A novel isopropyl bisphenol derivative, pharmaceutical composition thereof and use thereof

Abstract

The present application discloses a novel isopropyl bisphenol derivative, a pharmaceutical composition thereof and use, wherein the novel isopropyl bisphenol derivative has an anti-epilepsy effect. The novel isopropyl bisphenol derivative is shown as formula (I), wherein the definitions of the groups are described in the specification.

Description

Technical Field

[0001] This invention relates to, but is not limited to, the field of pharmaceutical chemistry, and particularly to a novel propofol derivative, its pharmaceutical composition, and its uses. Background Technology

[0002] Epilepsy is a common chronic neurological disorder primarily caused by abnormal electrical activity in the brain, clinically manifested as recurrent and unpredictable seizures. Globally, the number of people suffering from epilepsy is enormous. Although various antiepileptic drugs (AEDs) are available, a significant proportion of patients (approximately 20%–30%) remain refractory to or resistant to existing medications, failing to achieve adequate seizure control. Furthermore, current AEDs often come with certain side effects, such as sedation, ataxia, cognitive impairment, and hepatotoxicity or nephrotoxicity. Therefore, there is an urgent need to develop new, safer, and more effective AEDs.

[0003] In the central nervous system, γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter, which can interact with GABAA, GABA2, and GABA3. B GABAA receptors exert inhibitory regulatory effects by binding to them. Among them, GABAA receptors are ligand-gated chloride ion channels, promoting chloride ion influx and hyperpolarizing the membrane potential, thereby inhibiting excessive neuronal discharge and reducing epileptic seizures. Currently available antiepileptic drugs targeting GABAA receptors include benzodiazepines and barbiturates. Representative drugs of the former include diazepam and clonazepam, while representative drugs of the latter include phenobarbital. However, long-term use of both can easily lead to tolerance and dependence, and has side effects including sedation, drowsiness, muscle relaxation, and cognitive impairment.

[0004] In summary, while traditional antiepileptic drugs targeting the GABAA receptor play a vital role in clinical practice, their poor selectivity, high tolerability, dependence, and significant side effects have become bottlenecks in further improving the efficacy of epilepsy treatment. Therefore, developing innovative antiepileptic drugs based on the GABAA receptor target with higher selectivity, better tolerability, and fewer adverse reactions not only meets urgent clinical needs but also possesses significant commercial and social value. This direction is becoming a major focus of current antiepileptic drug research and has broad development prospects. Summary of the Invention

[0005] This invention provides a novel propionyl bisphenol derivative, which in [³ 5The [S]TBPS binding assay showed significantly superior activity, while exhibiting no significant effect on GABA and benzodiazepine sites, demonstrating good site selectivity. Furthermore, these compounds possess superior membrane permeability and blood-brain barrier penetration, and exhibit significantly stronger antiepileptic activity, showing promising potential for central nervous system drug development.

[0006] In one aspect, this invention provides a novel propionyl derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as shown in (I):

[0007]

[0008] In formula (I),

[0009] R1, R4, R7, R 10 R 13 R 14 R 15 and R 16 They were selected independently from H, and deuterium, respectively;

[0010] R2, R3, R5, R6, R8, R9, R 11 and R 12 They were independently selected from CH3 and CD3, respectively;

[0011] R 17 and R 18 Selected independently from H, , ,and ,in,

[0012] The above R a and R b Each is independently selected from H, deuterium, and C1-C6 alkyl groups;

[0013] R c and R d They were independently selected from H, Li, Na, and K, respectively;

[0014] R e and R f Each is independently selected from H, deuterium, and C1-C6 alkyl groups;

[0015] R g Selected from C1-C6 alkyl groups and C3-C8 cycloalkyl groups;

[0016] In particular,

[0017] R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R12 R 13 R 14 R 15 and R 16 At least one of them is deuterium or is replaced by deuterium;

[0018] When R 17 and R 18 When all atoms are hydrogen, the following structures are not included: .

[0019] In some embodiments, the present invention provides a novel propionyl derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as shown in formula (II):

[0020]

[0021] The substituents in formula (II) are defined as described in formula (I).

[0022] In some embodiments, the present invention provides a novel propionyl derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as shown in formula (III):

[0023]

[0024] The substituents in formula (III) are defined as described in formula (I).

[0025] In some embodiments, the present invention provides a novel propionyl derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as shown in formula (Ⅳ):

[0026]

[0027] The substituents in formula (Ⅳ) are defined as described in formula (I).

[0028] In some implementations, in equations (I)-(IV) above, R1, R4, R7, R... 10 R 13 R 14 R 15 and R 16 Each is independently selected from H or deuterium.

[0029] In some implementations, in equations (I)-(IV) above, R2, R3, R5, R6, R8, R9, R 11 and R 12 They are selected independently from CH3 or CD3.

[0030] In particular,

[0031] The above R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 and R 16 One of them must be deuterium or be replaced by deuterium.

