A deuterated fused ring compound and its preparation method and use

Abstract

The present invention provides a fused ring compound as shown in formula (I) and a preparation method and use thereof. The compound can significantly improve sleep conditions, can be developed into a drug for treating and preventing insomnia, and is suitable for development into a variety of dosage forms.

Description

[0001] This application is a divisional application of an application with a filing date of December 19, 2023, application number 202310200506.6, and invention name “A deuterated fused ring compound, preparation method and use thereof”. Technical Field

[0002] The present application relates to the field of pharmaceutical technology, and in particular to a class of deuterated fused ring compounds and compositions thereof as active ingredients, as well as the use of the compounds and compositions thereof for preparing drugs for treating or preventing insomnia. Background Art

[0003] Insomnia is a common sleep disorder that can have a significant impact on the gastrointestinal system, cardiac system, and nervous system. Long-term insomnia can lead to decreased immune function and various diseases, which has a great impact on society and patients' daily lives.

[0004] Nemorexant is an orexin receptor antagonist. On January 7, 2022, the U.S. FDA approved Idorsia Pharmaceuticals Ltd's Nemorexant (Daridorexant, ACT-541468, DORA, Nemorexant), trade name: Dosage form: Film-coated tablets, used to treat adult patients characterized by difficulty falling asleep and / or maintaining sleep. On April 29, 2022, Nemorexant was approved for marketing in the European Union.

[0005] The recommended dose of nemorexant is 25 mg to 50 mg, taken orally once a night within 30 minutes before bedtime, with at least 7 hours remaining before planned awakening. If taken after a meal, sleep onset may be delayed. The most common adverse reactions are headache and drowsiness or fatigue.

[0006] Compared with similar drugs such as Suhoresan and Lebroxan, the bioavailability of Nemoresan is relatively low, and food has a certain effect on its absorption. Based on a large number of studies, the inventors have found that a class of molecules can significantly improve bioavailability, and the administration is not affected by food, which is expected to further reduce the dosage and reduce side effects. Summary of the invention

[0007] The invention provides a novel condensed ring compound and a composition thereof, which has the effects of analgesia and sleep improvement.

[0008] On the other hand, the compounds provided by the present invention can overcome the shortcomings of the prior art, have a higher in vivo exposure in the organism, indicating improved bioavailability; are rapidly absorbed and are expected to take effect quickly; are eliminated faster, have a shorter half-life, and have lower risks of addiction and drowsiness; are not affected by food after administration; and have a better sleep-improving effect, which is expected to further reduce the dosage and reduce side effects.

[0009] The present invention provides a fused ring compound having formula (I), or a solvate, isotope derivative, enantiomer, racemic mixture and pharmaceutically acceptable salt thereof;

[0010]

[0011] In formula (I), R a and R f Each independently selected from the following groups in which one or more hydrogen atoms are substituted with deuterium or not: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl;

[0012] R b , R c , R d , R e , R g are each independently selected from hydrogen or deuterium; and R a , R b , R c , R d , R e , R g and R f There is at least one deuterium atom in

[0013] R is selected from

[0014] R1 and R2 are each independently selected from hydrogen and methyl;

[0015] R3 is selected from the following groups in which one or more hydrogen atoms are substituted by deuterium or not: C 1-8 Alkyl, C 1-8 Alkoxy;

[0016] R4 and R5 are each independently selected from hydrogen, or C in which one or more hydrogen atoms are substituted with or without deuterium. 1-8 Alkyl, or R4 and R5 are connected to form a ring.

[0017] In an embodiment of the present invention, R a Selected from the following groups in which one or more hydrogen atoms may be substituted by deuterium: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl;

[0018] In some embodiments, R a Selected from the following groups in which one or more hydrogen atoms may be substituted by deuterium: C 1-3 Alkyl; preferably, R aSelected from methyl group in which one or more hydrogen atoms may be substituted by deuterium;

[0019] In some embodiments, R a The following groups are deuterated: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl.

[0020] In an embodiment of the present invention, R f Selected from the following groups in which one or more hydrogen atoms may be substituted by deuterium: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl;

[0021] In an embodiment of the present invention, R f Selected from the following groups in which one or more hydrogen atoms may be substituted by deuterium: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl;

[0022] In some embodiments, R f Selected from the following groups in which one or more hydrogen atoms may be substituted by deuterium: C 1-3 Alkyl; preferably, R f Selected from methyl group in which one or more hydrogen atoms may be substituted by deuterium;

[0023] In some embodiments, R f The following groups are deuterated: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl.

