CN108558754A - A kind of drug for treating depression - Google Patents

A kind of drug for treating depression Download PDF

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CN108558754A
CN108558754A CN201810532702.2A CN201810532702A CN108558754A CN 108558754 A CN108558754 A CN 108558754A CN 201810532702 A CN201810532702 A CN 201810532702A CN 108558754 A CN108558754 A CN 108558754A
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郝惠敏
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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Abstract

The invention discloses a kind of drug for treating depression,Wherein：R1、R2、R3、R4It is independently selected from H, F or OH.In recent years, 5 hydroxytryptamine reuptakes of 5 hydroxytryptamine 1A acceptor portions excitements and selectivity inhibit the antidepressants of double action to have become the hot spot direction that newly-developed antidepressant is studied.In synaptosomes in rat brain in vivo to [3H] 5 HT intake inhibiting effect is tested and h5 HT1AConfirm that the compounds of this invention has 5 HT reuptake inhibitions and to 5 HT in binding affinity experiment1AReceptor has agonism, illustrates that the compound of the present invention can be as the drug for the treatment of mankind's central nervous system dysfunction such as depression, anxiety disorder.

Description

A kind of drug for treating depression
Technical field
The invention belongs to chemical medicines, are related to a kind of drug for treating depression.
Background technology
Depression (depressive disorder) is the psychiatric barrier of high pathogenicity rate, high disability rate and high homicide rate Hinder, has become serious society and public health problem at present.Clinically common antidepressants such as serotonin reuptake transporter One lines such as inhibitor (Selective serotonin reuptake inhibitors, SSRIs) class antidepressant Prozac Drug generally existing effective percentage is high, work slowly, sex dysfunction, many defects such as lead to introgression.In recent years, 5- hydroxyls Tryptamines 1A acceptor portions excitement and selective serotonin reuptake inhibit the antidepressants (serotonin of double action Partial agonist and reuptake inhibitors, SPARIs), it dives because it has stronger curative effect and quick acting etc. In feature and the extremely low advantage of adverse reaction (including sex dysfunction and weight gain etc.) incidence, it has also become novel anti- The hot spot direction of depressed drug research.
The compound of the present invention can effectively inhibit 5-HT reuptakes and to 5-HT1AReceptor has agonism, the present invention Compound can as treatment mankind's central nervous system (CNS) dysfunction such as depression, anxiety disorder drug.
Invention content
The invention discloses a kind of Formula I, structure is：
Wherein：R1、R2、R3、R4Separate choosing From H, F or OH.The invention further relates to the pharmaceutically acceptable salt of the Formula I or solvates.
Further, Formula I described in some preferred schemes is
The synthetic route that another object of the present invention discloses the Formula I is：
Specifically synthetic method is：
1) under cryogenic, using DMF as solvent, nitrobenzene and suitable inorganic base are stirred at low temperature, will be dissolved in Iodine in DMF is added drop-wise in reaction, through subsequent processing after the reaction was complete, you can obtains the iodo- 3- nitrobenzenes of light yellow solid 1-；
2) using DMF as solvent, by the iodo- 3- nitrobenzenes of 1- obtained in the previous step and 1- (trifluoromethyl) -4- vinyl benzenes, N, N- diisopropylethylamine, tri-o-tolyl phosphorus and palladium catalyst are placed in reaction bulb, are heated to 100 DEG C of reactions under nitrogen protection To the reaction was complete, (E) -1- nitros -3- (4- (trifluoromethyl) styryl) benzene can be obtained through subsequent processing within 12 hours；
3) (E) -1- nitros -3- (4- (three obtained in the previous step then will be added after ethyl alcohol, water and ammonium chloride stirring and dissolving Methyl fluoride) styryl) benzene, iron powder is then added, heating makes it, and the reaction was complete, and light yellow solid (E) -3- is obtained through subsequent processing (4- (trifluoromethyl) styryl) aniline；
4) it 1. is cooled to 0 DEG C by after sodium nitrite in water stirring and dissolving, (E) -3- (4- (fluoroforms that will be previously obtained Base) styryl) aniline is dissolved in glacial acetic acid, and it is then added drop-wise in reaction bulb and stirs 1 hour；2. HCl solution is added dropwise at 0 DEG C； 3. dichloromethane is added in stirring at 0 DEG C, by potassium iodide and iodine it is soluble in water after be added drop-wise in system at 0 DEG C, equality of temperature stirring 2 Hour to the reaction was complete, obtains the iodo- 3- of (E) -1- (4- (trifluoromethyl) styryl) benzene after subsequent processing；
5) the iodo- 3- of (E) -1- being previously obtained (4- (trifluoromethyl) styryl) benzene is dissolved in suitable polar solvent In, under nitrogen protection, [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, cesium carbonate, two are added Chloromethanes and corresponding mercaptan are then heated to 80 DEG C, and reaction obtains final for 16 hours to the reaction was complete after subsequent processing Product.