[0032] In some implementations, in equations (I)-(II) above, R 17 and R 18 All are hydrogen;

[0033] Specifically, in this case, the following structures are not included: .

[0034] In some implementations, in formulas (I) and / or (III) above, R 17 and R 18 Each is independently selected from H, or ;in,

[0035] The above R a and R b Each is independently selected from H, deuterium, or C1-C6 alkyl groups, preferably R. a and R b Both are H and R a and R b All are deuterium, or R a and R b One of them is hydrogen and the other is a C1-C6 alkyl group, more preferably, R a and R b All are hydrogen, R a and R b All are deuterium, or R a and R b One is hydrogen and the other is methyl;

[0036] R c and R d Each is independently selected from H, Li, Na, or K, preferably R. c and R d All are H, Na, or K;

[0037] In some implementations, in formulas (I) and / or (IV) above, R 17 and R 18 Each is independently selected from H, or ;in,

[0038] The above R e and R fEach is independently selected from H, deuterium, or C1-C6 alkyl groups, preferably R. e and R f All are H;

[0039] R g Selected from C1-C6 alkyl groups or C3-C8 cycloalkyl groups, preferably, R g It is methyl or cyclohexyl.

[0040] In some embodiments, the novel propionyl derivatives, tautomers, solvates, or pharmaceutically acceptable salts thereof provided by the present invention are selected from the following compounds:

[0041]

[0042]

[0043] On the other hand, in some embodiments, the present invention provides pharmaceutical compositions comprising the above-described novel propionyl derivatives, tautomers, solvates, or pharmaceutically acceptable salts thereof.

[0044] In some embodiments, the present invention discloses a pharmaceutical composition comprising, as an active ingredient or main active ingredient, the compound, tautomer, solvate or pharmaceutically acceptable salt thereof described herein, supplemented by a pharmaceutically acceptable carrier.

[0045] In one aspect, in some embodiments, the present invention provides the use of the above-described pharmaceutical composition in the preparation of drugs for inducing and maintaining anesthesia in animals or humans, promoting sedation and hypnosis in animals or humans, and treating and / or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, or epilepsy.

[0046] In some embodiments, the present invention provides a pharmaceutical composition comprising the above-described pharmaceutical composition for inducing and maintaining anesthesia in animals or humans, promoting sedation and hypnosis in animals or humans, and treating and / or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, or epilepsy.

[0047] In some examples of the present invention, the novel bisphenol A derivative of the present invention and suitable excipients are used together to prepare injections, tablets, capsules, microspheres, liposomes, etc.

[0048] This invention provides a novel propionyl bisphenol derivative, which in [³ 5The [S]TBPS binding assay showed significantly superior activity, while exhibiting no significant effect on GABA and benzodiazepine sites, demonstrating good site selectivity. Furthermore, these compounds possess superior membrane permeability and blood-brain barrier penetration, and exhibit significantly stronger antiepileptic activity, showing promising potential for central nervous system drug development.

[0049] definition:

[0050] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0051] Some compounds of this invention can exist in either a solvated or a solvent-based form, such as hydrates or ethanolates. Generally, the solvent-based and the solvent-based forms are equivalent and are both included within the scope of this invention.

[0052] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0053] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include aluminum, sodium, potassium, calcium, manganese, iron, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0054] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, more preferably one to three, and most preferably one or two.

[0055] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc.

[0056] The term "cycloalkyl" refers to a monocyclic or fused-ring group consisting entirely of carbon atoms (a "fused" ring means that each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system), wherein one or more rings do not have a fully connected π-electron system. Examples of cycloalkyl groups (but not limited to) include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cyclohepttriene. Cycloalkyl groups can be substituted or unsubstituted.

[0057] The numerical range mentioned in this application, such as "C1-C6", means that the group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 6 carbon atoms. Attached Figure Description

[0058] Figure 1 Effects of the test compound on seizure scores in a pentylenetetrazole-induced acute epilepsy model in rats. Detailed Implementation

[0059] The following examples are intended to enable those skilled in the art to fully understand the present invention, but do not limit the invention in any way. The structures of all compounds were determined by MS.

[0060] Example 1: Synthesis of DSC240-01

[0061] Reaction formula:

[0062]

[0063] Preparation method:

[0064] 4,4'-dihydroxybiphenyl (5.0 g, 26.9 mmol), chlorobenzene (60 mL), and aluminum trichloride (7.2 g, 54.0 mmol) were added to a reaction flask, stirred, and 2-bromopropane-D6 (14.3 g, 110.7 mmol) was added dropwise. The mixture was heated to 80 °C and stirred for 2 hours. 60 mL of 2 mol / L dilute hydrochloric acid was added, and the mixture was stirred for 0.5 hours. The mixture was then separated. The organic phase was concentrated under reduced pressure, and the resulting residue was slurried with ethyl acetate, filtered, and recrystallized from the filter cake to give 8.6 g of compound DSC240-01 (yield 84.4%). MS: 379.4 [M+1].