[0024] In an embodiment of the present invention, R b , R c , R d , R e , R g are each independently selected from hydrogen or deuterium.

[0025] In an embodiment of the present invention, R a , R b , R c , R d , R e , R g and R f There is at least one deuterium atom in it.

[0026] In an embodiment of the present invention, R is selected from

[0027] In some embodiments, R is in,

[0028] In some specific embodiments, R1 and R2 are each independently selected from hydrogen and methyl; preferably, R1 and R2 are both hydrogen;

[0029] In some specific embodiments, R3 is selected from the following groups: 1-8 Alkyl, C 1-8 Alkoxy; preferably, R3 is selected from C 1-3 Alkyl, C 1-3 Alkoxy;

[0030] In some specific embodiments, R3 is selected from the following groups in which one or more hydrogen atoms are replaced by deuterium: C 1-8 Alkyl, C 1-8 Alkoxy; preferably, R3 is selected from deuterated C 1-3 Alkyl, deuterated C 1-3 Alkoxy.

[0031] In some embodiments, R is selected from in,

[0032] In some specific embodiments, R1 and R2 are each independently selected from hydrogen and methyl; preferably, R1 and R2 are both hydrogen;

[0033] In some specific embodiments, R4 is hydrogen, and R5 is selected from C 1-8 Preferably, R4 is hydrogen, and R5 is selected from C 1-3 alkyl;

[0034] In some specific embodiments, R4 and R5 are selected from C 1-8 alkyl;

[0035] In some specific embodiments, R4 and R5 are connected to form a five-membered ring, a six-membered ring, or a seven-membered ring.

[0036] The compound provided by the present invention has the following structure:

[0037]

[0038]

[0039] On the other hand, in some embodiments, the present invention provides a pharmaceutical composition comprising the above-mentioned compound, or a solvate, isotopic derivative, enantiomer, racemic mixture, pharmaceutically acceptable salt thereof, and an inert carrier.

[0040] The composition can be administered in the form of injection, powder, spray, inhalant, tablet, pill, capsule, lozenge, gum, powder, granule, gel, cream, ointment, patch, suppository, suspension and syrup.

[0041] The active ingredient in the composition occupies a unit dose of 0.01 mg to 1.0 g of the body weight of an individual in need of treatment.

[0042] In some embodiments, the present invention provides use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing related diseases or disorders.

[0043] The related diseases or conditions include neuropathic pain, oral pain, facial pain, internal organ pain, headache, insomnia, cognitive impairment, appetite disorder, emotional disorder, sunset syndrome, and Alzheimer's disease.

[0044] A method of treating a disease or condition comprises administering a therapeutically effective amount of the compound or composition to a subject in need of treatment.

[0045] The compounds of the present invention have a high in vivo exposure in the organism, indicating that the bioavailability is improved, and it is expected to further reduce the dosage and reduce side effects. Pharmacokinetic studies have shown that the compounds of the present invention are rapidly absorbed and are expected to take effect quickly.

[0046] It is known that for drugs used to improve sleep, the risk of addiction and somnolence is of great importance, and the longer the half-life, the greater the risk. The compounds of the present invention have a faster elimination rate, a shorter half-life, and a lower risk of addiction and somnolence.

[0047] In addition, the compounds of the present invention are not affected by food after administration; in vivo efficacy studies have shown that the compounds of the present invention have a better sleep improvement effect.

[0048] In the present invention, in order to enable technical personnel to understand the present invention in more detail, each term has the following definition.

[0049] “C 1-8 "Alkyl" refers to a straight chain, side chain or cyclic hydrocarbon group having 1 to 8 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, isobutyl, pentyl, methylpentyl, 2-methylhexyl, isooctane, cyclopentyl, cyclohexyl, etc.

[0050] “C 1-8"Alkoxy" refers to a straight chain, side chain or cyclic hydrocarbon group with 1 to 8 carbon atoms, with -OH or -O- group inserted in any reasonable position. For example, methoxy, ethoxy, isopropoxy, isobutoxy, tert-butoxy, 2-methoxypropyl, (S)-(+)-1-methoxy-2-propyl, 1-propoxy-2-propyl, ethylene glycol monobutyl, etc.