Further, the inorganic base in the step 1) can be potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate etc., excellent Select potassium carbonate.
Further, palladium catalyst can be PdCl in the step 2)2, Pd (OAc)2, Pd (dppf) Cl2It is preferred that chlorination Palladium.
Further, polar solvent can be DMF, n,N-dimethylacetamide, N, N- diethyl first in the step 5) Amide, N, N- diethyl acetamides etc., preferably DMF.
Another object of the present invention discloses the Formula I and its pharmaceutically acceptable salt and/or solvate As 5-HT reuptaking inhibitors and/or 5-HT1AThe application of receptor stimulating agent.
Another object of the present invention discloses the Formula I and its pharmaceutically acceptable salt and/or solvate Application in the drug for preparing central nervous system dysfunction disease.
The compound and pharmaceutical composition provided by the invention can be used for preparing dynamic for preventing, treating or mitigating lactation Object includes the drug of the central nervous system dysfunction of the mankind, can be used for prepare for inhibit 5-HT reuptakes and/or Exciting 5-HT1AThe drug of receptor.
Specifically, the amount of compound effectively detectably can selectively inhibit 5-HT in the composition of the present invention Reuptake and to 5-HT1AReceptor has agonism, the compound of the present invention that can be used as treatment mankind's central nervous system (CNS) The drug of dysfunction such as depression, anxiety disorder.
The compound of the present invention can be applied to, but be not limited to, and use the effective of the compound of the present invention or composition Amount administers to a patient to prevent, treat or mitigate mammal, includes the central nervous system dysfunction disease of the mankind.Institute The central nervous system dysfunction disease of the mankind in response to 5-HT receptor modulators stated further comprises but and unlimited In, depression, anxiety disorder, mania, schizophrenia, sleep disturbance, bipolar disorders, besetment and behavior disorder, in terror Obstacle, posttraumatic stress disorder, dyskinesia, sex dysfunction, musculoskeletal pain obstacle, cognitive disorder, memory disorders, pa Golden Sen Shi diseases, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal symptom and premenstrualtension syndrome Deng.
Pharmaceutically acceptable salt of the present invention refers to the organic salt and inorganic salts of the compounds of this invention.Pharmaceutically may be used The salt that the nontoxic acid received is formed includes, but is not limited to, inorganic acid salt, such as hydrochloride, hydrobromate, phosphate, sulfuric acid Salt, perchlorate；Acylate, such as acetate, oxalates, maleate, tartrate, citrate, succinate, the third two Hydrochlorate；Or these salt are obtained by other methods described in the books or literature such as ion-exchange.Other can pharmaceutically connect The salt received includes adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, Borate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, second Sulfonate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, Caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, apple Hydrochlorate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfuric acid Salt, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, 11 Hydrochlorate, valerate, etc..By including alkali metal, alkaline-earth metal, ammonium and N+ (C1-4 alkane with alkali appropriate salt obtained by the reaction Base) 4 salt.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Can with the alkali metal of forming salt or Alkaline-earth metal includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises appropriate, nontoxic ammonium, season The amine cation that ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitre Acidulants, C1-8 azochlorosulfonate acid compounds and aromatic sulphonic acid compound.
Solvate of the present invention refers to that one or more solvent molecules are formed by with the compound of the present invention and form Close object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, Acetic acid and ethylaminoethanol.