[0065] Example 2: Synthesis of DSC240-02

[0066] Reaction formula:

[0067]

[0068] Preparation method:

[0069] 4,4'-dihydroxybiphenyl (5.0 g, 26.9 mmol), chlorobenzene (60 mL), and aluminum trichloride (7.2 g, 54.0 mmol) were added to a reaction flask, stirred, and 2-bromopropane-D7 (14.4 g, 110.7 mmol) was added dropwise. The mixture was heated to 80 °C and stirred for 2 hours. 2 mol / L dilute hydrochloric acid (60 mL) was added, and the mixture was stirred for 0.5 hours. The mixture was then separated. The organic phase was concentrated under reduced pressure, and the resulting residue was slurried with ethyl acetate, filtered, and recrystallized from the filter cake to give 8.1 g of compound DSC240-02 (yield 78.3%). MS: 383.4 [M+1].

[0070] Example 3: Synthesis of DSC240-03

[0071] Reaction formula:

[0072]

[0073] Preparation method:

[0074] 4,4'-dihydroxybiphenyl (5.0 g, 26.9 mmol), chlorobenzene (60 mL), and aluminum trichloride (7.2 g, 54.0 mmol) were added to a reaction flask, stirred, and 2-bromopropane-D1 (13.7 g, 110.7 mmol) was added dropwise. The mixture was heated to 80 °C and stirred for 2 hours. 2 mol / L dilute hydrochloric acid (60 mL) was added, and the mixture was stirred for 0.5 hours. The mixture was then separated. The organic phase was concentrated under reduced pressure, and the resulting residue was slurried with ethyl acetate, filtered, and recrystallized from the filter cake to give 7.3 g of compound DSC240-02 (yield 75.7%). MS: 359.3 [M+1].

[0075] Example 4: Synthesis of DSC240-04

[0076] Reaction formula:

[0077]

[0078] Preparation method:

[0079] 4,4'-dihydroxybiphenyl-D8 (5.23 g, 26.9 mmol), chlorobenzene (60 mL), and aluminum trichloride (7.2 g, 54.0 mmol) were added to a reaction flask, stirred, and 2-bromopropane (13.6 g, 110.7 mmol) was added dropwise. The mixture was heated to 80 °C and stirred for 2 hours. 2 mol / L dilute hydrochloric acid (60 mL) was added, and the mixture was stirred for 0.5 hours. The mixture was then separated. The organic phase was concentrated under reduced pressure, and the resulting residue was slurried with ethyl acetate, filtered, and recrystallized from the filter cake to give 7.5 g of compound DSC240-02 (yield 77.8%). MS: 359.3 [M+1].

[0080] Example 5: Synthesis of DSC240-05

[0081] Reaction formula:

[0082]

[0083] Preparation method:

[0084] Step 1: Synthesis of compound DSC240-0501

[0085] Under nitrogen protection, at 5 °C, compound DSC240-01 (8.01 g, 21.15 mmol) was slowly added to a suspension of sodium hydride (558 mg, 23.25 mmol) in hexamethylphosphoric triamine (15 mL) under stirring. The reaction mixture was stirred at room temperature for another 30 minutes. Chloromethyl sulfide (2.25 g, 23.25 mmol) was added dropwise to the mixture, and the reaction was stirred at room temperature. After 20 hours, water (75 mL) and toluene (150 mL) were added to the reaction mixture. The mixture was separated, and the organic phase was collected. The aqueous phase was extracted with toluene (75 mL). The organic phases were combined, washed with water (75 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting oily residue was purified by column chromatography (silica gel, hexane / dichloromethane 4:1) to give 6.93 g (74.7% yield) of the title compound.

[0086] Step 2: Synthesis of compound DSC240-0502

[0087] Under nitrogen protection, at 5 °C, sulfonyl chloride (2.16 g, 16.0 mmol) was slowly added dropwise to a stirred solution of compound DSC240-0501 (6.90 g, 15.73 mmol) in dichloromethane (60 mL). After the addition was complete, the reaction mixture was stirred at 5 °C for 10 minutes, and then stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the resulting oily residue was purified by column chromatography (silica gel, 1:20 hexane / ethyl acetate) to give 5.3 g (yield 48.9%) of the title compound.

[0088] Step 3: Synthesis of compound DSC240-0503

[0089] Compound DSC240-0502 (5.0 g, 11.7 mmol), silver dibenzyl phosphate (4.64 g, 12.06 mmol), and anhydrous toluene (50 mL) were added to a reaction flask. Stirring was started, and the mixture was heated to reflux temperature under nitrogen protection and maintained at this temperature for 1 hour. The mixture was cooled to room temperature and filtered. The solvent was evaporated under reduced pressure, and the resulting oily residue was purified by column chromatography (9:1 hexane / ethyl acetate, then 1:1 hexane / ethyl acetate) to give 6.3 g (80.5% yield) of the title compound.

