX receptor inhibitor suvorexant (marketed abroad) increases overall sleep efficiency and decreases wake times after sleep onset (WASO) with significant dose-effect relationships, while sleep wave monitoring has been shown to extend REM and SWS sleep duration and significantly improve patient sleep architecture. The results of the in vitro studies described above thus suggest that Compound (I) may have a different profile to that of acting on GABA aloneAThe sleep inducing effect of the receptor drug and the potential to ameliorate the above-mentioned drug deficiencies.
Further animal studies in the examples show that after the compound (I) is administered, the waking time and the light sleep time of a test rat are obviously reduced, and the SWS slow wave sleep and REM sleep time are increased, so that the compound has good potential for improving sleep quality, and positive drugs diazepam and eszopiclone show the characteristic of inhibiting SWS slow wave sleep or REM sleep, and have obvious influence on sleep structures; and the compound has little influence on the sleep structure of animals after the pharmacodynamic action is subsided, and the situations of epigenetic effect and medicine withdrawal rebound are not seen, while the sleep structure of rats dosed with eszopiclone and diazepam still does not return to normal after the pharmacodynamic action period, which is shown in that the shallow sleep is obviously prolonged and the REM sleep is obviously shortened.
Drawings
Figure 1 is the change in length of four phases of sleep for each group compared to the solvent group (Mean ± SEM, n-12, P <0.001, One-way ANOVA test, vs. example compound) over 4 hours after drug treatment (ZT17-ZT 21).
Fig. 2 shows the variation in length of time for each group compared to the solvent group four phases of sleep over 4 hours of non-drug effect (ZT0-ZT04) (Mean ± SEM, n-12, P <0.001, One-way anova, vs. example compound).
Detailed Description
The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.
Preparation example
Figure BDA0002438160730000081
Example 1
Compound 1: synthesis of 3,3',5,5' -tetraisopropyl-4, 4' -biphenol
Weighing 17.8g (0.1mol) of 2, 6-diisopropylphenol, adding 100mL of ethyl acetate for dissolving, adding 2.75 g (0.01mol) of silver carbonate and 24g of anhydrous magnesium sulfate, stirring at room temperature for 2h, monitoring the reaction by TLC, slowly adding water after the reaction is finished, quenching, performing suction filtration, extracting the filtrate by using ethyl acetate, combining organic phases, drying the anhydrous sodium sulfate, performing suction filtration, performing vacuum concentration on the filtrate, adding an appropriate amount of methanol, stirring for 1h, generating red crystals, and performing suction filtration to obtain 12.30g of solid. The reaction was carried out in the next step without purification.
The red solid obtained above was dissolved in 100mL of ethyl acetate, and 27.66g of sodium hydrosulfite Na2S2O4 was dissolved in 1mol/L NaOH, and then added to the ethyl acetate solution of the red solid obtained above, stirred at room temperature for 1.5h, monitored by TLC, and quenched after the reaction was completed with water. Extracting with ethyl acetate, combining organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product of 5g of a light yellow solid, performing column chromatography, and performing petroleum ether: ethyl acetate 10: 1 as eluent, the resulting fraction was collected, concentrated under reduced pressure and dried under vacuum to give 8.45g of a white solid in 22.5% yield.
MS(M+H+):355；
1H NMR(300MHz,CDCl3):δ7.22(s,4H),4.81(s,2H),3.27-3.20(m,4H),1.37-1.35(d,24H)。
Example 2
Compound 2: synthesis of 3, 5-diethyl-3 ', 5' -diisopropyl-4, 4' -biphenol
Respectively weighing 8.9g (0.05mol) of 2, 6-diisopropyl phenol and 7.8g (0.05mol) of 2, 6-dipropyl phenol, adding 150mL of ethyl acetate for dissolving, adding 2.75 g (0.01mol) of silver carbonate and 24g of anhydrous magnesium sulfate, stirring at room temperature for 2h, monitoring the reaction by TLC, slowly adding water for quenching after the reaction is finished, performing suction filtration, extracting the filtrate by ethyl acetate, combining organic phases, drying by anhydrous sodium sulfate, performing suction filtration, concentrating the filtrate under reduced pressure, adding an appropriate amount of methanol for stirring, generating red crystals after 1h, and performing suction filtration to obtain 13.4g of solid. The reaction was carried out in the next step without purification.
