CN105461608B - Ketone D3 receptors ligands of indoline 2 and its production and use - Google Patents

Abstract

The invention discloses a kind of ketone D3 receptors ligands of indoline 2, as shown in compound of formula I：Or its pharmaceutical salts, wherein, n=2 or 3；R represents H, 4 CH₃、2,3‑diCH₃、2‑CH₃、4‑OCF₃、3‑OCH₃、3,4‑di CH₃Or 4 Cl.Relative to prior art; the compounds against dopamine D3 acceptors of the present invention have very strong activity; for treating or preventing schizophrenia, Parkinson's, pharmacological dependence and the nervous centralis mental disorder such as relapsing; neuroprotection is can also be used for, and as instrument medicine for studying D3 receptor structures, function and the disease relevant with D3 receptor dysfunctions.

Description

Indolin-2-one class D3 receptors ligands and its production and use

Technical field

The present invention relates to a kind of Indolin-2-one class D3 receptors ligands and its production and use, belong to medicine conjunction Into technical field.

Background technology

Dopamine is neurotransmitter important in central nervous system, with Parkinson's (PD), Huntingdon disease, schizophrenia A variety of diseases such as disease (SCZD) are relevant.Dopamine receptor is divided into D1, D2, D3, D4 and D5 totally 5 kinds of different receptor subtypes, in cross-film Region has the amino acid sequence homology of height so that exploitation has high-affinity and the dopamine receptor ligands of high selectivity concurrently It is extremely important.However, the high consistency of dopamine D 3 and the monocyclic interior sequence of D2 receptor transmembranes, especially these By the intimate homogeneity for being inferred to be the residue to form binding site in vivo so that exploitation with quasi-medicated property physicochemical property D3 by Body alternative cpd is very difficult.

The non-ergot alkaloid compound Pramipexole of the second generation, Ropinirole by it is single or with levodopa drug combination, Parkinson's can effectively be treated.But, as other medicines, D3 receptors ligands also have not while therapeutic action is played With the side effect of degree, the Drug side reactions such as nausea, illusion are produced.Clinically typically use atypia anti-schizophrenia medicine Thing, such as sulfanilamide (SN) must profit, Clozapine drug therapy schizophrenia, achieve good effect.

The clinical treatment of drug habit, which seems, for a long time has difficulty in walking, and never finds particularly effective treatment side Method.At present, the main method treated both at home and abroad to drug habit is that detoxification or control drug rehabilitation symptom, non-drug therapy are few Use.Recent study finds that the D3 acceptor portion agonists such as BP897, NGB2904, S33138 and antagonist are in medicine A gleam of hope is illustrated in terms of habituation, however, the final success in terms of really obtaining clinical diagnosis and treatment, is still suffered from more Weight is difficult, is to shoulder heavy responsibilities.

The content of the invention

Goal of the invention：In order to solve the above-mentioned technical problem, the invention provides a kind of Indolin-2-one class D3 acceptors to match somebody with somebody Body and its production and use.

Technical scheme：In order to realize foregoing invention purpose, the invention discloses a kind of Indolin-2-one class D3 acceptors to match somebody with somebody Body, as shown in compound of formula I：

Or its pharmaceutical salts,

Wherein, n=2 or 3；R represents H, 4-CH₃、2,3-diCH₃、2-CH₃、4-OCF₃、3-OCH₃、3,4-di CH₃Or 4- Cl。

Preferably, during the n=2, R 3-OCH₃、4-Cl、4-OCF₃, H or 3,4-di CH₃；During n=3, R H, 4- CH₃、2,3-diCH₃、2-CH₃、4-OCF₃、3-OCH₃Or 3,4-di CH₃。

Preferable compound, as shown in table 1：

The melting point compound of table 1 and yield

^aFinal step yield；^bThick thing

Present invention also offers described Indolin-2-one class D3 receptors ligands or its pharmaceutical salts to prepare treatment or pre- Anti- Nervous and mental diseases, protection nerve, treatment and D3 receptor dysfunctions have the application in the medicine of related disorders.

Preferably, the Nervous and mental diseases are that Parkinson's, schizophrenia, pharmacological dependence or not peaceful leg are more dynamic Syndrome；It is described have with D3 receptor dysfunctions related disorders for schizophrenia, Parkinson's, pharmacological dependence or drug habit, Various forms of stress, anxiety, sleep-disorder or male sexual disfunctions.

The present invention still further provides described Indolin-2-one class D3 receptors ligands or its pharmaceutical salts is used in preparation Research D3 receptor structures, function and there is application in the instrument medicine of related disorders with D3 receptor dysfunctions.

The invention provides a kind of pharmaceutical composition, contains at least one Indolin-2-one class D3 receptors ligands Or its pharmaceutical salts, and pharmaceutical carrier or excipient.

Preferably, described pharmaceutical composition is injection, infusion solution, dripping pill, tablet, capsule, granule or oral liquid.