[0090] Step 4: Synthesis of compound DSC240-05

[0091] Compound DSC240-0503 (6.1 g, 9.1 mmol) was added to methanol (60 mL), followed by palladium on carbon (10%, 600 mg). The mixture was stirred under a hydrogen atmosphere (1 atm) for 1.5 h. The mixture was filtered, the solvent was evaporated from the filtrate under reduced pressure, the residue was purified by pre-HPLC, and lyophilized to give 1.08 g (yield 24.3%) of the title compound. MS: 489.4 [M+1].

[0092] Example 6: Synthesis of DSC240-06

[0093] Reaction formula:

[0094]

[0095] Preparation method:

[0096] Step 1: Synthesis of compound DSC240-0601

[0097] Under nitrogen protection, at 5 °C, compound DSC240-01 (12.0 g, 31.69 mmol) was slowly added to a suspension of sodium hydride (837 mg, 34.88 mmol) in hexamethylphosphoric triamine (25 mL) under stirring. The reaction mixture was stirred at room temperature for another 30 minutes. Chloromethyl methyl sulfide (6.12 g, 63.38 mmol) was added dropwise to the mixture, and the reaction was stirred at room temperature. After 20 hours, water (120 mL) and toluene (230 mL) were added to the reaction mixture. The mixture was separated, and the organic phase was collected. The aqueous phase was extracted with toluene (120 mL). The organic phases were combined, washed with water (120 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting oily residue was purified by column chromatography (silica gel, hexane / dichloromethane 4:1) to give 11.1 g (70.2% yield) of the title compound.

[0098] Step 2: Synthesis of compound DSC240-0602

[0099] Under nitrogen protection, at 5 °C, sulfonyl chloride (6.0 g, 44.5 mmol) was slowly added dropwise to a stirred solution of compound DSC240-0601 (11.0 g, 22.05 mmol) in 100 mL of dichloromethane. After the addition was complete, the reaction mixture was stirred at 5 °C for 10 minutes, and then stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the resulting oily residue was purified by column chromatography (silica gel, 1:20 hexane / ethyl acetate) to give 6.8 g (60.7% yield) of the title compound.

[0100] Step 3: Synthesis of compound DSC240-0603

[0101] Compound DSC240-0602 (6.5 g, 12.8 mmol), silver dibenzyl phosphate (10.4 g, 27.0 mmol), and anhydrous toluene (70 mL) were added to a reaction flask. Stirring was started, and the mixture was heated to reflux temperature under nitrogen protection and maintained at this temperature for 1 hour. The mixture was cooled to room temperature and filtered. The solvent was evaporated under reduced pressure, and the resulting oily residue was purified by column chromatography (9:1 hexane / ethyl acetate, then 1:1 hexane / ethyl acetate) to give 8.8 g (71.7% yield) of the title compound.

[0102] Step 4: Synthesis of compound DSC240-06

[0103] Compound DSC240-0603 (8.7 g, 9.1 mmol) was added to methanol (100 mL), and palladium on carbon (10%, 900 mg) was added. The mixture was stirred for 1.5 h under a hydrogen atmosphere (1 atm). The mixture was filtered, the solvent was evaporated from the filtrate under reduced pressure, and the residue was purified by pre-HPLC and lyophilized to give 1.1 g (yield 20.2%) of the title compound. MS: 599.3 [M+1].

[0104] Example 7: Synthesis of DSC240-11

[0105] Reaction formula:

[0106]

[0107] Preparation process:

[0108] Compound DSC240-05 (2.15 g, 4.4 mmol) was added to tetrahydrofuran (40 mL), stirred to dissolve, and then an aqueous solution of sodium carbonate (0.70 g, 5.0 mmol) (20 mL) was added and stirred for half an hour. The solvent was evaporated under reduced pressure, and the aqueous phase was washed with isopropyl ether (20 mL). The aqueous phase was concentrated under reduced pressure, and the residue was washed with isopropyl ether and filtered. The filter cake was purified by preparative liquid chromatography and lyophilized to give 0.50 g of the target compound (yield 21.3%). MS: 511.3 [M + Na].

[0109] Example 8: Synthesis of DSC240-12

[0110] Reaction formula:

[0111]

[0112] Preparation process:

[0113] Compound DSC240-06 (3.11 g, 5.2 mmol) was added to tetrahydrofuran (60 mL), stirred to dissolve, and then an aqueous solution of sodium carbonate (1.80 g, 13.0 mmol) (40 mL) was added. The mixture was stirred for half an hour. The solvent was evaporated under reduced pressure, and the aqueous phase was washed with diethyl ether. The aqueous phase was concentrated under reduced pressure, and the residue was washed with diethyl ether and filtered. The filter cake was purified by liquid chromatography and lyophilized to give 0.67 g of the target compound (yield 18.8%). MS: 621.3 [M + Na].

