CN105461608A - Indoline-2-ketone D3 receptor ligand and preparation method and application thereof - Google Patents

Indoline-2-ketone D3 receptor ligand and preparation method and application thereof Download PDF

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CN105461608A
CN105461608A CN201510818705.9A CN201510818705A CN105461608A CN 105461608 A CN105461608 A CN 105461608A CN 201510818705 A CN201510818705 A CN 201510818705A CN 105461608 A CN105461608 A CN 105461608A
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compound
indolin
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receptors ligand
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CN105461608B (en
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蔡进
吉民
周本华
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Southeast University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Abstract

The invention discloses an indoline-2-ketone D3 receptor ligand, which is a compound as shown in the formula I or pharmaceutical salt thereof, wherein n=2 or 3; R represents H, 4-CH3, 2,3-diCH3, 2-CH3, 4-OCF3, 3-OCH3, 3,4-diCH3 or 4-Cl. In comparison with the prior art, the compound has a strong activity to a dopamine D3 receptor, is used in treating or preventing central nervous and metal diseases such as schizophrenia, Parkinson's disease, drug dependence and relapse, etc., can be used in neuroprotection, and is used as a tool drug for researching D3 receptor structure, function and diseases related to D3 receptor dysfunction.

Description

Indolin-2-one class D3 receptors ligand and its production and use
Technical field
The present invention relates to a kind of Indolin-2-one class D3 receptors ligand and its production and use, belong to technical field of medicine synthesis.
Background technology
Dopamine HCL is neurotransmitter important in central nervous system, relevant with various diseases such as Parkinson's disease (PD), huntington disease, schizophrenia (SCZD).Dopamine Receptors is divided into D1, D2, D3, D4 and D5 totally 5 kinds of different receptor subtypes, has the amino acid sequence homology of height, make to develop the dopamine receptor ligands having high-affinity and highly selective concurrently and be extremely important in trans-membrane region.But the high consistency of sequence in dopamine D 3 and D2 receptor transmembrane monocycle, is especially inferred to be the intimate identity of the residue forming binding site, makes to develop the D3 receptor selective compound with quasi-medicated property physico-chemical property very difficult in these acceptors.
The s-generation non-ergotine compounds pramipexole, Ropinirole by single or with combined with levodopa medication, effectively can treat Parkinson's disease.But, the same with other medicines, D3 receptors ligand, while performance therapeutic action, also has side effect in various degree, the Drug side reactions such as generation is such as felt sick, illusion.Generally use atypia anti-schizophrenia medicine clinically, as sulfanilamide (SN) must the pharmacological agent schizophrenia such as profit, leoponex, achieve good effect.
The clinical treatment of drug habit seems and has difficulty in walking for a long time, never finds effective especially methods for the treatment of.At present, the main method for the treatment of drug habit is both at home and abroad detoxification or controls drug rehabilitation symptom, and non-drug therapy seldom uses.Recent study finds, the D3 acceptor portion agonists such as BP897, NGB2904, S33138 and antagonist illustrate a gleam of hope in treatment of drug addiction, but, really to obtain the final success of clinical diagnosis and treatment aspect, still facing multiple difficulty, is shoulder heavy responsibilities.
Summary of the invention
Goal of the invention: in order to solve the problems of the technologies described above, the invention provides a kind of Indolin-2-one class D3 receptors ligand and its production and use.
Technical scheme: in order to realize foregoing invention object, the invention discloses a kind of Indolin-2-one class D3 receptors ligand, shown in I:
Or its pharmaceutical salts,
Wherein, n=2 or 3; R represents H, 4-CH 3, 2,3-diCH 3, 2-CH 3, 4-OCF 3, 3-OCH 3, 3,4-diCH 3or 4-Cl.
As preferably, during described n=2, R is 3-OCH 3, 4-Cl, 4-OCF 3, H or 3,4-diCH 3; During n=3, R is H, 4-CH 3, 2,3-diCH 3, 2-CH 3, 4-OCF 3, 3-OCH 3or 3,4-diCH 3.
Preferred compound, as shown in table 1:
Table 1 melting point compound and yield
afinal step yield; bthick thing.
Present invention also offers the application in the medicine of preparation treatment or prevention Nervous and mental diseases, neuroprotective, treatment and D3 receptor dysfunction diseases related of described Indolin-2-one class D3 receptors ligand or its pharmaceutical salts.
As preferably, described Nervous and mental diseases is Parkinson's disease, schizophrenia, pharmacological dependence or peaceful restless leg syndrome; Described is schizophrenia, Parkinson's disease, pharmacological dependence or drug habit, various forms of stress, anxiety, somnopathy or male sexual disorder with D3 receptor dysfunction diseases related.
The present invention still further provides described Indolin-2-one class D3 receptors ligand or its pharmaceutical salts for the preparation of research D3 receptor structure, function and with the application in the instrument medicine of D3 receptor dysfunction diseases related.
The invention provides a kind of pharmaceutical composition, containing Indolin-2-one class D3 receptors ligand described at least one or its pharmaceutical salts, and pharmaceutical carrier or vehicle.
As preferably, described pharmaceutical composition is injection, infusion solution, dripping pill, tablet, capsule, granule or oral liquid.
The present invention finally provides the preparation method of described Indolin-2-one class D3 receptors ligand, and described Indolin-2-one class D3 receptors ligand is that reaction formula is as follows made by compound 3 and compound 2 react:
As preferably, described compound 3 be by compound 4 made by the following series reaction:
Wherein, in compound 6, R is H, 4-CH 3, 2,3-diCH 3, 2-CH 3, 4-OCF 3, 3-OCH 3, 3,4-diCH 3or 4-Cl.