The red solid obtained above was dissolved in 100mL of ethyl acetate, and 27.66g of sodium hydrosulfite Na2S2O4 was dissolved in 1mol/L NaOH, and then added to the ethyl acetate solution of the red solid obtained above, stirred at room temperature for 1.5h, monitored by TLC, and quenched after the reaction was completed with water. Extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product of 5g of a light yellow solid, performing column chromatography, and performing petroleum ether: ethyl acetate 10: 1 as eluent, the resulting fraction was collected, concentrated under reduced pressure and dried under vacuum to give 7.78g of a white solid in 23.8% yield.
MS(M+H+):327；
1H NMR(300MHz,CDCl3):δ7.67(s,6H),7.55(s,6H),4.77(s,3H),3.87(s,3H),3.05(s,2H),2.50(s,12H),1.13(d,J＝10.0Hz,5H).
Example 3
Compound 3: synthesis of 3, 5-diisopropyl-3 ', 5' -dipropyl-4, 4' -biphenol
Respectively weighing 8.9g (0.05mol) of 2, 6-diisopropyl phenol and 7.8g of 2, 6-diethyl phenol, adding 150mL of ethyl acetate to dissolve the mixture, adding 2.75 g (0.01mol) of silver carbonate and 24g of anhydrous magnesium sulfate, stirring at room temperature for 2h, monitoring the reaction by TLC, slowly adding water to quench after the reaction is finished, carrying out suction filtration, extracting the filtrate by using ethyl acetate, combining organic phases, drying the anhydrous sodium sulfate, carrying out suction filtration, concentrating the filtrate under reduced pressure, adding an appropriate amount of methanol to stir, generating red crystals after 1h, and carrying out suction filtration to obtain 12.30g of solid. The reaction was carried out in the next step without purification.
The red solid obtained above was dissolved in 100mL of ethyl acetate, and 27.66g of sodium hydrosulfite Na2S2O4 was dissolved in 1mol/L NaOH, and then added to the ethyl acetate solution of the red solid obtained above, stirred at room temperature for 1.5h, monitored by TLC, and quenched after the reaction was completed with water. Extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product of 5g of a light yellow solid, performing column chromatography, and performing petroleum ether: ethyl acetate 10: 1 as eluent, the resulting fraction was collected, concentrated under reduced pressure and dried under vacuum to give 8.5g of a white solid in 23.8% yield.
MS(M+H+):355；
1H NMR(300MHz,CDCl3):δ(7.67(s,2H),7.55(s,2H),4.80(s,1H),3.71(s,1H),3.05(s,1H),2.63(s,2H),1.64(s,2H),1.14(s,12H),0.94(s,3H).
Example 4
Compound 4: synthesis of 3, 5-diisopropyl-3 ', 5' -dibutyl-4, 4' -biphenol
Reference compound 3 was synthesized to finally obtain 11.1g of a yellow solid in a yield of 29%.
MS(M+H+):383；
1H NMR(300MHz,CDCl3):δ7.67(s,8H),7.55(s,8H),4.82(s,4H),3.64(s,4H),3.05(s,3H),2.59(s,8H),1.53(s,6H),1.30(s,9H),1.14(s,53H),0.89(s,13H).
Example 5
Compound 5: synthesis of 3,3',5,5' -tetraethyl-4, 4' -biphenol
Referring to the synthesis of compound 1, 7.7g of a white solid was obtained with a yield of 36%.