[0114] Example 9: Synthesis of DSC240-16

[0115] Reaction formula:

[0116]

[0117] Preparation method:

[0118] Under nitrogen protection, at 5 °C, compound DSC240-03 (5.06 g, 14.1 mmol) was slowly added to a suspension of sodium hydride (372 mg, 15.5 mmol) in hexamethylphosphoric triamine (10 mL) under stirring. The reaction mixture was stirred at room temperature for another 30 minutes. 1.76 g, 14.1 mmol, of chloromethyl carbonate was added dropwise to the mixture, and the reaction was stirred at room temperature. After 20 hours, water (50 mL) and toluene (100 mL) were added to the reaction mixture. The mixture was separated, and the organic phase was collected. The aqueous phase was extracted with toluene (50 mL). The organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting oily residue was purified by column chromatography (silica gel, hexane / dichloromethane 6:1) to give 3.5 g (55.6% yield) of the title compound. MS: 447.3 [M+1].

[0119] Example 10: Synthesis of DSC240-17

[0120] Reaction formula:

[0121]

[0122] Preparation method:

[0123] Under nitrogen protection, at 5 °C, compound DSC240-03 (5.06 g, 14.1 mmol) was slowly added to a suspension of sodium hydride (372 mg, 15.5 mmol) in hexamethylphosphoric triamine (10 mL) under stirring. The reaction mixture was stirred at room temperature for another 30 minutes. 1-Chloroethylcyclohexyl carbonate (2.91 g, 14.1 mmol) was added dropwise to the mixture, and the reaction was stirred at room temperature. After 20 hours, water (50 mL) and toluene (100 mL) were added to the reaction mixture. The mixture was separated, and the organic phase was retained. The aqueous phase was extracted with toluene (50 mL). The organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting oily residue was purified by column chromatography (silica gel, hexane / dichloromethane 6:1) to give 3.3 g (yield 44.3%) of the title compound. MS: 529.4 [M+1].

[0124] The compounds of the following examples were synthesized using the same method as in the above embodiments, either commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds.

[0125]

[0126] Example 11: The effect of specific ligands on isolated rat brain tissue cell membrane GABA A Effects of receptor binding

[0127] The structures of the compounds for comparison are as follows:

[0128]

[0129] GABA A The γ-aminobutyric acid type receptor (GABA receptor) is a ligand-gated chloride channel receptor widely distributed in the central nervous system and is an important molecular basis for mediating inhibitory neurotransmission. This receptor complex contains multiple functional sites, among which the chloride channel pore region, GABA binding site, and benzodiazepine regulatory site are involved in different receptor regulatory mechanisms. This example uses a radioligand competition binding assay to evaluate the GABA binding activity of the test compound. A The functional characteristics of different functional sites of the receptor, and in terms of IC 50 As a quantitative indicator.

[0130] SPF-grade 6-8 week old male SD rats weighing 180-220g (Liaoning Changsheng Biotechnology Co., Ltd.) were used. After anesthesia and cerebral cortex dislocation, the rats were rapidly isolated and homogenized in 0.32 mol / L sucrose solution under ice bath conditions. The homogenate was centrifuged at 1000g for 10 min at 4℃, and the supernatant was collected and ultracentrifuged at 48000g for 20 min at 4℃. The resulting precipitate was resuspended in 10 volumes of 10 mmol / L Tris-HCl buffer (pH 7.4) and washed again by centrifugation. The final precipitate was stored at −20℃. On the day of the experiment, after thawing, the precipitate was resuspended in the above Tris-HCl buffer and centrifuged twice more to remove endogenous inhibitors, obtaining rat brain tissue cell membrane specimens. The protein concentration of rat brain tissue cell membrane specimens was determined using the Coomassie Brilliant Blue method. The specimens were then appropriately diluted with the above-mentioned Tris-HCl buffer before the protein concentration was determined again, so that the protein content of the rat brain tissue cell membrane suspension used in the experiment was approximately 117 μg / 100 μL.

[0131] The test compounds were compounds DSC240-01 to DSC240-24 of this invention, and the control compounds were YBSF and d32-YBSF. All compounds were first prepared into 60 mmol / L stock solutions using dimethyl sulfoxide (DMSO) and stored at −20 °C. On the day of the experiment, working solutions of different concentrations were obtained by serial dilution with the above-mentioned Tris-HCl buffer, so that the final concentration range of the test compounds in the final reaction system was 0.3–30 μM.

[0132] Radioactive ligands include: [ 35 [S]TBPS (GABAA receptor chloride channel pore region specific antagonist, China Isotope & Radiation Corporation, batch number TF110105), [³H]Muscimol (GABA binding site agonist, Sigma-Aldrich, supplied in China, batch number S231215), and [³H]Flunitrazepam (benzodiazepine site agonist, PerkinElmer, supplied in China, batch number TRK590).

[0133] The total volume for the competitive binding reaction was 500 μL. 100 μL of brain tissue cell membrane suspension (containing approximately 117 μg of protein) was added to each well, followed by 25 μL of radioactive ligand (final concentration 10 nM) and 25 μL of solutions of different concentrations of the test compound, with the volume made up to the required level using Tris-HCl buffer. A solvent control group (containing 0.01% DMSO) and a blank group (containing excess unlabeled ligand to measure non-specific binding) were also included. The reaction system was incubated at room temperature for 30 min.