As preferably, described compound 2 is by compound 9 through following series reaction, made by last separation and purification or recrystallizing and refining:
The synthetic method of above-mentioned preferred compound as:
(1) synthesis of intermediate 1i-1l:
As shown in following reaction stream formula, the aniline that compound (6) replaces for various functional group, R is various substituting group (group), in table 1.Starting raw material diethanolamine, through series reaction, obtains each intermediate 1i-1l.Wherein each step reagent and condition are: (i) sulfur oxychloride, chloroform, 1-8 hour, room temperature, 0.5-5 hour, backflow; 80-95%; (ii) propyl carbinol, salt of wormwood, 40-100 hour, backflow, 60-80%; (iii) sodium hydroxide, water, pH=12,90-97%; (iv) the bromo-3-chloropropane of 1-, salt of wormwood, acetone, 1-5 hour, 0-60 DEG C, 0.5-5 hour, backflow, 50-70%; The bromo-2-monochloroethane of (v) 1-, salt of wormwood, acetone, 1-5 hour, 0-50 DEG C, 0.5-3 hour, backflow, 40-70%; (vi) salt of wormwood, acetone, 2-7 hour, 0-55 DEG C, 0.5-4 hour, backflow, 50-70%.
(2) synthesis of intermediate 2:
As shown in following reaction stream formula, by compound (9) through series reaction, finally obtain key intermediate (2).The finished product can through column chromatographic isolation and purification or organic solvent recrystallizing and refining.Wherein each step reagent and condition are: (i) zinc chloride, Benzoyl chloride, methylene dichloride, 1-5 hour, backflow, 85%-100%; (ii) methyl-sulphoxide, sodium bicarbonate, 1-5 hour, 100-130 DEG C, 60-80%. (iii) Nitromethane 99Min., n-Butyl Amine 99, acetic acid, methyl alcohol, 10-25 hour, 0-50 DEG C, 53%-80%. (iv) iron trichloride, chloracetyl, methylene dichloride, 1-3 hour ,-10-10 DEG C, 50%-70%; (v) hydrazine hydrate, methyl alcohol, 10% palladium charcoal, 1-5h, backflow; Sodium hydroxide, water, 1-5 hour, backflow, 64%-90%; (vi) Tosyl chloride, pyridine, methylene dichloride, 1-6 hour, 0-50 DEG C, 80%-96%; (vii) Tri N-Propyl Amine, ethanol, 50%-80%.
(3) synthesis of target compound (3a-3l):
The compound (1a-1l) of various replacement and intermediate (2) reacts, generation target compound (3a-3l), and wherein the reagent of each step and condition are: reagent and condition: (i) KI, K 2cO 3, CH 3cN, 2.5h-12.5h, backflow, 34%-81%.
Technique effect: relative to prior art; compounds against dopamine D3 acceptor of the present invention has very strong activity; especially 3a; 3b; 3g; be used for the treatment of or prevent schizophrenia, Parkinson's disease, pharmacological dependence and the nervus centralis mental disorder such as to relapse, also can be used for neuroprotective, and as instrument medicine for studying D3 receptor structure, function and the disease relevant with D3 receptor dysfunction.
Accompanying drawing explanation
Fig. 1 is the residence time contrast of each group of rat in white box;
Embodiment
Concrete steps of the present invention are described by the following examples, but do not limit by embodiment.
Term used in the present invention, except as otherwise noted, generally has the implication that those of ordinary skill in the art understand usually.
Below in conjunction with specific embodiment and comparable data describes in further detail the present invention.Should be understood that these embodiments just in order to demonstrate the invention, but not limit the scope of the invention by any way.
In the examples below, the various process do not described in detail and method are ordinary methods as known in the art.
Fusing point b shape melting point tube measures, and thermometer does not correct; Infrared spectrometer is NicoletImpact410 type, KBr compressing tablet; Nuclear magnetic resonance analyser is JEOLFX90Q type and Bruker-ACF-300 type, and TMS is interior mark; Ultimate analysis CarloErba1106 type elemental analyser measures; Mass spectrum FinniganFTMS-2000 type and HP1100LC/MSD type mass spectrograph measure.
Embodiment 14-(2-((3-(4-phenylpiperazine-1-base) propyl group) (propyl group) the is amino) ethyl) preparation (3a) of Indolin-2-one, the preparation (1a) of 1-(3-chloropropyl)-4-phenylpiperazine
(1) preparation (5) of two (2-chloroethyl) amine hydrochlorate
Sulfur oxychloride (128mL, 1.76mol) is added in 80mL chloroform, stir, in 1h, slowly drip the diethanolamine (40mL, 0.417mol) of 68mL chloroform dilution.Drip and finish, after reacting 2-5h under room temperature, be slowly warming up to 70 DEG C, after backflow 0.5-1h, terminate reaction.Cooling, suction filtration, filter cake washed with dichloromethane twice, dry, obtain white solid 66g, yield 89%, fusing point 214-215 DEG C (document 207-209 DEG C).
(2) preparation (7) of 1-php hydrochloride
By compound 5 (30g, 0.168mol) add in 150mL propyl carbinol, stir, slowly drip the aniline (14.25g, 0.153mol) with the dilution of 10mL propyl carbinol, drip and finish, back flow reaction 30h, then add salt of wormwood (23g, 0.168mol), after continuing backflow 40h, terminate reaction.Filtered while hot, obtains scarlet mother liquor, cooling crystallization, filter, a small amount of propyl carbinol of filter cake washes twice, drying, finally white (micro-red) solid 21.59g, yield 71%.
(3) preparation (8) of 1-php
By compound 7 (26.0g, 0.115mol) be dissolved in 250mL water, about pH to 12 is regulated with 40% sodium hydroxide solution, extraction into ethyl acetate (2 × 200mL), wash respectively once with water, saturated aqueous common salt, organic phase anhydrous sodium sulfate drying spends the night again, and filters, concentrating under reduced pressure give light yellow oil 20.8g, yield 95%.
(4) preparation (1a) of 1-(3-chloropropyl)-4-phenylpiperazine
In 50mL there-necked flask, add 25mL acetone, 1.2g (7.40mmol) 1-php (8), stirring and dissolving, then add 2.56g (18.5mmol) salt of wormwood.Slowly drip the bromo-3-chloropropane of 1.75g (11.1mmol) 1-under ice-water bath, be then slowly heated to 50 DEG C of reaction 3h, more slowly heat, gentle reflux 8h, terminate reaction.Cooling, filter, rotary evaporation under filtrate decompression, residue is purified by column chromatography for separation, with sherwood oil: ethyl acetate (volume ratio)=2:1 wash-out, finally obtains light yellow oil 1.04g, yield 59%.