Specific embodiment
Embodiment 1：(E) synthesis of -2- ((3- (4- (trifluoromethyl) styryl) phenyl) sulfenyl) quinoline
The synthesis of the iodo- 3- nitrobenzenes of 1-1,1-：
The DMF of 70mL is added in 500mL reaction bulbs, nitrobenzene (30.12g, 0.245mol) and potassium carbonate is then added (25.2g, 0.182mol) is cooled down in 10 DEG C or less ice baths, after stirring, is added drop-wise to after iodine (0.250mol) is dissolved in 30mLDMF In reaction system, time for adding is 1 hour, and reaction mixture is stirred 16 hours to the reaction was complete at 25 DEG C, is added thio The aqueous solution (150mL) of sodium sulphate (22.3g, 0.141mol) and potassium carbonate (0.150g), while maintaining interior 30 DEG C of temperature hereinafter, stirring It mixes 30 minutes, is added with stirring water 200mL, solid is precipitated, and filters, and filter cake is washed with water, and 60 DEG C are dried in vacuo 12 hours, obtain pale yellow The iodo- 3- nitrobenzenes of color solid 1-, 43.84g, yield 72%.1H-NMR(400MHz,CDCl3)δ:7.35(t,1H),8.15(d, 1H),8.20(d,1H),8.31(s,1H).13C-NMR(125MHz,CDCl3)δ:96.89,125.46,130.70,131.26, 144.68,148.36.LC-MS(ESI,pos,ion)m/z:250[M+H].
The synthesis of 1-2, (E) -1- nitros -3- (4- (trifluoromethyl) styryl) benzene：
The DMF of 200mL is added in 500mL reaction bulbs, the iodo- 3- nitre of 1- that synthesis step 1-1 is synthesized then is added Base benzene (43.84g, 0.176mol), 1- (trifluoromethyl) -4- vinyl benzenes (0.176mol), n,N-diisopropylethylamine (20.5g, 0.159mol), tri-o-tolyl phosphorus (2.23g, 0.0073mol) and palladium bichloride (0.49g, 0.0028mol), in nitrogen 100 DEG C of reactions are heated under gas shielded, and extremely the reaction was complete within 12 hours, is cooled to 45 DEG C, isopropanol 100mL is added, is stirred at 45 DEG C It mixes 30 minutes, is diluted with 500mL water, stirred 1 hour at room temperature, filter, be washed with water, filter cake is added in 120mL isopropanols, It stirs 30 minutes, is then stirred at room temperature 30 minutes at 55 DEG C, filter, filter cake is washed with cold isopropanol, 50 DEG C of vacuum It is 12 hours dry, obtain (E) -1- nitros -3- (4- (trifluoromethyl) styryl) benzene, 48.52g, yield 94.0%, fusing point 175~176 DEG C.1H-NMR(400MHz,CDCl3)δ:7.06(d,1H),7.15(d,1H),7.53(d,2H),7.69(d,2H), 7.74(t,2H),7.92(d,1H),8.11(d,1H),8.43(s,1H).13C-NMR(125MHz,CDCl3)δ:123.62, 124.42,124.67,125.45,127.87,127.90,129.14,130.50,131.91,135.09,136.35,139.21, 147.55.LC-MS(ESI,pos,ion)m/z:294[M+H].
The synthesis of 1-3, (E) -3- (4- (trifluoromethyl) styryl) aniline：
Ethyl alcohol 140mL, water 100mL and ammonium chloride (30.0g, 0.561mol), stirring and dissolving are added in 500mL reaction bulbs Addition (E) -1- nitros -3- (4- (trifluoromethyl) styryl) benzene (48.52g, 0.165mol) afterwards, addition iron powder (16.2g, 0.290mol), 50 DEG C are heated to, is stirred to react 2 hours, until the reaction was complete, 22 DEG C is cooled to, 200mL tetrahydrofurans, room is added Temperature stirring 1 hour, is filtered by diatomite, and filter cake is washed with tetrahydrofuran, and filtrate rotates to doing, and is cooled to room temperature, adds water 200mL is stirred at room temperature 1 hour, filters, filter cake petroleum ether, and 50 DEG C are dried in vacuo 12 hours, obtain light yellow solid (E) -3- (4- (trifluoromethyl) styryl) aniline, 38.49g, yield 88.6%.1H-NMR(400MHz,CDCl3)δ:3.65 (s,2H),6.39(d,1H),6.69(s,1H),6.90(d,1H),6.95(d,1H),6.99(d,1H),7.06(t,1H),7.53 (d,2H),7.69(d,2H).13C-NMR(125MHz,CDCl3)δ:113.69,116.37,118.03,123.62,125.45, 127.87,127.90,129.58,130.50,131.91,136.35,139.05,147.70.LC-MS(ESI,pos,ion)m/ z:264[M+H].