MS(M+H+):299；
1H NMR(300MHz,CDCl3):δ7.55(s,2H),4.78(s,1H),2.50(s,4H),1.12(s,3H).
Example 6
Compound 6: synthesis of 3,3',5,5' -tetrapropyl-4, 4' -biphenol
Referring to the synthesis process of compound 1, light yellow solid 8.5g was obtained finally with a yield of 24%.
MS(M+H+):355；
1H NMR(300MHz,CDCl3):δ7.22(s,2H),4.81(s,1H),2.63(s,2H),1.64(s,2H),0.94(s,3H).
Example 7
Compound 7: synthesis of 3,3' -diisopropyl-5, 5' -dipropyl-4, 4' -biphenol
Referring to the synthesis process of compound 1, 11.1g of a pale yellow solid was finally obtained in 31% yield.
MS(M+H+):355；
1H NMR(300MHz,CDCl3):δ7.38(s,4H),4.81(s,2H),),3.05(s,3H),2.63(s,9H),1.64(s,10H),1.14(s,55H),0.94(s,14H).
Example 8
Compound 8: synthesis of 3,3' -dipropyl-5-isopropyl-5 ' -propyl-4, 4' -biphenol
Referring to the synthesis process of compound 1, 10.6g of white solid was obtained with a yield of 30%.
MS(M+H+):355；
1H NMR(300MHz,CDCl3):δ7.42(s,4H),4.81(s,2H),3.27-3.20(m,12H),2.63(s,6H),1.64-0.94(m,9H).
Example 9
Compound 9: synthesis of 3,3' -diisopropyl-5, 5' -di-sec-butyl-4, 4' -biphenol
Referring to the synthesis process of compound 1, 9.87g of white solid was obtained finally with a yield of 24%.
MS(M+H+):411；
1H NMR(300MHz,CDCl3):δ7.25(s,4H),4.59(s,2H),3.27-3.20(m,4H),2.97-0.95(m,28).
Example 10
Compound 10: synthesis of 3,3',5,5' -tetra-sec-butyl-4, 4' -biphenol
Referring to the synthesis process of compound 3, 11.9g of a pale yellow solid was finally obtained in 29% yield.
MS(M+H+):411；
1H NMR(300MHz,CDCl3):δ7.30(s,4H),4.82(s,2H),3.37-3.20(m,4H),3.12-0.95(m,32).
Example 11
Compound 11: synthesis of 3,3',5,5' -tetraisobutyl-4, 4' -biphenol compound
Referring to the synthesis process of compound 3, 9.23g of white solid was obtained finally with a yield of 26%.
MS(M+H+):355；
1H NMR(300MHz,CDCl3):δ7.66(s,4H),4.81(s,2H),3.27-3.20(m,4H),2.9-0.85(m,32).
Example 12
Compound 12: synthesis of 3,3' -diethyl-5, 5' -di-sec-butyl-4, 4' -biphenol compound
Referring to the synthesis process of compound 1, 9.24g of a pale yellow solid was finally obtained in a yield of 30%.
MS(M+H+):411；
1H NMR(300MHz,CDCl3):δ7.52(s,4H),4.81(s,2H),3.27-3.20(m,2H),2.87-1.05(m,26).
Example 13
Compound 13: synthesis of 3,3' -dibutyl-5, 5' -di-sec-butyl-4, 4' -biphenol compound
Referring to the synthesis process of compound 3, 14.2g of a pale yellow solid was finally obtained in a yield of 35%.
MS(M+H+):411；
1H NMR(300MHz,CDCl3):δ7.13(s,4H),4.81(s,2H),3.27-3.20(m,2H),2.37-0.35(m,34).
Example 14
Compound 14: synthesis of 3-butyl-3 ' -isobutyl-5-butyl-, 5' -isobutyl-4, 4' -biphenol compound
Referring to the synthesis process of compound 1, 9.9g of white solid was obtained finally with a yield of 28%.