[0051] “C 1-3 The term "alkyl" refers to a hydrocarbon group having 1 to 3 carbon atoms, such as methyl, ethyl, propyl, isopropyl, and cyclopropyl.

[0052] “C 1-3 The term "alkoxy" refers to a hydrocarbon group having 1 to 3 carbon atoms with an -OH or -O- group inserted at any reasonable position, such as methoxy, ethoxy, and isopropoxy.

[0053] “C 3-6 "Cycloalkyl" refers to a saturated or unsaturated aliphatic cyclic hydrocarbon group having 3 to 6 carbon atoms, including but not limited to "cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl, etc.

[0054] The compounds of the present invention have an asymmetric center, and thus the present invention relates to all optical isomers and stereoisomers of all such compounds and mixtures thereof, and also includes compounds having tautomers and mixtures thereof.

[0055] The compounds of the present invention contain basic nitrogen atoms (heterocyclic or aliphatic amino groups, etc.), which are easily oxidized to N-oxides by oxidants such as oxygen in the air and hydrogen peroxide to generate other compounds of the present invention. Therefore, the converted N-oxide derivatives are selected as part of the compounds of the present invention.

[0056] The "compound and its salt" described in the present invention refers to a complex formed by the combination of the compound and the corresponding acid, and the properties depend on the characteristics of the compound, such as the addition salt of the compound and the acid, for example, inorganic acid salts such as hydrochloride, sulfate, hydrobromide, etc. Organic acid salts such as maleate, fumarate, acetate, propionate, malate, tartrate, malonate, succinate, citrate, cinnamate, mandelate, methanesulfonate, p-toluenesulfonate, salicylate, etc.

[0057] The "inert carrier" mentioned in the present invention refers to a substance that helps individuals take or absorb the active substance in the pharmaceutical composition and does not cause obvious adverse effects on patients or individuals, including glucose, disintegrants, fillers, flavoring agents, lubricants, fatty acid esters, hydroxymethyl cellulose, stabilizers, emulsifiers, colorants, starch, saccharin sodium, cellulose, etc.

[0058] The "disease or condition" mentioned in the present invention refers to neuropathic pain, joint pain, postoperative pain, obstetric pain, herpes zoster pain, gout, joint degeneration pain, intervertebral disc pain, trigeminal neuralgia, intractable headache, tumor pain, angina pectoris, idiopathic chest and abdominal pain, oral pain, facial pain, internal organ pain, etc.

[0059] The "diseases or conditions" described in the present invention also include insomnia, Alzheimer's disease, sunset syndrome, Parkinson's disease, memory loss, inattention, intellectual disability, addiction, etc.

[0060] The “composition” described in the present invention refers to any product containing a specific amount of the compound provided by the present invention, or obtained by direct or indirect means from a specific amount of the compound provided by the present invention.

[0061] The compounds of the present invention can be used alone or in combination with one or more other drugs to treat or prevent the diseases or symptoms described by the compounds of the present invention. The combined use can have a more significant therapeutic effect.

[0062] The compound of the present invention has a unit dose of 0.01 mg to 1.0 g of body weight of an individual in need of treatment, and more preferably has a unit dose of 0.1 mg to 0.5 g of body weight of an individual in need of treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 This is the drug-time curve of intragastric administration in SD rats. DETAILED DESCRIPTION

[0064] The present invention is further described below with reference to examples, but these examples are not limiting. Unless otherwise specified, the experimental solvents or reagents used in the following examples were purchased from the commercial market.

[0065] Example 1: Synthesis of Compound XX01

[0066]

[0067] Step 1: Preparation of compound IM02

[0068] IM01 (8.88 g, 38.73 mmol, 1.0 eq) was dissolved in dichloromethane (60 mL), and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 14.69 g, 38.73 mmol, 1.0 eq) and N,N-diisopropylethylamine (DIPEA, 13.02 g, 100.7 mmol, 2.6 eq) were added. The mixture was stirred for 0.5 h, and then a DCM solution (40 mL) containing SM02 (10.00 g, 63.85 mmol, 1.65 eq) was added. The mixture was reacted at room temperature overnight. The reaction was completed when detected by TLC.