[0134] After incubation, 5 mL of ice-cold Tris-Citrate buffer was added to terminate the reaction, and the precipitate was collected by centrifugation. The precipitate was quickly washed with double-distilled water, digested with formic acid and H2O2, and then xylene scintillation solution (Beijing Isotope Technology Co., Ltd.) was added. The radioactivity count (dpm) was measured using a Wallac 1400™ liquid scintillation counter (PerkinElmer, China: Meigu Molecular Instruments (Shanghai) Co., Ltd.).

[0135] The ligand binding rate is calculated using the following formula:

[0136] Y=Bound(%)=(dpm_sample−dpm_blank) / (dpm_control−dpm_blank)×100%

[0137] Where dpm_sample is the radioactivity count value of the test compound group, dpm_control is the radioactivity count value of the solvent control group, and dpm_blank is the radioactivity count value of the blank group.

[0138] Concentration-response curves were plotted based on the concentration of the test compound versus the ligand binding rate. Four-parameter logistic curve fitting was performed using GraphPadPrism9 software (Chinese agent: Genesys Pharma Ltd.) to calculate the IC50 of the test compound for different ligand binding rates. 50 Values. The results are shown in Table 1.

[0139]

[0140] The results in the table show that compounds DSC240-01 to DSC240-24 of this invention are effective in GABA. A Receptor chloride channel specific ligands [³ 5 S]TBPS showed significant inhibitory activity in competitive binding experiments, with an IC50 value of [missing information]. 50 The values ​​ranged from 0.515 to 1.523 μM, and were generally superior to the comparative compound YBSF (IC). 50 =2.523μM) and d32-YBSF (IC 50 =2.322μM). Among them, DSC240-01, DSC240-03, DSC240-05 and DSC240-16 have the strongest properties, IC 50 The activity ranged from 0.215 to 0.284 μM, approximately 8 to 12 times higher than that of the two comparative compounds. Furthermore, DSC240-02, DSC240-04, DSC240-06, DSC240-11, DSC240-12, DSC240-17, and DSC240-18 also exhibited high activity, with IC50 values ​​of 0.215–0.284 μM. 50The values ​​were all distributed in the range of 0.648–0.748 μM, which was about 3 to 4 times higher than that of the control compound.

[0141] Under the same experimental conditions, the above compounds can inhibit [in a concentration-dependent manner]. 35 S]TBPS and GABA A The binding of receptors to [³H]Muscimol (GABA binding site) and [³H]Flunitrazepam (benzodiazepine site) binds to GABA. A No significant inhibitory effect was observed on receptor binding (IC50). 50 (All >30 μM). This result indicates that the compounds of the present invention are effective against GABA. A The acceptor chloride ion channel pore region exhibits good selectivity, and its mechanism of action differs from the classic GABAergic or benzodiazepine-regulated pathways. The compounds of this invention exhibit GABAergic... A It has significant advantages and good site selectivity in the regulation of receptor chloride channels, and has the potential application value for further development as a drug for the treatment of central nervous system-related diseases.

[0142] Example 12: Parallel Artificial Membrane Permeation Model (PAMPA) Experiment

[0143] The test and control compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare stock solutions, which were then diluted with PBS buffer (pH 7.4) to a working solution of 25 μg / mL on the day of the experiment. Porcine brain lipid extract (PBL, Avanti Polar Lipids, Merck Life Sciences) was dissolved in dodecane to prepare a 20 mg / mL phospholipid solution. A PVDF filter membrane (Merck Millipore) from a 96-well PAMPA plate was used as the artificial membrane carrier. 4 μL of PBL phospholipid solution was dropped onto the surface of each well of the PVDF filter membrane to uniformly cover it, forming an artificial phospholipid membrane that simulates the lipid environment of the blood-brain barrier.

[0144] 300 μL of pH 7.4 PBS buffer was added to each well of the acceptor plate as the acceptor solution, and 150 μL of a 25 μg / mL test compound solution was added to each well of the donor plate as the donor solution. Three parallel wells were prepared for each compound. A 96-well filter plate coated with a phospholipid membrane was then placed between the donor and acceptor plates, ensuring full contact between the artificial phospholipid membrane and the donor solution, forming a typical PAMPA "donor-artificial membrane-acceptor" sandwich structure. The assembled system was incubated at 37 °C (Thermo Fisher Scientific) for 18 h to promote passive diffusion of the compound through the artificial lipid membrane to the acceptor side.

[0145] After incubation, the sandwich structure was carefully disassembled, and the solution in the acceptor plate was transferred to a new transparent 96-well plate. The absorbance (OD value) of each well was measured at 340 nm using a microplate reader (SpectraMax M5, Molecular Devices, China: Meigu Molecular Instruments (Shanghai) Co., Ltd.). Each well was measured once, and each compound had 3 parallel wells. The concentration of the acceptor-side compound was calculated according to the standard curve.