MS(M+H+):355；
1H NMR(300MHz,CDCl3):δ7.40(s,4H),4.81(s,2H),3.27-3.20(m,2H),2.37-0.55(m,34).
Example 15
Compound 15: synthesis of 3-sec-butyl-3 ' -isobutyl-5-sec-butyl-, 5' -isobutyl-4, 4' -biphenol
Referring to the synthesis process of compound 1, finally 6.57g of white solid is obtained with a yield of 16%.
MS(M+H+):411；
1H NMR(300MHz,CDCl3):δ7.62(s,4H),4.81(s,2H),3.27-3.20(m,4H),2.37-1.05(m,32).
Example 16
Compound 16: synthesis of 3,3' -diisobutyl-5, 5' -di-sec-butyl-4, 4' -biphenol
Figure BDA0002438160730000131
1) Synthesis of compound monomer 2- (1-methyl) propyl-6- (2-methyl) propylphenol
2- (1-methyl) propylphenol (1.1g, 7.3mmol) and 3-methylallyl bromide (1.97g, 14.6mmol) were added sequentially in a 25mL round-bottom flask and dissolved with dichloromethane; in another 50mL flask was added benzyltributylammonium bromide (0.26g, 0.73mmol) and dissolved with 1M NaOH solution; mixing the obtained solutions at room temperature, stirring at room temperature for 2 hr, separating organic phase, extracting water phase with dichloromethane, mixing organic phases, washing organic phase with water and saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating to obtain colorless liquid. Heating the liquid at 250 ℃ for 2h under the protection of nitrogen, cooling, and carrying out column chromatography to obtain colorless liquid; the colorless liquid was dissolved in absolute ethanol and reduced by adding Pd/C to give 1.0g of 2- (1-methyl) propyl-6- (2-methyl) propylphenol in a yield of 67%.
MS(M+H+):207；
1H NMR(400MHz,CDCl3)δ7.06(t,J＝7.6,Hz,1H),6.94(dd,J＝7.6,1.6Hz,2H),5.35(s,1H),3.4-2.62(m,5H),1.68–1.59(m,12H).
2) Synthesis of Compound 16
Referring to the synthesis process of compound 1, 9.15g of a pale yellow solid was finally obtained in 24% yield.
MS(M+H+):411；1H NMR(300MHz,CDCl3):δ7.52(s,4H),4.81(s,2H),3.50-3.28(m,4H),2.99-1.03(m,32).
Example 17
Compound 17: 4 '-hydroxy-3, 3',5,5 '-tetraisopropyl- [1,1' -biphenyl ] -4-oxymethyl disodium phosphate
Figure BDA0002438160730000132
Under the protection of nitrogen, adding phosphorus oxychloride (2.5g,16.8mmol) and dichloromethane (10mL) into a reaction bottle, controlling the temperature at 0 ℃, dissolving propofol (5g, 14mmol) and triethylamine (2g,20.2mmol) into dichloromethane (10mL), slowly dropwise adding into the reaction bottle, controlling the temperature below 10 ℃, raising the temperature to room temperature after dropwise adding, stirring for 4 hours, filtering to remove solids, adding water to quench the reaction, extracting with dichloromethane, drying an organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Column chromatography of the crude product gave the product (1.2g, 18%). The product was dissolved in ethanol, 2M aqueous sodium hydroxide (2.5mL,5.1mmol) was added while cooling on ice, stirred at room temperature for 2 hours, concentrated under reduced pressure to give a yellow crude product, which was recrystallized from 90% aqueous isopropanol to give a white solid (1g, 77%).
1H NMR(500MHz,Chloroform)δ7.67(s,1H),4.34(s,1H),3.05(s,1H),1.14(s,6H).
