CN108570004A - A kind of compound that there is double action to 5-HT and its application in treating depression - Google Patents
A kind of compound that there is double action to 5-HT and its application in treating depression Download PDFInfo
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Abstract
The invention discloses it is a kind of to 5 HT have double action compound and its application in 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
Technical field
The invention belongs to chemical medicines, are related to a kind of to compounds of the 5-HT with double action and its in treatment suppression
Application in strongly fragrant disease.
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、R4It is independently selected from H, F or OH.The present invention
Further relate to the pharmaceutically acceptable salt or solvate of the Formula I.
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 1,1- diphenylethlenes, N, N- diisopropyls
Base ethamine, tri-o-tolyl phosphorus and palladium catalyst are placed in reaction bulb, are heated to 100 DEG C under nitrogen protection and are reacted 12 hours extremely
The reaction was complete, and (E) -1- nitros -3- (2,2- Diphenyl-vinyl) benzene can be obtained through subsequent processing；
3) (E) -1- nitros -3- (2,2- bis- obtained in the previous step then will be added after ethyl alcohol, water and ammonium chloride stirring and dissolving
Phenyl-ethenyl) benzene, be then added iron powder, heating makes it, and the reaction was complete, through subsequent processing obtain light yellow solid (E) -3- (2,
2- Diphenyl-vinyls) aniline；
4) it 1. is cooled to 0 DEG C by after sodium nitrite in water stirring and dissolving, (E) -3- (2, the 2- hexichol that will be previously obtained
Base-vinyl) 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 is small
Up to the reaction was complete, after subsequent processing (E) -1- iodo- 3- (2,2- Diphenyl-vinyl) benzene；
5) (E) -1- iodo- 3- (2, the 2- Diphenyl-vinyl) benzene being previously obtained is dissolved in suitable polar solvent,
Under nitrogen protection, [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, cesium carbonate, dichloromethane is added
Alkane and corresponding mercaptan are then heated to 80 DEG C, and reaction is finally produced to the reaction was complete after subsequent processing for 16 hours
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- (2,2- Diphenyl-vinyls) 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 (22.5g, 0.183mol) and potassium carbonate is then added
(25.2g, 0.182mol) is cooled down in 10 DEG C or less ice baths, after stirring, after iodine (41.6g, 0.164mol) is dissolved in 30mLDMF
It is added drop-wise 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
Enter the aqueous solution (150mL) of sodium thiosulfate (22.3g, 0.141mol) and potassium carbonate (0.150g), while maintaining interior 30 DEG C of temperature
Hereinafter, stirring 30 minutes, it is added with stirring water 200mL, solid is precipitated, and filters, and filter cake is washed with water, and 60 DEG C of vacuum drying 12 are small
When, obtain the iodo- 3- nitrobenzenes of light yellow solid 1-, 43.84g, yield 96.2%.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- (2,2- Diphenyl-vinyls) 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), 1,1- diphenylethlenes (0.176mol), n,N-diisopropylethylamine (20.5g,
0.159mol), tri-o-tolyl phosphorus (2.23g, 0.0073mol) and palladium bichloride (0.49g, 0.0028mol), under nitrogen protection
Being heated to 100 DEG C of reactions, extremely the reaction was complete in 12 hours, is cooled to 45 DEG C, isopropanol 100mL is added, 30 points are stirred at 45 DEG C
Clock is diluted with 500mL water, is stirred 1 hour at room temperature, is filtered, is washed with water, filter cake is added in 120mL isopropanols, at 55 DEG C
Lower stirring 30 minutes, is then stirred at room temperature 30 minutes, filters, and filter cake is washed with cold isopropanol, 50 DEG C of vacuum drying 12
Hour, obtain (E) -1- nitros -3- (2,2- Diphenyl-vinyl) benzene, 47.15g, yield 89%.1H-NMR(400MHz,
CDCl3)δ:6.79(s,1H),7.22-7.38(m,10H),7.74(t,3H),7.92(td,1H),8.11(td,1H),8.43
(t,1H).13C-NMR(125MHz,CDCl3)δ:124.84,125.28,126.61,126.85,128,128.09,129.09,
134.25,137.57,138.39,139.7,141.07,147.17.LC-MS(ESI,pos,ion)m/z:302[M+H].