[0069] The solvent was removed by concentration under reduced pressure, and the reaction system was poured into water, extracted with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a brown oil. Column chromatography gave a white solid, namely compound IM02 (7.5 g), with a yield of 52.74%. [M+H] + =368.2.

[0070] Step 2: Preparation of compound IM03

[0071] IM02 (7.00 g, 19.03 mmol, 1.0 eq) was dissolved in acetic acid, heated to 100°C, and reacted for 1 h. The reaction was completed after TLC detection.

[0072] The solution was concentrated to remove most of the acetic acid, then diluted with DCM, added to an aqueous sodium bicarbonate solution (ice water), separated, and the aqueous phase was extracted three times with DCM. The organic phases were combined and concentrated to obtain a beige foamy solid, namely compound IM03 (6.0 g), with a yield of 90.10%. [M+H] + =350.2.

[0073] Step 3: Preparation of compound IM04

[0074] IM03 (6.0 g, 17.16 mmol, 1.0 eq) was dissolved in dioxane (50 mL), trifluoroacetic acid (TFA, 9.78 g, 85.82 mmol, 5.0 eq) was added under ice bath, and the mixture was stirred overnight. The reaction was completed after TLC detection.

[0075] The reaction solution was concentrated to dryness to obtain a brown oil, namely, crude compound IM04 (6.5 g), which was fed to the next step at 100% without further treatment.

[0076] Step 4: Preparation of compound IM05

[0077] The intermediate SM3 (8 g, 30.3 mmol, 1.0 eq) was dissolved in tetrahydrofuran (THF, 300 mL), and sodium hydroxide (3.64 g, 90.9 mmol, 3.0 eq) and isopropyl bromide-d6 (7.82 g, 60.6 mmol, 2.0 eq) were slowly added under nitrogen protection, and the mixture was heated to 60°C for 3 hours, washed with water (2*200 mL), and the organic phase was adjusted to acidity (pH 2-3) with hydrochloric acid (2.0 M), concentrated under reduced pressure, and separated by column chromatography to obtain 3.5 g of intermediate IM05, with a yield of 37%, [M+H] + =313.1.

[0078] Step 5: Preparation of compound IM06

[0079] IM05 (2.0 g, 6.41 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (DMF, 70 mL), and the solution was khaki. 1H-1,2,3-triazole (0.89 g, 12.81 mmol, 2.0 eq) and cesium carbonate (4.18 g, 12.81 mmol, 2.0 eq) were added, and the temperature was raised to 40°C. A small amount of gas was released. Cuprous iodide (61 mg, 0.32 mmol, 0.05 eq) was added, and the solution gradually turned green. The temperature was not significantly raised. The temperature was raised to 70°C, and the mixture was stirred for 1 h. The reaction was completed when detected by TLC.

[0080] The reaction solution was cooled to room temperature, poured into water, extracted once with ethyl acetate (EA), the aqueous phase was retained, the aqueous phase was adjusted to acidity with citric acid, extracted twice with EA, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a yellow-brown oil, namely compound IM06 (1.62 g). [M+H] + =254.2.

[0081] Step 6: Preparation of compound XX01

[0082] IM04 (2.0 g, 5.75 mmol, 1.0 eq) was dissolved in dichloromethane (30 mL), and IM06 (1.46 g, 5.75 mmol, 1.0 eq), DIPEA (3.72 g, 28.75 mmol, 5.0 eq), and HBTU (2.18 g, 5.75 mmol, 1.0 eq) were added in sequence in an ice bath to start the reaction (as the reaction proceeded, the color of the solution gradually turned brown-red), the reaction was stirred overnight, and the reaction was completed when detected by TLC.

[0083] The mixture was extracted with water and dichloromethane three times, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography to obtain compound XX01 (0.7 g) with a yield of 25.8%. [M+H] + =485.3. 1H-NMR (DMSO, 400MHz): 12.27 (brs, 1H), 8.05 (s, 2H), 7.74 (d, J = 8.8Hz, 1H), 7.44-7.21 (m, 3H), 7.14 (d,J=8.8,1H),3.95(s,1H),3.66(m,1H),2.65(s,3H),2.35(m,1H),2.03-1.94(m,4H),1.84(s,3H).

[0084] Example 2: Preparation of compound XX02

[0085]

[0086] Referring to the synthesis method of compound IM05, compound IM11 was synthesized using SM03 and deuterated iodomethane as starting materials, [M+H] + =282.0.