Example 18
Compound 18: 4 '-hydroxy-3, 3',5,5 '-tetraisopropyl- [1,1' -biphenyl ] -4-butanoate
Figure BDA0002438160730000141
4, 4' -dihydroxy-3, 3',5,5' -tetraisopropyl biphenyl (5g, 14.10mmol) was added to 10mL of butyric anhydride, and after refluxing for 1 hour under nitrogen, the reaction mixture was cooled to room temperature, butyric anhydride was removed under reduced pressure, and 3,3',5,5' -tetraisopropyl biphenyl-4-propionate (1g, 16%) was isolated by column chromatography. A white solid.
1H NMR(500MHz,Chloroform)δ7.84(s,2H),7.67(s,2H),4.33(s,1H),3.05(s,4H),2.59(s,2H),1.68(s,2H),1.14(s,24H),0.99(s,3H).
Example 19
Compound 19: 3,3',5,5' -Tetraisopropylbiphenyl-4 ' 4-dicarboxylate
Figure BDA0002438160730000142
4,4 '-dihydroxy-3, 3',5,5 '-tetraisopropyl biphenyl (10g, 28.2mmol) was added to 30mL of formic acid anhydride, and after refluxing for 1h under nitrogen, the reaction mixture was cooled to room temperature, the formic acid anhydride was removed under reduced pressure, and column chromatography was performed to obtain 3,3',5,5 '-tetraisopropyl biphenyl-4' 4-dicarboxylate (1g, 8%) and 3,3',5,5' -tetraisopropyl biphenyl-4-carboxylate (0.5g, 4.5%), respectively. A white solid.
1H NMR(500MHz,Chloroform-d)δ8.22(s,2H),7.32(s,4H),3.42–2.62(m,4H),1.19(d,J＝6.8Hz,24H).
Example 20
Compound 20: 1- (4 ' -hydroxy-3, 3',5,5' -tetraisopropylbiphenyl-4-yloxy) acetic acid ethyl ester
Figure BDA0002438160730000151
To a 100mL round-bottom flask were added 4, 4' -dihydroxy-3, 3',5,5' -tetraisopropyl biphenyl (1g,2.8mmol), ethyl chloroacetate (0.4llg,3.36mmol), sodium hydroxide (0.336g,8.4mmol), and 60mL dichloromethane in that order, and the mixture was stirred at room temperature for 8 h. After completion of the reaction, the reaction mixture was filtered, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain a white solid (0.12g, 10%).
1H NMR(300MHz,CDCl3)δ7.57(s,2H),7.48(s,2H),5.25(s,1H),3.01-2.98(m,4H),2.21(s,3H),1.82-1.80(d,3H),1.16-1.14(d,24H)。
Test example 1
Prodrug plasma conversion assay
Placing fresh rat plasma into EP tube, adding compounds 1, 17, 18, 19, 20 (final concentration is 0.3uM) respectively, recording as test groups 1-4, mixing, incubating at 37 deg.C for 5min and 10min, taking sample, adding ice-cold acetonitrile with three times volume, shaking, terminating reaction, centrifuging at 13000rpm for 5min at 4 deg.C, sucking supernatant, testing, analyzing concentration of compound 1 in plasma after incubation, and calculating prodrug conversion rate of compounds 17, 18, 19, 20 in plasma (1-C-1)x0.3 uM). times.100%, where CxRepresents the concentration of compound 1 after incubation in the experiments 1 to 4 groups. The results are shown in table 1 below.
TABLE 1
Figure BDA0002438160730000152
Figure BDA0002438160730000161
As shown by the results in the table, compound 1 was very stable and unchanged in amount under incubation conditions at 37 ℃ in plasma, prodrug compound 17 had been completely converted to compound 1 after 5min incubation in plasma, compound 19 was substantially completely converted to compound 1, compound 18 was also completely converted after 10min incubation in plasma, and compound 20 conversion was slightly slow, but could reach around 50% within 10 min. The above results indicate that compounds 17, 18, 19 and 20 are prodrugs of compound 1, and are expected to be rapidly converted to compound 1 in animals after administration to produce pharmacological effects.