The synthesis of 1-3, (E) -3- (2,2- Diphenyl-vinyls) 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- (2,2- Diphenyl-vinyl) benzene (47.15g, 0.157mol) 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- (2,2- Diphenyl-vinyl) aniline, 38.72g, yield 91%.1H-NMR(400MHz,CDCl3)δ:3.53(s,
2H),6.39(dt,1H),6.69(t,1H),6.76(s,1H),6.99-7.06(m,2H),7.22-7.38(m,10H).13C-NMR
(125MHz,CDCl3)δ:115.01,116.79,119.29,125.28,126.61,128,128.09,129.71,136.52,
138.39,139.7,141.07,148.59.LC-MS(ESI,pos,ion)m/z:272[M+H].
The synthesis of 1-4, (E) -1- iodo- 3- (2,2- Diphenyl-vinyls) 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- (2,2- Diphenyl-vinyl) aniline (38.72g, 0.143mol) is dissolved in 130mL glacial acetic acid, is then added drop-wise to
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, and it is molten that HCl is added dropwise at 0 DEG C
Liquid (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 and generate
React (PE:EA=1：1).It is added with stirring 80mL dichloromethane at 0 DEG C；By potassium iodide (0.150mol) and iodine (0.792g,
It 0.0031mol) is dissolved in 60mL water, is added drop-wise in system at 0 DEG C, extremely the reaction was complete within 2 hours for stirring.System reaction solution is imported into
It in the mixture of 20% hypo solution (200mL) and dichloromethane (80mL), stirs, layering, the two of water phase frost
Chloromethanes extracts (2*80mL), and diazomethane mutually merges, dropwise addition 3mol/L sodium hydroxide solution 0.35L, and adjusting water phase pH=9~
12, ammonium hydroxide 20mL and water 40mL is added, stirs 30 minutes, layering, water phase extracts (2*120mL) with dichloromethane, organic to be harmonious
And rotate to doing, column chromatography purifying obtains (E) -1- iodo- 3- (2,2- Diphenyl-vinyl) benzene, 38.78g, yield 71%.1H-NMR(400MHz,CDCl3)δ:6.71(s,1H),7.09(t,1H),7.22-7.38(m,10H),7.52(dt,1H),7.61
(dt,1H),7.83(t,1H).13C-NMR(125MHz,CDCl3)δ:95.66,125.28,126.61,128,128.09,
130.55,132.24,137.32,138.39,138.45,139.7,140.04,141.07.LC-MS(ESI,pos,ion)m/z:
383[M+H].
The synthesis of 1-5, (E) -2- ((3- (2,2- Diphenyl-vinyls) phenyl) sulfenyl) quinoline：
Be added in 500mL reaction bulbs 175mLDMF and (E) -1- iodo- 3- (2,2- Diphenyl-vinyl) benzene (38.78g,
0.102mol), nitrogen protection, addition [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (1.49g,
0.0018mol), quinoline -2- mercaptan (0.105mol), heating is added in cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL
To 80 DEG C, to the reaction was complete, revolving removes DMF, is cooled to room temperature within 16 hours for reaction, and ethyl acetate 100mL, water 150mL is added,
Stirring 40 minutes separates organic phase, and salt washing is layered, and organic phase is dried with sodium sulphate, is filtered, revolving to dry, flash column chromatography
Isolated faint yellow (E) -2- ((3- (2,2- Diphenyl-vinyl) phenyl) sulfenyl) quinoline, 32.17g, yield 76%.1H-
NMR(400MHz,CDCl3)δ:6.56(s,1H),7.01(t,1H),7.16-7.43(m,14H),7.58-7.74(m,4H),
7.95(dd,1H).13C-NMR(125MHz,CDCl3)δ:122.47,125.28,126.51,126.61,126.7,127.56,
127.83,128,128.09,128.65,129.66,130.54,131.09,134.86,137.29,138.39,139.38,
139.7,141.07,150.79,159.13.LC-MS(ESI,pos,ion)m/z:416[M+H]。
Embodiment 2：(E) synthesis of -2- ((3- (2,2- Diphenyl-vinyls) phenyl) sulfenyl) -4- Hydroxy-quinolins：
Be added in 500mL reaction bulbs 175mLDMF and (E) -1- iodo- 3- (2,2- Diphenyl-vinyl) benzene (38.78g,
0.102mol), nitrogen protection, addition [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (1.49g,
0.0018mol), 4- Hydroxy-quinolin -2- mercaptan is added in cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL
(0.105mol) 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- (2,2- Diphenyl-vinyl) phenyl) the sulfenyl) -4- hydroxyls of flash column chromatography
Yl-quinoline, 34.29g, yield 78%.LC-MS(ESI,pos,ion)m/z:432[M+H].