[0087] The same synthetic process as IM06 was followed to obtain compound IM12.

[0088] After the same synthetic process as XX01, compound XX02 was obtained, [M+H] + =454.2. 1 H-NMR (DMSO, 400MHz): 12.21 (brs, 1H), 8.05 (s, 2H), 7.72 (d, J = 8.8Hz, 1H), 7.41-7.22 (m, 3H) ,7.15(d,J=8.8,1H),3.64(m,1H),2.62(s,3H),2.32(m,1H),2.05-1.97(m,4H),1.91(s,3H).

[0089] Example 3: Preparation of Compound XX08

[0090]

[0091] Under ice bath, compound XX02 (300 mg, 0.661 mmol, 1.0 eq) was dissolved in DMF, 60% sodium hydride (52.86, 1.32 mmol, 2.0 eq) was added and stirred for 30 minutes, then chloromethyl isobutyrate (180 mg, 1.32 mmol, 2.0 eq) was added, the mixture was reacted for half an hour, the temperature was raised to room temperature, the reaction was allowed to proceed overnight, and the reaction was completed by TLC detection.

[0092] After quenching with water, the mixture was extracted with EA and water for 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, and the product was separated by chromatography (PE:EA=2:1). After concentration, a powdery solid was obtained, namely compound XX08 (103.6 mg), with a yield of 28.3%. [M+H] + =554.1. 1 H-NMR (DMSO, 400MHz): 8.10 (s, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.43 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8. 0Hz,1H), 7.01(s,1H), 6.45(m,2H), 3.62(m,2H), 2.54(s,3H), 2.33-2.11(m,5H), 1.94(s,3H), 1.09(d,6H).

[0093] Example 4: Preparation of Compound XX09

[0094]

[0095] Under ice bath, XX02 (300 mg, 0.661 mmol, 1.0 eq) was dissolved in DMF (5 mL), 60% sodium hydride (52.86 mg, 1.32 mmol, 2.0 eq) was added and stirred for 30 minutes, then chloromethyl pivalate (200 mg, 1.32 mmol, 2.0 eq) was added and reacted for half an hour. The reaction was completed by TLC detection.

[0096] After quenching with water, the mixture was extracted three times with EA and water, the organic phases were combined, dried with anhydrous sodium sulfate, and the product was separated by chromatography (PE:EA=2:1). After concentration, compound XX09 (80 mg) was obtained with a yield of 21.3%. [M+H] + =568.2. 1 H-NMR (DMSO, 400MHz): 8.08 (s, 2H), 7.80 (d, J = 8.4Hz, 1H), 7.31 (m, 2H), 7.26 (d, J = 8.0Hz, 1H), 7 .07(s,1H), 6.45(m,2H), 3.62(m,2H), 2.53(s,3H), 2.38-2.05(m,4H), 1.90(s,3H), 1.12(s,9H).

[0097] Example 5: Preparation of Compound XX10

[0098]

[0099] Under ice bath, compound XX02 (0.5 g, 1.1 mmol, 1 eq) was dissolved in DMF (5.5 mL), 60% sodium hydride (88.1 mg, 2.2 mmol, 2 eq) was added and stirred for 30 minutes, then chloromethyl methyl carbonate (0.28 g, 2.2 mmol, 2 eq) was added, reacted for half an hour, warmed to room temperature, and continued to react for 5 hours. After quenching with water, the mixture was extracted with EA and water for 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, and then separated by chromatography and preparative liquid separation to obtain the product compound XX10 (125 mg) with a yield of 21%. [M+H] + =542.2; 1 H-NMR (DMSO, 400MHz): 8.06 (s, 2H), 7.81 (d, J=8.8Hz, 1H), 7.45 (d, J=8.4Hz, 1H), 7.342 (d, J=8.8Hz, 1H), 7.24 (d, J= 8.4Hz,1H),7.11(s,1H),6.45(m,2H),3.97(s,3H),3.74-3.63(m,2H),2.63(s,3H),2.32-2.07(m,4H),1.92(s,3H).