Test example 2
In vitro recombinant expression of OX1And OX2Receptor antagonism assay
The test system adopts human source recombination to express OX1CHO cell line of receptor and expression of recombinant expression OX of human origin2Receptor HEK-293 cell line, to which different concentrations (1, 10, 50, 100, 200 and 400nM) of each of the compounds of the examples were added in the presence of receptor agonists orexin-A (3nM) and orexin-B (10nM), respectively, and the inhibitory effect of the compounds on the change in intracellular calcium ion concentration caused by the agonist (fluorescence detection) was examined, and the IC was calculated50The results are shown in Table 2.
TABLE 2
Figure BDA0002438160730000162
Figure BDA0002438160730000171
The results show that: the compound of the embodiment of the invention can obviously inhibit the orexin OX1And OX2Receptors, with good potential for improving sleep architecture.
Test example 3
Effect of Compound 1 of the present invention on sleep in rats
The experiment adopts 12 adult male SD rats with age of 6-9 months and 400-600 g. One week before the start of the experiment, rats were implanted subcutaneously with a 4ET four-channel central nervous system electrical signal monitoring implant (DSI corporation, USA) by surgical procedures, with cortical electrodes embedded in the brain for collecting the cortical electro-encephalogram (EEG/ECoG) and cervical myoelectricity (EMG) embedded in the cervical muscle. The animals after the operation were fed freely and recovered, and were raised in a single cage under 12:12 light-dark cycle conditions: the dark cycle starts at 4:00 (time ZT12) and the light cycle starts at 16:00 (time ZT 0).
The first administration of 12 rats was divided into 4 subgroups, 3 rats per group, 80mg/kg of compound 1 injection (1% compound 1 and 10% HS-15 in water) and solvent (equal volume of 10% HS-15 in water) were given intravenously at time ZT17, 10mg/kg of diazepam and 60mg/kg of zolpidem were given orally, after administration, sleep waves of animals were recorded by EEG/ECoG-EMG, and the overall activity of the animals was recorded by video monitoring. Four sleeping times of 4h duration of pharmacodynamic action (ZT17-ZT21) and 4h duration of non-pharmacodynamic action (ZT0-ZT04) after administration of the animals were counted using Somnologic Science software (Embla, Denver, USA). After a 7 day wash period, each subgroup of animals was sequentially replaced with another drug, 4 cycles were followed to ensure that each animal was given all the drugs, and each drug treatment group was given n-12.
The four sleep judgment standards are as follows: (1) waking activity-low amplitude high frequency EEG, high amplitude EMG or with spontaneous activity; (2) shallow sleep-delta and theta wave ratios are higher in the EEG frequency formation compared to the awake state, EMG amplitude is reduced without spontaneous activity; (3) delta sleep (SWS slow wave insomnia) - - -EEG formation is mainly based on Delta waves, the muscle tension is reduced, and no autonomic activity exists; (4) rapid Eye Movement (REM) sleep-a similar proportion of high intensity theta waves to the awake state is elevated, but EMG and muscle tone is reduced and there is no voluntary activity.
The experimental results are shown in the following table 3 and fig. 1, the total sleeping time of the animals is obviously prolonged and the waking time is shortened compared with the solvent control group by the treatment of the three medicines, and the three medicines have no obvious difference (P is more than 0.05). From the sleep structure, the diazepam and zolpidem groups significantly extended the light sleep duration, while the example compound group had no effect on the light sleep duration; both zolpidem and the example compound can prolong delta sleep time without significant difference (P >0.05, while delta sleep time of the diazepam group is significantly shortened, while for REM sleep time, animals of both benzodiazepine drug groups are significantly shortened, while the example compound is significantly prolonged, therefore, after the treatment with the compound 1, the sleep efficiency of the animals is significantly improved, no adverse effect on the structure is caused, the prolonged sleep time mainly consists of delta sleep and REM sleep, and the sleep quality is obviously better than that of the diazepam and zolpidem.