Two, the preparation (2) of 4-(2-(propylcarbamic) ethyl) Indolin-2-one
(1) preparation (10) of phenylformic acid (2-chloromethyl) phenethyl ester
Compound 9 (65.0g, 484mmol) is added in 120mL methylene dichloride, stir, then add zinc chloride (1.95g, 14.3mmol).Reaction mixture slowly drips Benzoyl chloride (71.5g, 509mmol) after being heated to backflow, drips and finishes, and continue backflow 2.5h, raw material 9 primitive reaction is complete.Terminate reaction, cooling, washing (3 × 200mL), anhydrous sodium sulfate drying spends the night.Filter, filtrate reduced in volume, obtains brown crystal product 132g, yield 99%, fusing point < 50 DEG C.
1HNMR(300MHz,CDCl 3),δ H,ppm:3.23(t,J＝7.2Hz,2H),4.58(t,J＝7.2Hz,2H),4.72(s,2H),7.20-7.30(m,3H),7.38(d,J＝7.3Hz,1H),7.44(t,J＝7.7Hz,2H),7.56(t,J＝7.3Hz,1H),8.02(d,J＝7.3Hz,2H).
(2) preparation (11) of phenylformic acid (2-carboxaldehyde radicals) phenethyl ester
Compound 10 (2.70g, 9.83mmol) is dropped in 35mL methyl-sulphoxide, stir, then add sodium bicarbonate (1.67g, 19.9mmol), be heated to 110 DEG C.Reaction 3h, raw material 10 primitive reaction is complete, terminates reaction.Filter, concentrating under reduced pressure obtains red-brown oily matter, thin up, and with dichloromethane extraction (3 × 50mL), washing, solvent is removed in decompression, obtains crude product.Add dehydrated alcohol (9.2mL), stir, then add sodium bisulfite (8.64g, 83.0mmol) and the mixture of water (20mL), fully stir 30min under 20 DEG C of conditions, adularescent solid is separated out.Filter, be washed till white with cold methylene dichloride, dry, obtain white solid.Solid obtained above is added in the mixture of sodium bicarbonate (5.0g), water (80mL) and methylene dichloride (45mL), 2h is stirred under normal temperature, stratification, water layer uses dichloromethane extraction (2 × 40mL) again.Merge organic layer, washing (2 × 50mL), then wash (50mL) with saturated common salt, anhydrous sodium sulfate drying spends the night, and concentrating under reduced pressure obtains light green oil 1.67g, yield 67%.
1HNMR(300MHz,CDCl 3),δ H,ppm:3.53(t,J＝6.7Hz,2H),4.57(t,J＝6.7Hz,2H),7.37-7.48(m,4H),7.53(t,J＝7.3Hz,2H),7.84(d,J＝7.4Hz,1H),7.97(d,J＝7.3Hz,2H),10.26(s,1H).
(3) preparation (12) of phenylformic acid (2-β-nitroethylene base) phenethyl ester
Take 9.33g (36.69mmol) compound 11, add in 30mL methyl alcohol, stirring and dissolving.Slowly drip 3.32g (54.39mmol) Nitromethane 99Min., 2.21g (36.80mmol) acetic acid and 2.73g (37.33mmol) n-Butyl Amine 99 under ice-water bath successively, in dropping process, system temperature controls below 15 DEG C.Drip and finish, in about 25 DEG C reaction 14h, terminate reaction.Reaction system is cooled to-5 DEG C, leaves standstill 2h.Filter, by cold washed with isopropyl alcohol twice, vacuum-drying at 40 DEG C, obtains yellow solid 5.24g.Yield: 48%, fusing point: 65-67 DEG C (literature value 66-68 DEG C).
(4) preparation (13) of chloro-1, the 3-dihydro-2H-indol-2-one of 4-(2-Phenylacetic acid ethylester) 3-
Added by iron trichloride (15.9g, 98.0mmol) in 80mL methylene dichloride, stir, slowly drip Acetyl Chloride 98Min. (7.69g, 98.0mmol) under condition of ice bath, temperature of reaction controls at about 5 DEG C.Drip and finish, slowly instillation is dissolved in the compound 12 (7.28g, 24.5mmol) of 30mL methylene dichloride.React 3h under 5 DEG C of conditions, then instill 100mL water, the temperature controlling reaction mixture is no more than 30 DEG C.Drip and finish, continue to stir 1h.Stratification, water layer is with dichloromethane extraction (2 × 200mL).Merge organic layer, washing (3 × 200mL), saturated common salt washing (2 × 200mL), anhydrous sodium sulfate drying.Filter, be evaporated to about 100mL, add 55mL sherwood oil, under 0 DEG C of condition, cool 3h, have yellow solid particle to separate out.Filter, with mixed solution (methylene dichloride: sherwood oil=4:1, the volume ratio) washing that 40mL is cold, 65 DEG C of vacuum-dryings, obtain pale solid 4.58g.Yield 59%, fusing point 154-155 DEG C (literature value: 154-155 DEG C).
1HNMR(300MHz,DMSO-d 6),δ H,ppm:3.15(m,2H),4.56(t,J＝6.7Hz,2H),5.69(s,1H),6.76(d,J＝7.7Hz,1H),6.99(d,J＝7.8Hz,1H),7.28(t,J＝7.8Hz,1H),7.52(t,J＝7.6Hz,2H),7.66(t,J＝7.4Hz,1H),7.94(d,J＝7.3Hz,2H),10.76(s,1H).