Embodiment 3：(E) synthesis of -2- ((3- (2,2- Diphenyl-vinyls) phenyl) sulfenyl) fluoro- quinoline of -4-：
Be added in 500mL reaction bulbs 175mLDMF and (E) -1- iodo- 3- (2,2- Diphenyl-vinyl) benzene (38.78g,
0.102mol), nitrogen protection, addition [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (1.49g,
0.0018mol), the fluoro- quinoline -2- mercaptan of 4- is added in cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL
(0.105mol) 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 doing, isolated faint yellow (E) -2- ((3- (2,2- Diphenyl-vinyl) phenyl) the sulfenyl) -4- of flash column chromatography is fluoro-
Quinoline, 34.89g, yield 79%.LC-MS(ESI,pos,ion)m/z:434[M+H].
Embodiment 4：(E) synthesis of -2- ((3- (2,2- Diphenyl-vinyls) phenyl) sulfenyl) -4,5- difluoro-quinolins：
Be added in 500mL reaction bulbs 175mLDMF and (E) -1- iodo- 3- (2,2- Diphenyl-vinyl) benzene (38.78g,
0.102mol), nitrogen protection, addition [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (1.49g,
0.0018mol), 4,5- difluoro-quinolin -2- mercaptan is added in cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL
(0.105mol) 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- (2,2- Diphenyl-vinyl) phenyl) sulfenyl) -4, the 5- bis- of flash column chromatography
Fluoro- quinoline, 38.18g, yield 83%.LC-MS(ESI,pos,ion)m/z:452[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, 1.08mMNaH2PO4,
2.5mM NaHCO3, 9.9mM glucose, 9 μM of EGTA, 45 μM of ascorbicacid (pH7.4)), synaptosome (150 μ g) with
0.1μCi[3H] in the mixed system that is formed of serotonin, test compound or positive drug or negative control is added, is incubated altogether
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, use
In 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.It is a kind of to 5-HT
Compound with double action and its application in treating depression
Technical field
The invention belongs to chemical medicines, are related to a kind of to compounds of the 5-HT with double action and its in treatment suppression
Application in strongly fragrant disease.
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、R4It is independently selected from H, F or OH.The present invention
Further relate to the pharmaceutically acceptable salt or solvate of the Formula I.
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 1,1- diphenylethlenes, N, N- diisopropyls
Base ethamine, tri-o-tolyl phosphorus and palladium catalyst are placed in reaction bulb, are heated to 100 DEG C under nitrogen protection and are reacted 12 hours extremely
The reaction was complete, and (E) -1- nitros -3- (2,2- Diphenyl-vinyl) benzene can be obtained through subsequent processing；
3) (E) -1- nitros -3- (2,2- bis- obtained in the previous step then will be added after ethyl alcohol, water and ammonium chloride stirring and dissolving
Phenyl-ethenyl) benzene, be then added iron powder, heating makes it, and the reaction was complete, through subsequent processing obtain light yellow solid (E) -3- (2,
2- Diphenyl-vinyls) aniline；
4) it 1. is cooled to 0 DEG C by after sodium nitrite in water stirring and dissolving, (E) -3- (2, the 2- hexichol that will be previously obtained
Base-vinyl) 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 is small
Up to the reaction was complete, after subsequent processing (E) -1- iodo- 3- (2,2- Diphenyl-vinyl) benzene；
5) (E) -1- iodo- 3- (2, the 2- Diphenyl-vinyl) benzene being previously obtained is dissolved in suitable polar solvent,
Under nitrogen protection, [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, cesium carbonate, dichloromethane is added
Alkane and corresponding mercaptan are then heated to 80 DEG C, and reaction is finally produced to the reaction was complete after subsequent processing for 16 hours
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- (2,2- Diphenyl-vinyls) 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 (22.5g, 0.183mol) and potassium carbonate is then added