TABLE 3 Change in four-phase length of sleep (mean + -SD, n-12) for each group compared to the solvent group over 4 hours post drug treatment (ZT17-ZT21)
Figure BDA0002438160730000181
P <0.001, One-way anova, vs. example compound.
The sleep efficiency of animals in each group is evaluated within 4 hours from 7 hours (ZT0) after administration, the total sleep duration of benzodiazepine drugs is still prolonged to a certain extent in the non-pharmacodynamic action period, wherein diazepam has a significant difference (P <0.05) compared with compound 1, the structure of diazepam is shown as slight prolongation of delta sleep and obvious prolongation of light sleep, and the REM sleep time is obviously shortened compared with a solvent control group. The compound 1 only slightly changes the total waking time, the light sleep, the Delta sleep and the REM sleep, but has no obvious difference with a solvent control group, so that the compound of the embodiment has little influence on the sleep structure of animals after the pharmacodynamic action is relieved, excessive sleepiness caused by other medicines in clinic is not easy to occur, and the situation of medicine withdrawal rebounding is not easy to occur; compared with the prior art, diazepam and zolpidem generate certain adverse effects on sleep structures after the action period, which is represented by obvious prolongation of light sleep and obvious shortening of REM sleep, and the phenomena of influence on the sleep structures, medicine withdrawal rebound and the like of benzodiazepine medicines observed in clinic are consistent. As shown in table 4 and fig. 2.
TABLE 4 Change in length of four phases of sleep (mean + -SD, n-12) for each group over 4 hours of nonpharmaceutical expiration (ZT0-ZT04) compared to the solvent group
Figure BDA0002438160730000191
P <0.001, One-way ANOVA test, vs. example compounds
Test example 4
Study of sleep-inducing Effect of Compound 1 of the present invention on healthy human
The formulations prepared with compound 1 of the present invention have now completed single-center, double-blind, dose-escalation, placebo-controlled phase I tolerance and pharmacokinetic studies on chinese healthy subjects (clinical trial lot No.: 2016L 09981). The study designed 8 doses of 0.5,1,2,4,8,12,18 and 24mg/kg, administered intravenously, with 4 cases in each of the 0.5,1,18 and 24mg/kg dose groups and 8 cases in each of the 2,4,8 and 12mg/kg dose groups, and the proportion of subjects given to isopropylbisphenol and placebo in each dose group was 3: 1. During the experiment, subjects were studied for sleep observation and the results are shown in table 5 below:
TABLE 5 sleep comparison of subjects
Dose groups The number of people who enter the group Number of sleep cases Percentage of sleep
Placebo 12 3 25％
0.5mg/kg 3 0 0
1mg/kg 3 0 0
2mg/kg 6 0 0
4mg/kg 6 0 0
8mg/kg 6 3 50％
12mg/kg 6 3 50％
18mg/kg 3 2 66.7％
24mg/kg 3 2 66.7％
The results show that subjects at doses of 8mg/kg and above experienced sleep after administration and presented dose-dependent, with the rate of sleep of subjects increasing with increasing dose.
The test also carries out electroencephalogram double-frequency index (BIS) monitoring on 8mg/kg groups of subjects, and the significance of each numerical value section of BIS is as follows according to literature and relevant clinical research: the results are shown in Table 6 below for waking 85-100, sedation 65-85 and anesthesia < 85:
TABLE 6.8 comparative analysis of BIS monitoring values for the subjects in the mg/kg group
Figure BDA0002438160730000201
The results show that the BIS values of the subjects in the administration group are obviously reduced, most of the subjects in the administration group show obviously continuous sedation, and the subjects in the placebo group do not see sedation.
The results show that the compound 1 has a clear sleep induction effect on a human body and has the potential of treating sleep disorders.