(5) preparation (14) of 4-(beta-hydroxyethyl)-1,3-dihydro-2H-indol-2-one
In 15mL methyl alcohol, add intermediate 13 (1.20g, 3.80mmol), stir, then add 10%Pd/C (0.075g, 0.070mmol), be heated to backflow.Slowly instill hydrazine hydrate (0.38g, 7.59mmol), drip and finish, continue backflow 3h.Drip the sodium hydroxide (8.10g, 202mmol) being dissolved in 26mL water, then the 2h that refluxes.Claim heat filtering, concentrating under reduced pressure removes most of methyl alcohol (just having started have solid particulate to separate out in solution), is placed in refrigerator and cooled but 2h.Filter, cold water washing (2 × 15mL), 65 DEG C of vacuum-dryings, obtain clear crystal 0.48g.Yield 71%, fusing point 146-147 DEG C (document 147-149 DEG C).
IR(KBr)δ max(cm -1):3261,3166,1682,1618,1608； 1HNMR(300MHz,DMSO-d 6),δ H,ppm:2.64(t,J＝7.0Hz,2H),3.41(s,2H),3.59(t,J＝6.9Hz,2H),4.56(t,J＝5.2Hz,1H),6.64(d,J＝7.6Hz,1H),6.77(d,J＝7.7Hz,1H),7.07(t,J＝7.7Hz,1H),10.23(br,s,1H)； 13CNMR(300MHz,DMSO-d 6),δ:34.8,36.3,61.0,106.9,121.9,124.9,127.3,135.7,143.3,176.3。
(6) preparation (15) of tosic acid 2-(2-oxo-dihydro-4-indoles) ethyl ester
In 50mL reaction flask, add compound 14 (2.00g, 11.29mmol), 13mLPy, stir, drip with the 3.02g of 15mL dchloromethane (15.84mmol) TsCl at 5 DEG C.Drip and finish, stir 3h at 10 DEG C, react completely.Drip 20mL water, 9mL methylene dichloride, 15mL concentrated hydrochloric acid, stratification after stirring 2h, aqueous phase, with dichloromethane extraction (40mL × 2), merges organic layer, and washing, anhydrous sodium sulfate drying spends the night.Filtrate is steamed to just occurring solid particulate, cooling crystallization, suction filtration, dry, obtains faint yellow solid 3.22g.Yield 86%, fusing point: 128-129 DEG C.
(7) preparation (2) of 4-(2-(propylcarbamic) ethyl) Indolin-2-one
65mL dehydrated alcohol is added, 9.08g (27.40mmol) compound 15, stirring and dissolving, N in reaction flask 2protection, adds 85mL (1.03mol) Tri N-Propyl Amine under ice-water bath.Drip and finish, continue to stir 10min, then slowly heat, backflow 2.5h, terminates reaction.Concentrating under reduced pressure (<30 DEG C), adds 150mL water in residue, adjusts pH to 11 with 40%NaOH.With dichloromethane extraction (250mL × 3), merge organic layer, washing, anhydrous sodium sulfate drying spends the night, and filters, concentrated.Purify through column chromatography, using methylene dichloride: methyl alcohol: triethylamine=150:3:2 carries out drip washing as elutriant, obtain viscous brown shape compound 3.59g, yield 60%.
1HNMR(300MHz,DMSO-d 6),δ H,ppm:0.85(t,J＝7.4Hz,3H),1.36-1.43(m,2H),2.45-2.51(m,3H),2.61(t,J＝6.81Hz,2H),2.68-2.74(m,2H),3.43(s,2H),6.64(d,J＝7.6Hz,1H),6.77(d,J＝7.7Hz,1H),7.08(t,J＝6.81Hz,1H),10.31(br,s,1H)；MS:219.1[M+H] +.
Three, the preparation (3a) of 4-(2-((3-(4-phenylpiperazine-1-base) propyl group) (propyl group) is amino) ethyl) Indolin-2-one
In reaction flask, 30mL acetonitrile is added under ice-water bath, 0.70g (3.21mmol) compound 2,0.77g (3.24mmol) compound 1a, stirring and dissolving, add 0.89g (6.44mmol) salt of wormwood again, 0.54g (3.25mmol) potassiumiodide, is slowly warming up to 60 DEG C, and after 11h, raw material primitive reaction is complete.Filtered while hot, filtrate reduced in volume, residue is purified with column chromatography for separation, with methylene dichloride: methyl alcohol: triethylamine=200:0.5:1 wash-out, obtains viscous brown shape compound 0.86g, yield 64%.
1HNMR(300MHz,CDCl 3),δ H,ppm:0.92(t,J＝7.2Hz,3H),1.54-1.59(m,2H),1.75-1.85(m,2H),2.45(t,J＝7.0Hz,2H),2.63-2.81(m,12H),3.22(s,4H),3.46(s,2H),6.81(d,J＝7.4Hz,1H),6.86(d,J＝7.4Hz,1H),6.91-6.94(m,3H),7.12(t,J＝7.7Hz,1H),7.23-7.30(m,2H),9.71(s,1H)； 13C-NMR(300MHz,CDCl 3),δ:11.7,19.5,24.2,30.6,35.5,48.6,51.4,52.9,53.3,53.9,55.1,56.7,107.9,115.8,120.4,122.9,124.2,128.02,129.1,136.5,142.8,149.6,177.1；MS:421.3[M+H] +.
Embodiment 23-(3-(4-(4-chloro-phenyl-) piperazine-1-base) propyl group)-10-methoxymethyl-2,3,4,4a, 5,6-six hydrogen-1H-
Pyrazine [1,2-a] the preparation of quinoline (3b)
The preparation method of reference compound 3a, prepares compound 1b, drops into intermediate 2 (0.70g, 3.21mmol), obtains viscous brown shape compound 0.93g, yield 67% after reaction terminates.
1HNMR(300MHz,CDCl 3),δ H,ppm:0.88(t,J＝7.2Hz,3H),1.41-1.53(m,2H),1.63-1.73(m,2H),2.26(s,3H),2.39(t,J＝7.4Hz,2H),2.46(t,J＝7.5Hz,2H),2.54(t,J＝7.3Hz,2H),2.60(s,4H),2.67(s,4H),3.15(s,4H),3.47(s,2H),6.71(d,J＝7.7Hz,1H),6.84(d,J＝7.9Hz,3H),7.06(d,J＝8.0Hz,2H),7.13(t,J＝7.7Hz,1H),9.28(s,1H)； 13C-NMR(300MHz,CDCl 3),δ:11.9,20.3,20.3,24.5,30.9,35.1,49.6,52.1,53.2,54.3,56.1,56.6,107.5,116.3,122.7,124.0,127.9,129.1,129.5,137.1,142.5,149.2,177.6；IR(KBr,cm -1):3368,2954,2815,1687,1610,1577,1511,1459,1451,1237,811,720,651；MS:435.3[M+H] +.