[0146] Apparent permeability Pe (cm / s) was calculated according to the method described in the literature (Kiyohiko S., et al. Optimized conditions of biomimetic artificial membrane permeation assay. Int. J. Pharm., 2001, 228: 181–188) to evaluate the passive membrane permeability of the compound in a parallel artificial membrane model, thereby predicting its potential blood-brain barrier penetration ability. The results are shown in Table 2.

[0147]

[0148] The results in the table show that the apparent permeability Pe of compounds DSC240-01, DSC240-02, DSC240-03, DSC240-04, DSC240-05, DSC240-06, DSC240-11, DSC240-12, DSC240-16, DSC240-17, and DSC240-18 in the PAMPA test ranges from 11.38 to 17.23 × 10⁻ 6 Within the cm / s range, the overall performance was significantly higher than that of the comparative compound YBSF (7.22 × 10⁻⁻⁶ cm / s). 6 cm / s) and d32-YBSF (8.43⁻ 6cm / s), indicating that the compounds of the present invention have superior passive membrane permeability. Among them, DSC240-01, DSC240-03, DSC240-05 and DSC240-16 have the highest Pe values, reaching 16~17×10⁻ 6 cm / s, which is significantly higher than other compounds, showing excellent membrane permeability. The above results show that the compounds of the present invention exhibit good lipid membrane permeability in the parallel artificial membrane model and have high potential blood-brain barrier penetration ability.

[0149] Example 13: Distribution experiment in rat brain tissue

[0150] Eighteen male SD rats of SPF grade aged 6 to 8 weeks and weighing 200 to 220 g were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (production license number SCXK (Jing) 2021-0006). The animals were housed under conditions of temperature 22±2°C, relative humidity 50±10%, 12h light-dark cycle, with free access to food and water. They were acclimatized for 3 days before the experiment.

[0151] The test compounds are the compounds of the present invention DSC240-01, DSC240-03, DSC240-05 and DSC240-16, and the reference compounds are YBSF and d32-YBSF. Each compound was firstly dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution, and then diluted with a mixed solvent containing PEG-400 and 0.9% sodium chloride injection to obtain a working solution for administration.

[0152] The experimental animals were randomly divided into 6 groups, with 3 rats in each group. Each compound was administered by continuous intravenous infusion via the tail vein at an equimolar dose for 30 min. The administration doses were as follows: YBSF 25.00 mg / kg, d32-YBSF 27.27 mg / kg, DSC240-01 26.71 mg / kg, DSC240-03 25.29 mg / kg, DSC240-05 34.46 mg / kg, DSC240-16 31.50 mg / kg. Immediately after the end of administration, the animals were sacrificed by cervical dislocation, and the brain tissue was rapidly isolated. The brain tissue was washed with PBS buffer of pH 7.4 and then weighed.

[0153] Brain tissue was homogenized with acetonitrile at a ratio of 1:4 (w / v). The homogenate was centrifuged at 12000g for 10 min at 4℃, and the supernatant was collected for later use. The concentrations of compounds in the brain tissue samples were determined by HPLC-MS / MS. Compounds YBSF, d32-YBSF, DSC240-01, and DSC240-03 were detected as their original form; DSC240-05 was detected as a derivative of DSC240-01; and DSC240-16 was detected as a derivative of DSC240-03. The distribution of each compound in rat brain tissue was analyzed and evaluated. The results are shown in Table 3.

[0154]

[0155] Experimental results showed that, at equimolar doses, the brain tissue concentrations of compounds DSC240-01, DSC240-03, DSC240-05, and DSC240-16 after continuous intravenous infusion in rats for 30 minutes were significantly higher than those of the control compounds YBSF (16.22 ng / g) and d32-YBSF (20.36 ng / g), indicating that the compounds of this invention are superior to the control compounds in terms of blood-brain barrier permeability. Combined with the aforementioned PAMPA parallel artificial membrane permeability experiment (Pe value), it was found that DSC240-01, DSC240-03, DSC240-05, and DSC240-16 had the highest in vitro membrane permeability, which is highly consistent with their high in vivo brain tissue concentrations, indicating a significant positive correlation between the in vitro permeability test and the in vivo brain distribution of the compounds of this invention. This suggests that these compounds have high blood-brain barrier penetration ability, providing an effective basis for their central nervous system effects.

[0156] Example 14: Efficacy evaluation in a pentylenetetrazole-induced acute epilepsy model in rats

[0157] Ninety male SPF-grade SD rats, aged 5-6 weeks and weighing 120-130g (purchased from Liaoning Changsheng Biotechnology Co., Ltd.), were housed in an animal room at a temperature of 24-27℃ and a relative humidity of 40-70%, with free access to standard feed and water. After 3 days of acclimatization, rats weighing 140-160g were selected for experiments.