[0100] Example 6: Preparation of Compound XX16

[0101]

[0102] Step 1: Synthesis of compound IM33

[0103] 4 g of deuterated ethanol (IM32), 14 ml of triethylamine and 70 ml of dichloromethane were added to the reaction flask. After the system was cooled to 0°C, 10 g of chloromethyl chloroformate (IM31) was slowly added dropwise. After the addition, the system was naturally warmed to room temperature and reacted for 3 hours. Water was added to quench the reaction, and dichloromethane was extracted to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to obtain 8.35 g of liquid compound IM33 with a yield of 75%.

[0104] Step 2: Synthesis of compound XX16

[0105] Under ice bath, compound XX02 (0.4 g, 0.881 mmol, 1 eq) was dissolved in DMF (5.5 mL), 60% sodium hydride (70.5 mg, 1.76 mmol, 2 eq) was added and stirred for 30 minutes, then IM33 (0.25 g, 1.76 mmol, 2 eq) was added, and the mixture was reacted for half an hour, warmed to room temperature, and continued to react for 5 hours. According to TLC detection, most of the material reacted, and after quenching with water, it was extracted with EA and water for 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, and then separated by chromatography and preparative liquid separation to obtain the product compound XX16 (140 mg) with a yield of 28.3%. [M+H] + =561.2. 1 H-NMR (DMSO, 400MHz): 8.04 (s, 2H), 7.73 (d, J = 8.8Hz, 1H), 7.45 (d, J = 8.4Hz, 1H), 7.31 (d, J = 8.8Hz, 1H), 7.24 (d,J=8.4Hz,1H), 7.11(s,1H), 6.42(m,2H), 3.75-3.55(m,2H), 2.62(s,3H), 2.32-2.06(m,4H), 1.95(s,3H).

[0106] The following example compounds were prepared by a similar synthetic method through reasonable addition and removal of protecting groups:

[0107]

[0108]

[0109] Example 7: Synthesis of comparative compounds DB01 and DB02

[0110]

[0111] DB00 was synthesized by referring to the synthesis methods in patents 202211366859.5 and 201480065780.6, and on this basis, compound DB01 ([M+H] + =542.2), DB02([M+H] + =539.2), and nemorexant were used for comparative studies.

[0112] Example 8: Oral Pharmacokinetic Study in Rats

[0113] 30 SD rats, male, 180g-220g, free access to food and water, room temperature: 20-26℃; humidity: 40-70%; light illumination: dark = 12h: 12h; experimental animals were adaptively raised for 3 days. Fasting but not water was allowed from 5 pm the day before administration, administration was given after fasting for 16-17h, and animals were fed 4h after administration, and water was not allowed during the whole process. Rats were randomly divided into groups A, B, C, D and E, with 6 rats in each group, of which group A was given nemoresan, group B was given XX10, group C was given XX15, group D was given DB01, and group E was given DB02, all of which were given in equimolar amounts, and the dosage of nemoresan was 4 mg / kg. Five test samples were administered by gavage, and the test samples were all suspended in 0.5% carboxymethyl cellulose solution.

[0114] About 300 μL of venous blood was collected from all animals through the orbital venous plexus of rats at 0 h before single oral administration and 0.083 h, 0.17 h, 0.33 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. The blood was added to a centrifuge tube with sodium heparin precooled in ice water and placed in an ice bath. After standing, it was centrifuged (4000 rpm, 10 min). The plasma was collected and divided into 50 μL units, placed in sterile EP tubes, and stored at -80°C for later use. The concentration of the test substance in the plasma was determined as soon as possible (DB00 was tested in the nemorexan group, DB01 group, and DB02 group; XX02 was tested in the XX10 group and XX15 group). The results are shown in the table. Figure 1 .

[0115] Depend on Figure 1 It can be seen that after oral administration, compared with nemorexan, the Cmax of other groups increased, but the Cmax increase of XX10 and XX15 administration groups was much greater than that of DB01 and DB02. In addition, it can also be seen that the peak time of XX10 and XX15 administration groups was earlier than that of DB01, DB02 and nemorexan, indicating that the compounds of the present invention are rapidly absorbed and are expected to take effect quickly. In addition, from Figure 1 It can be clearly seen that the elimination rate of the XX10 and XX15 administration groups is faster and their half-life is shorter. It is known that this product is used to improve sleep, and the risk of addiction and drowsiness is crucial to this type of product, and the longer the half-life, the greater the risk. The compound of the present invention has a shorter half-life and a lower risk of addiction and drowsiness.