The preparation (3c) of embodiment 34-(2-((3-(4-(2,3-3,5-dimethylphenyl) piperazine-1-base) propyl group) (propyl group) is amino) ethyl) Indolin-2-one
The preparation method of reference compound 3a, prepares compound 1c, drops into intermediate 2 (0.70g, 3.21mmol), obtains viscous brown shape compound 0.89g, yield 62% after reaction terminates.
1HNMR(300MHz,CDCl 3),δ H,ppm:0.89(t,J＝7.3Hz,3H),1.43-1.55(m,2H),1.65-1.75(m,2H),2.22(s,3H),2.27(s,3H),2.39-2.49(m,4H),2.53-2.69(m,10H),2.91-2.94(m,4H),3.48(s,2H),6.72(d,J＝7.7Hz,1H),6.83-6.93(m,3H),7.07(t,J＝7.7Hz,1H),7.15(t,J＝7.7Hz,1H),9.08(s,1H)； 13C-NMR(300MHz,CDCl 3),δ:11.9,13.9,20.2,20.5,24.5,30.8,35.1,52.0,52.1,53.7,54.2,56.0,56.7,107.5,116.6,122.7,124.0,124.8,125.7,127.9,131.1,137.1,137.8,142.5,151.5,177.6；IR(KBr,cm -1):3440,3067,3025,2952,2872,1679,1619,1606,1581,1475,1460,1452,1376,1243,1145,1082,779,721,651；MS:449.4[M+H] +.
The preparation (3d) of embodiment 44-(2-(propyl group (3-(4-(o-tolyl) piperazine-1-base) propyl group) is amino) ethyl) Indolin-2-one
The preparation method of reference compound 3a, prepares compound 1d, drops into intermediate 2 (0.70g, 3.21mmol), obtains viscous brown shape compound 0.92g, yield 66% after reaction terminates.
1HNMR(300MHz,CDCl 3),δ H,ppm:0.89(t,J＝7.2Hz,3H),1.44-1.51(m,2H),1.64-1.74(m,2H),2.30(s,3H),2.41(t,J＝7.2Hz,2H),2.46(t,J＝7.3Hz,2H),2.54(t,J＝7.4Hz,2H),2.60(s,4H),2.68(s,4H),2.94(s,4H),3.48(s,2H),6.72(d,J＝7.6Hz,1H),6.84(d,J＝7.7Hz,1H),6.96(t,J＝7.3Hz,1H),7.02(d,J＝7.8Hz,1H),7.15-7.17(m,3H),9.31(s,1H)； 13C-NMR(300MHz,CDCl 3),δ:11.9,17.8,20.3,24.6,30.9,35.1,51.6,52.1,53.7,54.3,56.0,56.7,107.5,118.9,122.7,123.0,124.0,126.5,127.9,130.9,132.5,137.1,142.5,151.4,177.7；IR(KBr,cm -1):3199,3066,3021,2954,2872,1687,1618,1607,1492,1458,1375,1266,1146,1084,777,722,650；MS:435.2[M+H] +.
The preparation (3e) of embodiment 54-(2-(propyl group (3-(4-(4-(trifluoromethoxy) phenyl) piperazine-1-base) propyl group) is amino) ethyl) Indolin-2-one
The preparation method of reference compound 3a, prepares compound 1e, drops into intermediate 2 (0.70g, 3.21mmol), obtains viscous brown shape compound 1.13g, yield 70% after reaction terminates.
1HNMR(300MHz,CDCl 3),δ H,ppm:0.89(t,J＝7.2Hz,3H),1.43-1.54(m,2H),1.65-1.75(m,2H),2.40(t,J＝7.2Hz,2H),2.51(t,J＝7.5Hz,2H),2.58-2.71(m,10H),3.18(t,J＝4.5Hz,4H),3.45(s,2H),6.81-6.89(m,4H),7.08-7.14(m,3H),9.64(s,1H)； 13C-NMR(300MHz,CDCl 3),δ:11.7,19.7,23.9,29.6,,30.3,35.1,49.0,51.8,52.8,53.0,54.0,55.7,56.2,108.0,116.4,121.8,122.4,124.0,127.9,136.1,141.8,142.9,149.9,177.1；IR(KBr,cm -1):3392,3079,2955,2874,2818,1697,1618,1607,1512,1457,1380,1264,1159,1085,1008,834,807,710,647；MS:505.2[M+H] +.
The preparation (3f) of embodiment 64-(2 – ((3-(4-(3-p-methoxy-phenyl) piperazine-1-base) propyl group) (propyl group) is amino) ethyl) Indolin-2-one
The preparation method of reference compound 3a, prepares compound 1f, drops into intermediate 2 (0.70g, 3.21mmol), obtains viscous brown shape compound 0.94g, yield 65% after reaction terminates.
1HNMR(300MHz,CDCl 3),δ H,ppm:0.89(t,J＝7.0Hz,3H),1.43-1.55(m,2H),1.66-1.76(m,2H),2.40(t,J＝7.1Hz,2H),2.51(t,J＝7.4Hz,2H),2.59-2.72(m,10H),3.20(s,4H),3.44(s,2H),3.78(s,3H),6.40(d,J＝7.9Hz,1H),6.46(s,1H),6.53(d,J＝8.0Hz,1H),6.81(d,J＝7.7Hz,1H),6.87(d,J＝7.6Hz,1H),7.11(t,J＝6.9Hz,1H),7.16(t,J＝7.8Hz,1H),9.71(s,1H)； 13C-NMR(300MHz,CDCl 3),δ:11.8,19.9,24.1,30.5,35.1,48.8,51.8,52.9,54.1,55.1,55.8,56.3,102.3,104.3,108.0,108.7,122.3,123.9,127.9,129.6,136.3,142.9,152.5,160.4,177.0；IR(KBr,cm -1):3392,3079,2954,2871,2816,1683,1605,1576,1533,1496,1456,1255,1171,1050,1011,801,776,689,650；MS:451.3[M+H] +.