[0158] Preparation of the working solution containing the comparative compound or the test compound in 5% DMSO + 95% physiological saline (V / V): First, dissolve an appropriate amount of the comparative compound or the test compound in dimethyl sulfoxide (DMSO). Measure appropriate amounts of the DMSO solution and physiological saline, and mix them at a ratio of 1:19 (V / V) to obtain the working solution. The blank solvent is a 5% DMSO + 95% physiological saline (V / V) solution without the comparative compound or the test compound.

[0159] Seventy rats were randomly divided into seven groups of ten each, based on their body weight: a model group (treated with blank solvent), a YBSF 25.00 mg / kg group, a d32-YBSF 27.27 mg / kg group, a DSC240-01 26.71 mg / kg group, a DSC240-03 25.29 mg / kg group, a DSC240-05 34.46 mg / kg group, and a DSC240-16 31.50 mg / kg group. The dosages of all tested compounds were converted to equimolar doses equivalent to YBSF 25.00 mg / kg based on their molecular weights. All animals were administered the drugs via tail vein infusion over a period of 30 minutes.

[0160] Thirty minutes after administration, rats in each group were intraperitoneally injected with 80 mg / kg of pentylenetetrazole (PTZ, Sigma-Aldrich, batch number MKCX5352) to induce acute epileptic seizures. Behavioral changes were observed immediately after PTZ injection, and seizure occurrences within 30 minutes were recorded.

[0161] The severity of epileptic seizures was evaluated using the modified Racine scoring system (grades 0–V), and the occurrence of grade IV–V seizures was recorded to evaluate the anticonvulsant effects of each compound. Experimental data are expressed as mean ± standard deviation (x̄±s). One-way ANOVA was used for statistical comparison, and a p-value < 0.05 was considered statistically significant. Results are shown in Table 4 and [Table data would be inserted here]. Figure 1 .

[0162] Before the induction of acute epileptic seizures, all rats in each group had normal diet and activity, and their paws were in good condition with no abnormalities. The seizure score of the PTZ model group was 5.30±0.67, and the rate of grade IV-V epileptic seizures was over 80%, indicating that the model was successfully established.

[0163]

[0164] In the above scoring results, the scores of the YBSF and d32-YBSF groups were significantly lower than those of the model group (p<0.01), indicating that they have a certain anti-epileptic effect. Although the scores of the d32-YBSF group and the YBSF group were lower than those of the model group, there was no significant difference (p>0.05). Compared with the model group, the seizure scores of the DSC240-01, DSC240-03, DSC240-05, and DSC240-16 groups of the present invention were significantly lower (p<0.01), indicating that the above compounds all have significant anti-epileptic effects; compared with the YBSF and d32-YBSF groups, the seizure scores of the above compounds of the present invention were also significantly lower (p<0.01), indicating that the inhibitory effect of the compounds of the present invention on pentylenetetrazol-induced seizures at equimolar doses is significantly better than that of the YBSF and d32-YBSF compounds. Overall, the results show that the DSC240 series compounds of this invention all exhibit strong anti-epileptic activity in this acute epilepsy model.

[0165] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can 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 defined by the claims.

Claims

1. A novel propionyl bisphenol derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as shown in (I): In formula (I), R1, R4, R7, R 10 R 13 R 14 R 15 and R 16 They were selected independently from H, and deuterium, respectively; R2, R3, R5, R6, R8, R9, R 11 and R 12 They were independently selected from CH3 and CD3, respectively; R 17 and R 18 Selected independently from H, , ,and ,in, The above R a and R b Each is independently selected from H, deuterium, and C1-C6 alkyl groups; R c and R d They were independently selected from H, Li, Na, and K, respectively; R e and R f Each is independently selected from H, deuterium, and C1-C6 alkyl groups; R g Selected from C1-C6 alkyl groups and C3-C8 cycloalkyl groups; In particular, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 and R 16 At least one of them is deuterium or is replaced by deuterium; When R 17 and R 18 When all atoms are hydrogen, the following structures are not included: .

2. The novel propionyl derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as described in claim 1, having the structure of formula (II): in, The above-mentioned substituents are defined as in claim 1 (I).

3. The novel propionyl derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as described in claim 1, having the structure of formula (III): in, The above-mentioned substituents are defined as in claim 1 (I).

4. The novel propionyl derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as described in claim 1, having the structure of formula (Ⅳ): in, The above-mentioned substituents are defined as in claim 1 (I).

5. The novel propionyl derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as described in claim 1, selected from the following compounds:

6. A pharmaceutical composition comprising any novel propionyl derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5.

7. Use of any novel propionyl derivative, tautomer, solvate, or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5, or the pharmaceutical composition of claim 6, in the preparation of drugs for inducing and maintaining anesthesia in animals or humans, promoting sedation and hypnosis in animals or humans, and treating and / or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, or epilepsy.

8. The use according to claim 7, wherein the preparation is a medicament for treating and / or preventing epilepsy, wherein the epilepsy is generalized tonic-clonic seizures, absence seizures, simple partial seizures, complex partial seizures, and autonomic seizures.

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