(25.2g, 0.182mol) is cooled down in 10 DEG C or less ice baths, after stirring, after iodine (41.6g, 0.164mol) is dissolved in 30mLDMF
It is added drop-wise 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
Enter the aqueous solution (150mL) of sodium thiosulfate (22.3g, 0.141mol) and potassium carbonate (0.150g), while maintaining interior 30 DEG C of temperature
Hereinafter, stirring 30 minutes, it is added with stirring water 200mL, solid is precipitated, and filters, and filter cake is washed with water, and 60 DEG C of vacuum drying 12 are small
When, obtain the iodo- 3- nitrobenzenes of light yellow solid 1-, 43.84g, yield 96.2%.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- (2,2- Diphenyl-vinyls) 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), 1,1- diphenylethlenes (0.176mol), n,N-diisopropylethylamine (20.5g,
0.159mol), tri-o-tolyl phosphorus (2.23g, 0.0073mol) and palladium bichloride (0.49g, 0.0028mol), under nitrogen protection
Being heated to 100 DEG C of reactions, extremely the reaction was complete in 12 hours, is cooled to 45 DEG C, isopropanol 100mL is added, 30 points are stirred at 45 DEG C
Clock is diluted with 500mL water, is stirred 1 hour at room temperature, is filtered, is washed with water, filter cake is added in 120mL isopropanols, at 55 DEG C
Lower stirring 30 minutes, is then stirred at room temperature 30 minutes, filters, and filter cake is washed with cold isopropanol, 50 DEG C of vacuum drying 12
Hour, obtain (E) -1- nitros -3- (2,2- Diphenyl-vinyl) benzene, 47.15g, yield 89%.1H-NMR(400MHz,
CDCl3)δ:6.79(s,1H),7.22-7.38(m,10H),7.74(t,3H),7.92(td,1H),8.11(td,1H),8.43
(t,1H).13C-NMR(125MHz,CDCl3)δ:124.84,125.28,126.61,126.85,128,128.09,129.09,
134.25,137.57,138.39,139.7,141.07,147.17.LC-MS(ESI,pos,ion)m/z:302[M+H].
The synthesis of 1-3, (E) -3- (2,2- Diphenyl-vinyls) 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- (2,2- Diphenyl-vinyl) benzene (47.15g, 0.157mol) 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- (2,2- Diphenyl-vinyl) aniline, 38.72g, yield 91%.1H-NMR(400MHz,CDCl3)δ:3.53(s,
2H),6.39(dt,1H),6.69(t,1H),6.76(s,1H),6.99-7.06(m,2H),7.22-7.38(m,10H).13C-NMR
(125MHz,CDCl3)δ:115.01,116.79,119.29,125.28,126.61,128,128.09,129.71,136.52,
138.39,139.7,141.07,148.59.LC-MS(ESI,pos,ion)m/z:272[M+H].
The synthesis of 1-4, (E) -1- iodo- 3- (2,2- Diphenyl-vinyls) 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- (2,2- Diphenyl-vinyl) aniline (38.72g, 0.143mol) is dissolved in 130mL glacial acetic acid, is then added drop-wise to
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, and it is molten that HCl is added dropwise at 0 DEG C
Liquid (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 and generate
React (PE:EA=1：1).It is added with stirring 80mL dichloromethane at 0 DEG C；By potassium iodide (0.150mol) and iodine (0.792g,
It 0.0031mol) is dissolved in 60mL water, is added drop-wise in system at 0 DEG C, extremely the reaction was complete within 2 hours for stirring.System reaction solution is imported into
It in the mixture of 20% hypo solution (200mL) and dichloromethane (80mL), stirs, layering, the two of water phase frost
Chloromethanes extracts (2*80mL), and diazomethane mutually merges, dropwise addition 3mol/L sodium hydroxide solution 0.35L, and adjusting water phase pH=9~
12, ammonium hydroxide 20mL and water 40mL is added, stirs 30 minutes, layering, water phase extracts (2*120mL) with dichloromethane, organic to be harmonious
And rotate to doing, column chromatography purifying obtains (E) -1- iodo- 3- (2,2- Diphenyl-vinyl) benzene, 38.78g, yield 71%.1H-NMR(400MHz,CDCl3)δ:6.71(s,1H),7.09(t,1H),7.22-7.38(m,10H),7.52(dt,1H),7.61
(dt,1H),7.83(t,1H).13C-NMR(125MHz,CDCl3)δ:95.66,125.28,126.61,128,128.09,
130.55,132.24,137.32,138.39,138.45,139.7,140.04,141.07.LC-MS(ESI,pos,ion)m/z:
383[M+H].