The preparation (3g) of embodiment 74-(2-((3-(4-(3,4-3,5-dimethylphenyl) piperazine-1-base) propyl group) (propyl group) is amino) ethyl) Indolin-2-one
The preparation method of reference compound 3a, prepares compound 1g, drops into intermediate 2 (0.70g, 3.21mmol), obtains viscous brown shape compound 0.91g, yield 63% after reaction terminates.
1HNMR(300MHz,CDCl 3),δ H,ppm:0.88(t,J＝7.3Hz,3H),1.41-1.53(m,2H),1.62-1.72(m,2H),2.17(s,3H),2.22(s,3H),2.39(t,J＝7.5Hz,2H),2.45(t,J＝7.5Hz,2H),2.53(t,J＝7.4Hz,2H),2.59(t,J＝4.6Hz,4H),2.67(s,4H),3.15(t,J＝4.5Hz,4H),3.47(s,2H),6.67-6.74(m,3H),6.83(d,J＝7.7Hz,1H),7.00(d,J＝8.2Hz,1H),7.12(t,J＝7.7Hz,1H),9.15(s,1H)； 13C-NMR(300MHz,CDCl 3),δ:11.9,18.7,20.1,20.3,24.6,30.9,35.1,49.7,52.1,53.3,54.3,56.1,56.6,107.4,113.7,118.0,122.7,124.0,127.9,130.1,137.0,137.2,142.5,149.6,177.6；IR(KBr,cm -1):3195,3021,2954,2872,1695,1614,1572,1505,1455,1379,1149,1085,880,803,719,651；MS:449.3[M+H] +.
The preparation (3h) of embodiment 84-(2-((2-(4-(3-p-methoxy-phenyl) piperazine-1-base) ethyl) (propyl group) is amino) ethyl) Indolin-2-one
The preparation method of reference compound 3a, prepares compound 1h, drops into intermediate 2 (0.70g, 3.21mmol), obtains viscous brown shape compound 0.91g, yield 65% after reaction terminates.
1HNMR(300MHz,CDCl 3),δ H,ppm:0.89(t,J＝7.3Hz,3H),1.43-1.52(m,2H),2.47-2.53(m,4H),2.62(t,J＝4.7Hz,4H),2.68-2.70(m,6H),3.19(t,J＝4.7Hz,4H),3.48(s,2H),3.78(s,3H),6.41(d,J＝8.0Hz,1H),6.46(s,1H),6.52(d,J＝8.3Hz,1H),6.71(d,J＝7.7Hz,1H),6.84(d,J＝7.7Hz,1H),7.11-7.18(q,J＝7.3Hz,2H),9.15(s,1H)； 13C-NMR(300MHz,CDCl 3),δ:11.9,20.3,30.9,35.1,48.9,51.5,53.6,54.7,55.1,56.5,56.6,102.4,104.4,107.5,108.8,122.7,124.0,128.0,129.7,137.0,142.5,152.6,160.5,177.6；IR(KBr,cm -1):3200,3083,2950,2873,2822,1701,1604,1580,1497,1453,1299,1248,1204,1171,1055,774,759,719,687,650；MS:437.2[M+H] +.
Embodiment 94-(2-((2-(4-(4-chloro-phenyl-) piperazine-1-base) ethyl) (propyl group) amino)) ethyl) preparation (3i) of Indolin-2-one
The preparation method of reference compound 3a, prepares compound 1i, drops into intermediate 2 (0.70g, 3.21mmol), obtains gray solid 0.96g, yield 68%, fusing point: 136-137 DEG C after reaction terminates.
1HNMR(300MHz,CDCl 3),δ H,ppm:0.88(t,J＝7.2Hz,3H),1.44-1.52(m,2H),2.50-2.70(m,14H),3.15(s,4H),3.49(s,2H),6.72(d,J＝7.6Hz,1H),6.83(t,J＝8.3Hz,3H),7.11-7.19(m,3H),9.19(s,1H)； 13C-NMR(300MHz,CDCl 3),δ:11.9,20.3,31.0,35.2,49.0,51.6,53.5,54.7,56.5,56.6,107.5,117.1,122.8,124.0,124.4,128.0,128.9,137.0,142.5,149.8,177.6；IR(KBr,cm -1):3211,3066,3039,3019,2948,2873,1669,1603,1498,1451,1299,1245,1128,1082,813,769,696,658；MS:441.2[M+H] +.
The preparation (3j) of embodiment 104-(2-(propyl group (2-(4-(4-(trifluoromethoxy) phenyl) piperazine-1-base) ethyl) is amino) ethyl) Indolin-2-one
The preparation method of reference compound 3a, prepares compound 1j, drops into intermediate 2 (0.70g, 3.21mmol), obtains viscous brown shape compound 0.93g, yield 59% after reaction terminates.
1HNMR(300MHz,CDCl 3),δ H,ppm:0.89(t,J＝7.3Hz,3H),1.45-1.52(m,2H),2.47-2.53(m,4H),2.63(t,J＝4.7Hz,4H),2.68-2.71(m,6H),3.17(t,J＝4.6Hz,4H),3.49(s,2H),6.73(d,J＝7.7Hz,1H),6.83-6.88(m,3H),7.08-7.16(m,3H),9.39(s,1H)； 13C-NMR(300MHz,CDCl 3),δ:11.9,20.4,31.0,35.2,49.1,51.6,53.6,54.8,56.6,56.7,107.5,116.5,121.9,122.3,122.8,124.0,128.0,137.1,141.9,142.4,150.0,177.5；IR(KBr,cm -1):3166,3019,2955,2871,2819,1684,1605,1515,1458,1268,1238,1159,1003,832,718,646；MS:491.2[M+H] +.