The synthesis of 1-4, the iodo- 3- of (E) -1- (4- (trifluoromethyl) styryl) benzene：
60mL water is added in 500mL reaction bulbs and sodium nitrite (7.02g, 0.102mol), stirring and dissolving are cooled to 0 DEG C, (E) -3- (4- (trifluoromethyl) styryl) aniline (38.49g, 0.146mol) is dissolved in 130mL glacial acetic acid, is then dripped It is added in reaction bulb, time for adding is 0.5 hour, and the process that is added dropwise maintains interior 0 DEG C of temperature, while stirring 1 hour, is added dropwise at 0 DEG C HCl solution (concentrated hydrochloric acid 11.2mL, water 20mL), drips off in 10 minutes, and temperature is kept to stir 1 hour, and TLC contact plates track diazol Reaction of formation (PE:EA=1：1).It is added with stirring 80mL dichloromethane at 0 DEG C；By potassium iodide (20.7g, 0.125mol) and iodine (0.792g, 0.0031mol) is dissolved in 60mL water, is added drop-wise in system at 0 DEG C, and extremely the reaction was complete within 2 hours for stirring.System is reacted Liquid is imported into the mixture of 20% hypo solution (200mL) and dichloromethane (80mL), is stirred, and layering, water phase is used The dichloromethane extraction (2*80mL) of frost, diazomethane mutually merges, and 3mol/L sodium hydroxide solution 0.35L are added dropwise, and adjusts water Ammonium hydroxide 20mL and water 40mL is added in phase pH=9~12, stirs 30 minutes, and layering, water phase extracts (2*120mL) with dichloromethane, Organic phase merges, and for revolving to doing, column chromatography purifying obtains the iodo- 3- of (E) -1- (4- (trifluoromethyl) styryl) benzene, 35.77g yield 65.4%.1H-NMR(400MHz,CDCl3)δ:6.90(d,1H),6.95(d,1H),7.09(t,1H),7.52 (d,1H),7.53(d,2H),7.61(d,1H),7.69(d,2H),7.89(s,1H).13C-NMR(125MHz,CDCl3)δ: 95.66,123.62,125.45,127.87,127.90,129.85,130.50,130.98,131.91,136.35,137.77, 139.09,140.44.LC-MS(ESI,pos,ion)m/z:375[M+H].
The synthesis of 1-5, (E) -2- ((3- (4- (trifluoromethyl) styryl) phenyl) sulfenyl) quinoline：
175mLDMF and the iodo- 3- of (E) -1- (4- (trifluoromethyl) styryl) benzene are added in 500mL reaction bulbs The complexing of [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane is added in (35.77g, 0.096mol), nitrogen protection Quinoline -2- mercaptan is added in object (1.49g, 0.0018mol), cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL (0.102mol) is heated to 80 DEG C, and to the reaction was complete, revolving removes DMF, is cooled to room temperature within 16 hours for reaction, and acetic acid second is added Ester 100mL, water 150mL are stirred 40 minutes, separate organic phase, and salt washing is layered, and organic phase is dried with sodium sulphate, is filtered, rotation It steams to dry, isolated faint yellow (E) -2- ((3- (4- (trifluoromethyl) styryl) phenyl) sulfenyl) quinoline of flash column chromatography Quinoline, 34.38g, yield 88%, fusing point：162~163 DEG C.1H-NMR(400MHz,CDCl3)δ:6.90-6.95(m,2H),7.01 (t,1H),7.16-7.31(m,3H),7.43(td,1H),7.53-7.74(m,8H),7.95(dd,1H).13C-NMR(125MHz, CDCl3)δ:121.23,122.47,123.62,125.22,125.45,126.7,127.56,127.83,127.87,127.9, 128.59,129.24,130.5,130.54,131.14,131.91,134.24,136.35,137.29,138,150.79, 159.13.LC-MS(ESI,pos,ion)m/z:408[M+H]。
Embodiment 2：(E) synthesis of -2- ((3- (4- (trifluoromethyl) styryl) phenyl) sulfenyl) -4- oxyquinolines：
175mLDMF and the iodo- 3- of (E) -1- (4- (trifluoromethyl) styryl) benzene are added in 500mL reaction bulbs The complexing of [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane is added in (35.77g, 0.096mol), nitrogen protection 4- Hydroxy-quinolin -2- sulphur is added in object (1.49g, 0.0018mol), cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL Alcohol (0.102mol) is heated to 80 DEG C, and to the reaction was complete, revolving removes DMF, is cooled to room temperature within 16 hours for reaction, and acetic acid is added Ethyl ester 100mL, water 150mL are stirred 40 minutes, separate organic phase, and salt washing is layered, and organic phase is dried with sodium sulphate, is filtered, It rotates to dry, isolated faint yellow (the E) -2- ((3- (4- (trifluoromethyl) styryl) phenyl) sulfenyl)-of flash column chromatography 4- oxyquinolines, 33.30g, yield 82%.LC-MS(ESI,pos,ion)m/z:424[M+H].