Claims (10)

1. Use of a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for the treatment of sleep disorders, wherein the compound of formula I has the structure:
Figure FDA0002438160720000011
R1、R2、R3、R4each independently selected from ethyl, propyl or butyl.
2. Use according to claim 1, wherein R1、R2、R3、R4Each independently selected from n-propyl or isopropyl.
3. Use according to claim 1, wherein R1、R2、R3、R4Each independently selected from n-butyl, sec-butyl or tert-butyl.
4. Use according to any one of claims 1 to 3, wherein the compound of formula (I) is selected from the following compounds:
Figure FDA0002438160720000012
Figure FDA0002438160720000021
5. the use according to any one of claims 1 to 4, wherein the prodrug is represented by a compound of formula II:
Figure FDA0002438160720000022
R5is selected from
Figure FDA0002438160720000023
R6Selected from H or R5，
Wherein Y is+Selected from Na+，K+Or H+，R7Is selected from CH3(CH2) n-, n is selected from 0 to 3.
6. The use according to claim 1, wherein the compound I or the pharmaceutically acceptable salt or prodrug thereof is formulated into a pharmaceutical composition comprising the compound I or the pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable excipient.
7. The use of claim 1, wherein the compound of formula I or the pharmaceutically acceptable salt or prodrug thereof is formulated as a tablet, capsule, injection, emulsion, liposome, lyophilized powder, or microsphere formulation containing the same; the capsule is, for example, a soft capsule.
8. The use according to claim 1, wherein said compound I or a pharmaceutically acceptable salt or prodrug thereof is formulated as a pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt or prodrug thereof and a further drug having activity in the treatment of sleep disorders selected from the group consisting of benzodiazepines, barbiturates, zolpidem, zopiclone, zaleplon, antihistamines, melatonin receptor agonists, orexin receptor inhibitors and 5-HT receptor modulators.
9. The use according to any one of claims 1-4, wherein the sleep disorders include insomnia, postoperative sleep disorders, and ICU patient sleep disorders.
10. Use according to any one of claims 1 to 4, of compound I or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for inducing, prolonging and/or improving sleep (preferably improving sleep architecture) and/or sleep quality.
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Citations (4)

* Cited by examiner, † Cited by third party
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CN107709288A (en) * 2016-02-03 2018-02-16 四川海思科制药有限公司 A kind of phosphinylidyne amine derivative and preparation method and purposes
CN110719774A (en) * 2017-05-11 2020-01-21 韩国食品研究院 Composition for improving, preventing or treating sleep disorder or inhibiting tolerance to or reducing side effects of an agonist of the benzodiazepine binding site of GABA-A receptor, each composition comprising phloroglucinol as an active ingredient
CN110872213A (en) * 2018-08-31 2020-03-10 西安力邦肇新生物科技有限公司 GABAAReceptor allostericEnhancing compounds, their preparation and use
CN110870856A (en) * 2018-08-31 2020-03-10 西安力邦肇新生物科技有限公司 GABAAApplication of receptor allosteric enhancer in medicine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107709288A (en) * 2016-02-03 2018-02-16 四川海思科制药有限公司 A kind of phosphinylidyne amine derivative and preparation method and purposes
CN110719774A (en) * 2017-05-11 2020-01-21 韩国食品研究院 Composition for improving, preventing or treating sleep disorder or inhibiting tolerance to or reducing side effects of an agonist of the benzodiazepine binding site of GABA-A receptor, each composition comprising phloroglucinol as an active ingredient
CN110872213A (en) * 2018-08-31 2020-03-10 西安力邦肇新生物科技有限公司 GABAAReceptor allostericEnhancing compounds, their preparation and use
CN110870856A (en) * 2018-08-31 2020-03-10 西安力邦肇新生物科技有限公司 GABAAApplication of receptor allosteric enhancer in medicine

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