The preparation (3k) of embodiment 114-(2-((2-(4-phenylpiperazine-1-base) ethyl) (propyl group) is amino) ethyl) Indolin-2-one
The preparation method of reference compound 3a, prepares compound 1k, drops into intermediate 2 (0.70g, 3.21mmol), obtains gray solid 0.93g after reaction terminates.Yield 71%, fusing point: 113-114 DEG C.
1HNMR(300MHz,CDCl 3),δ H,ppm:0.89(t,J＝7.2Hz,3H),1.44-1.56(m,2H),2.47-2.53(m,4H),2.64(t,J＝4.6Hz,4H),2.67-2.80(m,6H),3.12-3.27(m,4H),3.50(s,2H),6.71(d,J＝7.7Hz,1H),6.83-6.88(m,2H),6.92(d,J＝8.0Hz,2H),7.15(t,J＝7.7Hz,1H),7.26(t,J＝7.6Hz,2H),8.12(s,1H)； 13C-NMR(300MHz,CDCl 3),δ:11.9,20.4,31.0,35.1,49.0,51.6,53.7,54.8,56.6,56.7,107.5,116.0,119.6,122.8,124.0,128.0,129.0,137.1,142.4,151.2,177.5；IR(KBr,cm -1):3183,3058,3039,3021,2957,2867,1664,1606,1577,1505,1456,1321,1301,1249,1140,1084,753,690,656；MS:407.3[M+H] +.
The preparation (3l) of embodiment 124-(2-((2-(4-(3,4-3,5-dimethylphenyl) piperazine-1-base) ethyl) (propyl group) is amino) ethyl) Indolin-2-one
The preparation method of reference compound 3a, prepares compound 1l, drops into intermediate 2 (0.70g, 3.21mmol), obtains viscous brown shape compound 0.98g, yield 70% after reaction terminates.
1HNMR(300MHz,CDCl 3),δ H,ppm:0.88(t,J＝7.2Hz,3H),1.44-1.52(m,2H),2.17(s,3H),2.22(s,3H),2.47-2.53(m,4H),2.63-2.70(m,10H),3.14(s,4H),3.48(s,2H),6.66-6.74(m,3H),6.84(d,J＝7.7Hz,1H),7.00(d,J＝8.1Hz,1H),7.13(t,J＝7.7Hz,1H),9.22(s,1H)； 13C-NMR(300MHz,CDCl 3),δ:11.9,18.7,20.1,20.4,31.0,35.1,49.6,51.6,53.7,54.8,56.6,56.7,107.5,113.7,118.0,122.7,124.0,127.9,128.0,130.1,137.0,137.0,142.5,149.5,177.6；IR(KBr,cm -1):3186,3080,3025,2948,2856,1702,1605,1569,1505,1455,1307,1242,1140,1091,886,804,704,660；MS:435.3[M+H] +.
Experimental example bioactivity research
Test 1 compounds against dopamine D 3acceptor and D 2the avidity test of acceptor
Bioactive research is carried out to compound of the present invention, with the D of stable transfection 3r-HEK-293 cell strain is carrier, by radioligand [ 3h] Spiperone competion experiment, carry out the test of series of receptors in conjunction with concentration, deterministic compound is to D 3acceptor and D 2the K of acceptor ivalue.
Medicine and reagent:
[ 3h] Spiperone (98Ci/mmol) is all purchased from PE company; (+) Butaclamol, purchased from RBI company; GF/C glass fiber filter paper, purchased from Whatman company; Fat-soluble scintillation solution Tris, by the packing of Ji Tai Science and Technology Ltd..
Experimental technique:
D 3r-HEK-293 cell, receptor protein great expression on film after 48-72 hour, abandons supernatant by after centrifugal for cell 1000rpm 5min, precipitation is resuspended in 5mMTris, 5mMEDTA .in 2Na, 5mMEGTA lysate (pH=7.4), place 30min on ice.Mediate and shake 5-10 time, 4 DEG C, the centrifugal 20min of 40000g.Abandon supernatant, precipitation is resuspended in ice-cold 50mMTris-HCl (pH=7.4) damping fluid, crosses syringe needle 5-10 time, 4 DEG C, the centrifugal 20min of 40000g.Coomassie brilliant G-250 method surveys protein concentration.
A certain amount of testing compound and radioactive ligand and receptor protein are added in reaction tube, after 50min is hatched in 30 DEG C of water-baths, at once moves to ice bath and stop its reaction.Then, on Millipore cell sample collection device, through GF/C glass fiber filter paper rapid filtration under suction, and with elutriant (50mMTris-HCl, PH=7.5) 3ml × 3 time, dry with microwave oven 3 ~ 4min, filter paper is moved in 0.5ml centrifuge tube, add the fat-soluble scintillation solution of 500ul.Lucifuge leaves standstill more than 30min, and counting measures radioactive intensity.
Respectively ask for a certain amount of tested compound sample, carry out the test of series of receptors in conjunction with concentration, deterministic compound is to D 3acceptor and D 2the K of acceptor ivalue.Compounds against dopamine D 3acceptor and D 2avidity (the K of acceptor ivalue) measurement result is in table 2.
Table 2 compounds against dopamine D 3acceptor and D 2the K of acceptor ivalue
* positive control is represented
Test 2 the experiment of environmental conditioned place preferences
Preferred above-claimed cpd 3g (code name ZBH-II-A-8), studies its impact on morphine induced rat conditioned place preference.
Experimental principle the experiment of environmental conditioned place preference (ConditionedPlacePreference, CPP) be the Classic Experiments evaluating Drug psychological dependence at present, laboratory animal (rat) is placed in the white observation area of conditioned place preference case, inject psychic dependence medicine morphine, the black region of observation experiment animal at conditioned place preference case and the active situation (having wicket freely can pass through for animal between white area, black region and grey area wherein) of white area.Because of the drug dependence effect of medicine, animal is in administration district at every turn will to the preference on generation position, black and white region under the effect of drug reward effect.