The synthesis of 1-5, (E) -2- ((3- (2,2- Diphenyl-vinyls) phenyl) sulfenyl) quinoline：
Be added in 500mL reaction bulbs 175mLDMF and (E) -1- iodo- 3- (2,2- Diphenyl-vinyl) benzene (38.78g,
0.102mol), nitrogen protection, addition [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (1.49g,
0.0018mol), quinoline -2- mercaptan (0.105mol), heating is added in cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL
To 80 DEG C, to the reaction was complete, revolving removes DMF, is cooled to room temperature within 16 hours for reaction, and ethyl acetate 100mL, water 150mL is added,
Stirring 40 minutes separates organic phase, and salt washing is layered, and organic phase is dried with sodium sulphate, is filtered, revolving to dry, flash column chromatography
Isolated faint yellow (E) -2- ((3- (2,2- Diphenyl-vinyl) phenyl) sulfenyl) quinoline, 32.17g, yield 76%.1H-
NMR(400MHz,CDCl3)δ:6.56(s,1H),7.01(t,1H),7.16-7.43(m,14H),7.58-7.74(m,4H),
7.95(dd,1H).13C-NMR(125MHz,CDCl3)δ:122.47,125.28,126.51,126.61,126.7,127.56,
127.83,128,128.09,128.65,129.66,130.54,131.09,134.86,137.29,138.39,139.38,
139.7,141.07,150.79,159.13.LC-MS(ESI,pos,ion)m/z:416[M+H]。
Embodiment 2：(E) synthesis of -2- ((3- (2,2- Diphenyl-vinyls) phenyl) sulfenyl) -4- Hydroxy-quinolins：
Be added in 500mL reaction bulbs 175mLDMF and (E) -1- iodo- 3- (2,2- Diphenyl-vinyl) benzene (38.78g,
0.102mol), nitrogen protection, addition [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (1.49g,
0.0018mol), 4- Hydroxy-quinolin -2- mercaptan is added in cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL
(0.105mol) 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- (2,2- Diphenyl-vinyl) phenyl) the sulfenyl) -4- hydroxyls of flash column chromatography
Yl-quinoline, 34.29g, yield 78%.LC-MS(ESI,pos,ion)m/z:432[M+H].
Embodiment 3：(E) synthesis of -2- ((3- (2,2- Diphenyl-vinyls) phenyl) sulfenyl) fluoro- quinoline of -4-：
Be added in 500mL reaction bulbs 175mLDMF and (E) -1- iodo- 3- (2,2- Diphenyl-vinyl) benzene (38.78g,
0.102mol), nitrogen protection, addition [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (1.49g,
0.0018mol), the fluoro- quinoline -2- mercaptan of 4- is added in cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL
(0.105mol) 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 doing, isolated faint yellow (E) -2- ((3- (2,2- Diphenyl-vinyl) phenyl) the sulfenyl) -4- of flash column chromatography is fluoro-
Quinoline, 34.89g, yield 79%.LC-MS(ESI,pos,ion)m/z:434[M+H].
Embodiment 4：(E) synthesis of -2- ((3- (2,2- Diphenyl-vinyls) phenyl) sulfenyl) -4,5- difluoro-quinolins：
Be added in 500mL reaction bulbs 175mLDMF and (E) -1- iodo- 3- (2,2- Diphenyl-vinyl) benzene (38.78g,
0.102mol), nitrogen protection, addition [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (1.49g,
0.0018mol), 4,5- difluoro-quinolin -2- mercaptan is added in cesium carbonate (19.8g, 0.061mol) and dichloromethane 2mL
(0.105mol) 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- (2,2- Diphenyl-vinyl) phenyl) sulfenyl) -4, the 5- bis- of flash column chromatography
Fluoro- quinoline, 38.18g, yield 83%.LC-MS(ESI,pos,ion)m/z:452[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, use
In 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810532966.8A CN108570004A (en) | 2018-05-29 | 2018-05-29 | A kind of compound that there is double action to 5-HT and its application in treating depression |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810532966.8A CN108570004A (en) | 2018-05-29 | 2018-05-29 | A kind of compound that there is double action to 5-HT and its application in treating depression |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108570004A true CN108570004A (en) | 2018-09-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810532966.8A Withdrawn CN108570004A (en) | 2018-05-29 | 2018-05-29 | A kind of compound that there is double action to 5-HT and its application in treating depression |
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| Country | Link |
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| CN (1) | CN108570004A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113284553A (en) * | 2021-05-28 | 2021-08-20 | 南昌大学 | Method for testing binding capacity of drug target for treating drug addiction |
Citations (1)
| 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 |
-
2018
- 2018-05-29 CN CN201810532966.8A patent/CN108570004A/en not_active Withdrawn
Patent Citations (1)
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113284553A (en) * | 2021-05-28 | 2021-08-20 | 南昌大学 | Method for testing binding capacity of drug target for treating drug addiction |
| CN113284553B (en) * | 2021-05-28 | 2023-01-10 | 南昌大学 | Method for testing binding capacity of drug target for treating drug addiction |
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Application publication date: 20180925 |