Embodiment 3：(E) synthesis of -2- ((3- (4- (trifluoromethyl) styryl) phenyl) sulfenyl) fluoro- quinoline of -4-：
175mLDMF and the iodo- 3- of (E) -1- (4- (trifluoromethyl) styryl) benzene are added in 500mL reaction bulbs The complexing of [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane is added in (35.77g, 0.096mol), nitrogen protection Fluoro- quinoline -2- the mercaptan of 4- is added in object (1.49g, 0.0018mol), cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL (0.102mol) is heated to 80 DEG C, and to the reaction was complete, revolving removes DMF, is cooled to room temperature within 16 hours for reaction, and acetic acid second is added Ester 100mL, water 150mL are stirred 40 minutes, separate organic phase, and salt washing is layered, and organic phase is dried with sodium sulphate, is filtered, rotation It steams to dry, isolated faint yellow (E) -2- ((3- (4- (trifluoromethyl) styryl) phenyl) the sulfenyl) -4- of flash column chromatography Fluoro- quinoline, 37.13g, yield 91%.LC-MS(ESI,pos,ion)m/z:426[M+H].
Embodiment 4：(E) conjunction of -2- ((3- (4- (trifluoromethyl) styryl) phenyl) sulfenyl) -4,5- difluoro-quinolins At：
175mLDMF and the iodo- 3- of (E) -1- (4- (trifluoromethyl) styryl) benzene are added in 500mL reaction bulbs The complexing of [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane is added in (35.77g, 0.096mol), nitrogen protection 4,5- difluoro-quinolins -2- is added in object (1.49g, 0.0018mol), cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL Mercaptan (0.102mol) is heated to 80 DEG C, and to the reaction was complete, revolving removes DMF, is cooled to room temperature within 16 hours for reaction, and second is added Acetoacetic ester 100mL, water 150mL are stirred 40 minutes, separate organic phase, and salt washing is layered, and organic phase is dried with sodium sulphate, mistake Filter, revolving to dry, isolated faint yellow (E) -2- ((3- (4- (trifluoromethyl) styryl) phenyl) sulphur of flash column chromatography Base) -4,5- difluoro-quinolins, 39.13g, yield 92%.LC-MS(ESI,pos,ion)m/z:444[M+H].
Test example 1：Compound in synaptosomes in rat brain in vivo to [3H] 5-HT intake inhibiting effect
Under the conditions of 37 DEG C, to buffer solution (6.2mM NaCl, 4.5mM KCl, 2.25mM MgSO4, 1.08mM NaH2PO4, 2.5mM NaHCO3, 9.9mM glucose, 9 μM of EGTA, 45 μM of ascorbicacid (pH7.4)), synaptosome (150 μ g) and 0.1 μ Ci [3H] in the mixed system that is formed of serotonin, test compound or positive drug or negative right is added According to, altogether be incubated 15 minutes.
Imipramine is added 10 as the standard positive drug for inhibiting serotonin intake in above-mentioned identical mixed system μM imipramine, blocking 5-hydroxytryptamine intake, is incubated 15 minutes under the conditions of 4 DEG C, to measure Basal control activity value.Pass through reality It tests, tests intake inhibiting value of the imipramine to rat brain synaptosome of various concentration, produce suppression curve.