Instrument and material Conditioned Place Preference in Rats instrument; Wistar rat, male, body weight 200 ± 20g;
Reagent: Srm-Rhotaard; Compound ZBH-II-A-8, is synthesized by contriver.
Experimentation is divided into four-stage: medicine prepares, time span of forecast, training period, testing period.
1) medicine prepares
Morphine solution: 10mg/kg, claims 1mg morphine to be dissolved in 100mL distilled water; Compound sample ZBH-II-A-8 solution: 1.0mg/kg, claims 0.1mg compound ZBH-II-A-8 to be first dissolved in a small amount of DMSO, then adds distilled water to 100mL; 5.0mg/kg, claims 0.5mg compound ZBH-II-A-8 to be first dissolved in a small amount of DMSO, then adds distilled water to 100mL; 10.0mg/kg, claims 1mg compound ZBH-II-A-8 to be first dissolved in a small amount of DMSO, then adds distilled water to 100mL.
2) time span of forecast
First 3 days, extract the dividing plate between case out, rat is put into intermediate box, is allowed to condition in three casees the 15min that can freely run.Measure the residence time of rat in each case, judge that rat is to preference situation that is black, white box.
3) training period
4-11 days, plugs dividing plate, stops rat freely to pass through between case.Every morning 9:00 and afternoon 14:00 start experiment.Every day salt solution and medicine respectively train 1 time, the altogether continuous 8 day time.3 dosage groups of ZBH-II-A-8, abdominal cavity is to each dosage of ZBH-II-A-8 after 20 minutes, and subcutaneous injection morphine 10mg/kg, then puts into white box (companion's medicine-chest) 45min immediately, put into black box (non-companion's medicine-chest) 45min after subcutaneous injection salt solution immediately, every day circulation primary.Morphine group abdominal cavity gave solvent after 30 minutes, was put in white box (companion's medicine-chest) 45min after subcutaneous injection morphine (10mg/kg) immediately, put into black box (non-companion's medicine-chest) 45min after pump pickle immediately, every day circulation primary.Group of solvents abdominal cavity gave salt solution after 30 minutes, put into white box 45min immediately after subcutaneous injection solvent, put into black box 45min after pump pickle, every day circulation primary.
4) testing period
12nd day, extract dividing plate out, rat is put into intermediate box position, be allowed to condition in three chests the 15min that freely runs, with the computer note residence time of rat in white box (companion's medicine-chest).
Whole experiment is divided into five groups: (a) solvent+physiological saline (NS); (b) morphine+solvent (Mor-10mg/kg); (c) morphine+ZBH-II-A-8 (1.0mg/kg); (d) morphine+ZBH-II-A-8 (5.0mg/kg); (e) morphine+ZBH-II-A-8 (10.0mg/kg).
Experimental result: according to the multilevel variance analysis data statistic analysis of single factor test, contrasts the residence time of each group of rat in companion's medicine-chest.Experimental result shows, in the Conditioned Place Preference in Rats experiment of morphine induction, ZBH-II-A-8 obviously can reduce the generation of the conditioned place preference of morphine induction when 5.0mg/kg and 10.0mg/kg two dosage.The results are shown in Figure of description 1.
In above conditioned place preference, the compound of other embodiment of the present invention all has the test-results with ZBH-II-A-8 basic simlarity, obviously can reduce the generation of the conditioned place preference of morphine induction when doses.

Claims (10)

1. Indolin-2-one class D3 receptors ligand, shown in I:
Or its pharmaceutical salts,
Wherein, n=2 or 3; R represents H, 4-CH 3, 2,3-diCH 3, 2-CH 3, 4-OCF 3, 3-OCH 3, 3,4-diCH 3or 4-Cl.
2. Indolin-2-one class D3 receptors ligand according to claim 1, is characterized in that, during described n=2, R is 3-OCH 3, 4-Cl, 4-OCF 3, H or 3,4-diCH 3; During n=3, R is H, 4-CH 3, 2,3-diCH 3, 2-CH 3, 4-OCF 3, 3-OCH 3or 3,4-diCH 3.
3. the application in the medicine of preparation treatment or prevention Nervous and mental diseases, neuroprotective, treatment and D3 receptor dysfunction diseases related of the Indolin-2-one class D3 receptors ligand described in any one of claim 1-2 or its pharmaceutical salts.
4. the application of Indolin-2-one class D3 receptors ligand according to claim 3 or its pharmaceutical salts, is characterized in that, described Nervous and mental diseases is Parkinson's disease, schizophrenia, pharmacological dependence or not peaceful restless leg syndrome; Described is schizophrenia, Parkinson's disease, pharmacological dependence or drug habit, various forms of stress, anxiety, somnopathy or male sexual disorder with D3 receptor dysfunction diseases related.
5. the Indolin-2-one class D3 receptors ligand described in any one of claim 1-2 or its pharmaceutical salts for the preparation of research D3 receptor structure, function and with the application in the instrument medicine of D3 receptor dysfunction diseases related.
6. a pharmaceutical composition, is characterized in that, containing Indolin-2-one class D3 receptors ligand or its pharmaceutical salts described in any one of at least one claim 1-2, and pharmaceutical carrier or vehicle.
7. pharmaceutical composition according to claim 6, is characterized in that, described pharmaceutical composition is injection, infusion solution, dripping pill, tablet, capsule, granule or oral liquid.
8. the preparation method of Indolin-2-one class D3 receptors ligand described in any one of claim 1-2, is characterized in that, described Indolin-2-one class D3 receptors ligand is that reaction formula is as follows made by compound 3 and compound 2 react:
9. the preparation method of Indolin-2-one class D3 receptors ligand according to claim 8, is characterized in that, described compound 3 be by compound 4 made by the following series reaction:
Wherein, in compound 6, R is H, 4-CH 3, 2,3-diCH 3, 2-CH 3, 4-OCF 3, 3-OCH 3, 3,4-diCH 3or 4-Cl.
10. the preparation method of Indolin-2-one class D3 receptors ligand according to claim 8, it is characterized in that, described compound 2 is by compound 9 through following series reaction, made by last separation and purification or recrystallizing and refining:
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