[0116] Example 9: Oral Pharmacokinetic Study of Cynomolgus Monkeys

[0117] Twenty male cynomolgus monkeys, weighing 3.5-6 kg, were randomly divided into Group A, Group B, Group C and Group D. Group A and Group C began fasting at 5 pm the day before administration, and were administered after fasting for 16-17 hours. Animals were fed 4 hours after administration, and water was not allowed during the whole process; Group B and Group D did not fast, and were fed 30 minutes before administration. Animals were fed 4 hours after administration, and water was not allowed during the whole process. Group A and Group B were both gavaged with XX10, and Group C and Group D were both gavaged with DB02. The samples were suspended in 0.5% carboxymethyl cellulose solution and then administered, and the dosage was 1 mg / kg. About 0.5 mL of blood was collected from the jugular vein at 0 h before administration and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 4 h, 8 h, and 24 h after administration. Add to a centrifuge tube with sodium heparin precooled in ice water, place in an ice bath, stand and centrifuge (4000rpm, 10min), take plasma and divide into 50μL units, place in sterile EP tubes, and store at -80℃ for later use. Determine the concentration of the analyte in plasma (DB00 for DB02 group; XX02 for XX10 group) as soon as possible, and calculate the pharmacokinetic parameters using winnonlin software, see Table 1.

[0118] Table 1: PK parameters in cynomolgus monkeys

[0119]

[0120] As can be seen from the table above, under fasting and non-fasting conditions, after oral administration of XX10, there was no difference in the peak time and in vivo exposure of XX02, which shows that food feeding did not have a significant effect on the absorption of XX10; while after oral administration of DB02, its peak time, peak concentration and in vivo exposure all changed significantly, with the peak time extended by 25%, the peak concentration reduced by 20%, and the in vivo exposure reduced by 12%; in addition, according to literature data, after administration of nemorexan, food had a significant effect on its absorption. The absorption of the compound of the present invention is not affected by food.

[0121] Example 10: Pharmacodynamics of PCPA-induced insomnia model in rats

[0122] 80 SPF male Wistar rats were fed adaptively for 7 days, and 70 rats were randomly selected and intraperitoneally injected with PCPA suspension (PCPA is p-chlorophenylalanine, PCPA is prepared as a suspension with 0.9% sodium chloride solution, and stirred evenly for standby use) at a dose of 300 mg / kg, 10 ml / kg, once a day for 2 consecutive days. The remaining 10 rats were intraperitoneally injected with an equal amount of 0.9% sodium chloride solution at the same dose, once a day for 2 consecutive days, as a blank control group.

[0123] 24 hours after the second injection of PCPA, the animals were observed to have lost their circadian rhythm, increased aggression, decreased sleep, increased drinking water, and decreased appetite, indicating that the model was successfully established. 50 rats with successful modeling were randomly selected and randomly divided into 5 groups, 10 in each group. They were model group, XX10 low-dose group, XX10 medium-dose group, XX10 high-dose group, and nemorexan group (positive control group). Each group was gavaged according to Table 2, once a day, for 7 consecutive days.

[0124] Table 2 Grouping and dosage settings

[0125]

[0126] During the experiment, the general condition of the animals was evaluated and their body weight was monitored. In addition, 5 animals in each group were intraperitoneally injected with sodium pentobarbital (50 mg / kg) 1 hour after the last oral administration. The sleep latency (i.e., the time from the start of sodium pentobarbital injection to the disappearance of the righting reflex) and sleep duration (i.e., the time from the disappearance of the righting reflex to the recovery of the righting reflex) of the rats were recorded. The results are shown in Table 3. The remaining 5 animals in each group were dissected in a low-temperature environment 12 hours after the last oral administration, and the brains were removed, and the hippocampal tissues were isolated on ice. The left and right hippocampi were placed in cryopreservation tubes, quickly frozen in liquid nitrogen, and stored at -80°C for later use. The right hippocampus was taken out of the -80°C refrigerator, and total RNA was extracted according to the kit steps, and cDNA was synthesized by reverse transcription. Real-time fluorescence quantitative PCR (RT-qPCR) was used for amplification, with ACTB as the internal reference gene, according to 2 -ΔΔCt The relative mRNA expression of OX1R and OX2R was calculated by Livak method. The results are shown in Table 4. The experimental data were processed by SPSS23.0 software, and the mean and standard deviation were calculated by The independent sample T test was used for comparison between the groups, and P < 0.05 indicated that the difference was statistically significant.