Sample after incubation passes through glass fibers under vacuum with 96 like cell collectors (Unifilter, Packard) Filter membrane (GF/B, Packard) fast filtering is tieed up, and is rinsed twice in ice-cold incubation buffer, is dissociated to elimination [3H] serotonin.Dry filter membrane, in scintillation counter (Topcount, Packard), with scintillation solution (Microscint0, Packard remaining radioactivity) is calculated.Experimental result with relative to control group [3H] serotonin intake suppression percentage It indicates.
The SERT transporters inhibiting effect of synaptosomes in rat brain in vivo by [3H] concentration of 5-HT weighs.Test-compound needs It in the case of concentration is more than 6log, at least tests twice, data carry out nonlinear regression analysis through Hill equation curves, obtain IC50Value. As a result referring to table 1.
1 the compounds of this invention of table in synaptosomes in rat brain in vivo to [3H] 5-HT intake inhibiting effect
Experimental result shows, the compounds of this invention to [3H] 5-HT reuptakes have preferable inhibitory activity, can conduct 5-HT reuptaking inhibitors carry out more in-depth study.
Test example 2：h5-HT1ABinding affinity is tested
Under the conditions of 22 DEG C, to people's HEK-293 cell membrane homogenates, 36 μ g albumen, 0.3nM [3H] 8-OH-DPAT (Perkin-Elmer) and buffer solution (50mM Tris-HCl (pH7.4), 10mM MgSO4, 0.5mM EDTA, 2 μ g/ml Aprotinine) in the mixed system formed, it is added or is added without test compound, is incubated 60 minutes altogether.
Standard reference compound is 8-OH-DPAT, and in the mixed system of above-mentioned condition, 10 μM of 8-OH-DPAT are added, For measuring non-specific binding value.By the data of the 8-OH-DPAT of different experiments test series concentration, obtain competitive bent Line.
Sample after incubation is with 96 like cell collectors (Unifilter, Packard) under vacuum by pre- dipped Glass fiber filter (GF/B, Packard) fast filtering of 0.3%PEI, and rushed repeatedly using ice-cold 50mM Tris-HCl It washes several times.Dry filter membrane, in scintillation counter (Topcount, Packard), with scintillation solution (Microscint0, Packard remaining radioactivity) is calculated.Inhibition hundred of the experimental result to be specifically bound relative to control group radioligand Divide than indicating.
[3H] 8-OH-DPAT (0.3nM) and 5-HT in people's HEK-293 cells1AThe flicker that the combination experiment of receptor passes through film Proximity test method is completed.Test-compound needs in concentration to be more than 6log, at least tests three times, data are through the side Hill Journey curve carries out nonlinear regression analysis, obtains IC50Value, then calculated through ChengPrusoff equations, obtain Ki values.As a result referring to table 2。
2 the compounds of this invention of table is to 5-HT1AThe binding affinity of receptor
Experimental result shows that the compounds of this invention is to 5-HT1AReceptor shows stronger binding affinity, the present invention Compound has 5-HT1AReceptor stimulating agent acts on, and can be used as 5-HT1AReceptor stimulating agent carries out drug development.

Claims (7)

1. a kind of Formula I, structure are
Wherein：R1、R2、R3、R4It is independently selected from H, F Or OH.
2. the pharmaceutically acceptable salt or solvate of Formula I as described in claim 1.
3. Formula I as described in claim 1, characterized in that be selected from following compound：
4. the synthetic route of Formula I as described in claim 1 is：
5. Formula I as claimed in claim 1 or 2 is used as 5-HT reuptaking inhibitors and/or 5-HT1AReceptor stimulating agent Using.
6. Formula I as claimed in claim 1 or 2 is in the drug for preparing central nervous system dysfunction disease Using.
7. application as claimed in claim 6, which is characterized in that the central nervous system dysfunction disease is selected from depression Disease, anxiety disorder, mania, schizophrenia, sleep disturbance, bipolar disorders, besetment and behavior disorder, panic disorder, wound Stress disorders, dyskinesia, sex dysfunction, musculoskeletal pain obstacle, cognitive disorder, memory disorders, op parkinson's after wound Disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal symptom and premenstrualtension syndrome.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1858852B1 (en) * 2005-03-09 2009-07-01 MERCK SHARP & DOHME LTD. Heteroarylsulfonyl stilbenes as 5-ht2a antagonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1858852B1 (en) * 2005-03-09 2009-07-01 MERCK SHARP & DOHME LTD. Heteroarylsulfonyl stilbenes as 5-ht2a antagonists

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