[0127] During the experiment, the weight changes of rats also showed a trend similar to that of the general state: the model group had a significant decrease in weight, while the test group and the control group had a lesser degree of weight loss, and the recovery time was shorter and faster; the weight changes in the low, medium and high dose groups of XX10 showed a dose-dependent trend, and the medium and high dose groups of XX10 had a significant improvement on the weight loss of rats caused by PCPA-induced insomnia; the weight of the nemorexan group was between the low and medium dose groups of XX10, which also shows that the efficacy of the medium dose group of XX10 is stronger than that of the nemorexan group.

[0128] Table 3: Results of pentobarbital sodium righting test

[0129]

[0130] Note: # indicates P<0.01 compared with the blank group; * indicates P<0.01 compared with the model group.

[0131] As can be seen from Table 3, compared with the blank group, the sleep latency of the model group was prolonged and the sleep duration was reduced, both with significant differences (P<0.01). Both the test group and the positive control group significantly reduced the sleep latency of rats and prolonged the sleep duration. Among them, compared with the model group, there was no significant difference in the sleep latency of the low-dose XX10 group, but there was a significant difference in the sleep duration (P<0.01); the sleep latency of the medium- and high-dose XX10 groups and the positive control group was significantly shortened, and the sleep duration was significantly prolonged, both with significant differences (P<0.01), and the sleep duration of the high-dose XX10 group was significantly different from that of the positive control group (P<0.01). It can also be seen from the table that the efficacy of the medium- and high-dose XX10 groups was stronger than that of the nemorexan group, which is consistent with the results of body weight and animal state reactions.

[0132] Table 4: Relative expression of OX1R and OX2R mRNA in rat hippocampus

[0133] Grouping OX1R OX2R Blank group 1.11±0.31 1.10±0.29 Model Group <![CDATA[3.09±0.33 # ]]> <![CDATA[2.33±0.28 # ]]> XX10 low dose group 1.28±0.13* 2.02±0.15 XX10 medium dose group 1.06±0.21* 1.42±0.07* XX10 high dose group 0.90±0.10* 1.28±0.21* Nemorison Group 1.12±0.25* 1.45±0.15*

[0134] Note: # indicates P<0.01 compared with the blank group; * indicates P<0.01 compared with the model group.

[0135] As can be seen from Table 4: Compared with the blank group, the relative expression of OX1R and OX2R in the hippocampal tissue of the model group was significantly increased (P<0.01). Compared with the model group, the relative expression of OX1R in the low-dose group of XX10 was significantly decreased (P<0.01), and the relative expression of OX2R did not change significantly; the relative expression of OX1R and OX2R in the medium- and high-dose groups of XX10 and the positive control group (nemorexan) was significantly decreased (P<0.01); it can also be seen from the table that the efficacy of the medium- and high-dose groups of XX10 was stronger than that of the nemorexan group, which is consistent with the results suggested by other indicators. In addition, it can be seen that the decrease in the relative expression of OX1R in the low-, medium-, and high-dose groups of XX10 and the positive control group (nemorexan) was significantly greater than the decrease in the relative expression of OX2R.

[0136] Overall, in the PCPA-induced insomnia rat model, XX10 showed a dose-dependent therapeutic effect on insomnia, and its effect was better than that of nemorexant at the same dose.

[0137] Although the present invention has been disclosed as above with preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art may make some modifications and improvements without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention shall be based on the definition of the claims.

Claims

1. A compound, and a pharmaceutically acceptable salt thereof, having the following structure:

2. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and an inert carrier.

3. The composition according to claim 2, wherein the composition can be administered in the form of: Injections, powders, sprays, inhalers, tablets, pills, capsules, lozenges, gums, powders, granules, gels, creams, ointments, patches, suppositories, suspensions, syrups.

4. Use of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 2 to 3 in the preparation of a drug for treating and / or preventing related diseases or conditions; wherein, The diseases or conditions include neuropathic pain, oral pain, facial pain, internal organ pain, headache, insomnia, cognitive impairment, appetite disorders, mood disorders, sundown syndrome, and Alzheimer's disease.

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