The preparation method of the invention for finally providing the Indolin-2-one class D3 receptors ligands, the indoline- 2- ketone D3 receptors ligands are to react made by compound 3 and compound 2, and reaction equation is as follows：

Preferably, the compound 3 is as made by compound 4 through following series reaction：

Wherein, in compound 6, R H, 4-CH₃、2,3-diCH₃、2-CH₃、4-OCF₃、3-OCH₃、3,4-di CH₃Or 4- Cl。

Preferably, the compound 2 is to be finally separating purifying or recrystallization through following series reaction by compound 9 It is refined made：

The synthetic method of above-mentioned preferred compound is such as：

(1) intermediate 1i-1l synthesis：

As shown in following reaction stream formula, compound (6) is the aniline of various functional groups substitution, and R is various substituents (group), is shown in Table 1.Initiation material diethanol amine passes through series reaction, obtains each intermediate 1i-1l.Wherein each step reagent and Condition is：(i) thionyl chloride, chloroform, 1-8 hours, room temperature, 0.5-5 hours, backflow；80-95%；(ii) n-butanol, carbonic acid Potassium, 40-100 hours, backflow, 60-80%；(iii) sodium hydroxide, water, pH=12,90-97%；(iv) the bromo- 3- chloropropanes of 1-, Potassium carbonate, acetone, 1-5 hours, 0-60 DEG C, 0.5-5 hours, backflow, 50-70%；(v) the bromo- 2- chloroethanes of 1-, potassium carbonate, third Ketone, 1-5 hours, 0-50 DEG C, 0.5-3 hours, backflow, 40-70%；(vi) potassium carbonate, acetone, 2-7 hours, 0-55 DEG C, 0.5-4 Hour, backflow, 50-70%.

(2) synthesis of intermediate 2：

As shown in following reaction stream formula, series reaction is passed through by compound (9), finally obtains key intermediate (2). Final products can be through column chromatographic isolation and purification or organic solvent recrystallizing and refining.Wherein each step reagent and condition are：(i) chlorination Zinc, chlorobenzoyl chloride, dichloromethane, 1-5 hours, backflow, 85%-100%；(ii) dimethyl sulfoxide, sodium acid carbonate, 1-5 hours, 100-130 DEG C, 60-80%. (iii) nitromethane, n-butylamine, acetic acid, methanol, 10-25 hours, 0-50 DEG C, 53%-80%. (iv) ferric trichloride, chloracetyl, dichloromethane, 1-3 hours, -10-10 DEG C, 50%-70%；(v) hydrazine hydrate, methanol, 10% palladium Charcoal, 1-5h, backflow；Sodium hydroxide, water, 1-5 hours, backflow, 64%-90%；(vi) paratoluensulfonyl chloride, pyridine, dichloromethane Alkane, 1-6 hours, 0-50 DEG C, 80%-96%；(vii) n-propylamine, ethanol, 50%-80%.

(3) synthesis of target compound (3a-3l)：

Various substituted compounds (1a-1l) are reacted with intermediate (2), generation target compound (3a-3l), wherein each step Rapid reagent and condition be：Reagent and condition:(i)KI,K₂CO₃,CH₃CN, 2.5h-12.5h, backflow, 34%-81%.

Technique effect：Relative to prior art, compounds against dopamine D3 acceptors of the invention have very strong activity, especially It is 3a, 3b, 3g, for treating or preventing schizophrenia, Parkinson's, pharmacological dependence and the nervous centralis mental such as relapsing Disease, it can also be used to neuroprotection, and as instrument medicine be used for study D3 receptor structures, function and with D3 receptor dysfunctions Relevant disease.

Brief description of the drawings

Fig. 1 is residence time contrast of each group rat in white box；

Embodiment

Illustrate the specific steps of the present invention by the following examples, but be not limited by the example.

Used term in the present invention, unless otherwise indicated, typically there are those of ordinary skill in the art generally to manage The implication of solution.

The present invention is described in further detail with reference to specific embodiment and with reference to data.It should be understood that these embodiments are only It is rather than the scope limiting the invention in any way in order to demonstrate the invention.

In the examples below, the various processes and method not being described in detail are conventional methods as known in the art.

Fusing point is determined with b shapes melting point tube, and thermometer does not correct；Infrared spectrometer is the types of Nicolet Impact 410, KBr Tabletting；NMR is JEOL FX90Q types and Bruker-ACF-300 types, and TMS is internal standard；Elementary analysis Carlo The type elemental analysers of Erba 1106 determine；Mass spectrum is surveyed with Finnigan FTMS-2000 types and HP1100LC/MSD types mass spectrograph It is fixed.

The 4- of embodiment 1 (2- ((3- (4- phenylpiperazine -1- bases) propyl group) (propyl group) amino) ethyl) Indolin-2-one Preparation (3a) one, the preparation (1a) of 1- (3- chloropropyls) -4- phenylpiperazines

(1) preparation (5) of double (2- chloroethyls) amine hydrochlorates

Thionyl chloride (128mL, 1.76mol) is added in 80mL chloroforms, stirring, in being slowly added dropwise in 1h, 68mL chloroforms are dilute The diethanol amine (40mL, 0.417mol) released.Drop finishes, and after reacting 2-5h at room temperature, is to slowly warm up to 70 DEG C, after the 0.5-1h that flows back Terminate reaction.Cooling, filter, filter cake is washed twice with dichloromethane, is dried, is obtained white solid 66g, yield 89%, fusing point 214-215 DEG C (207-209 DEG C of document).

(2) preparation (7) of 1-php hydrochloride

Compound 5 (30g, 0.168mol) is added in 150mL n-butanols, stirring, be slowly added dropwise dilute with 10mL n-butanols The aniline (14.25g, 0.153mol) released, drop finish, and back flow reaction 30h, then add potassium carbonate (23g, 0.168mol), continue Terminate reaction after backflow 40h.Filter while hot, obtain peony mother liquor, cooling crystallization filters, and filter cake washs two with a small amount of n-butanol It is secondary, drying, finally white (micro- red) solid 21.59g, yield 71%.

(3) preparation (8) of 1-php

Compound 7 (26.0g, 0.115mol) is dissolved in 250mL water, it is left to adjust pH to 12 with 40% sodium hydroxide solution The right side, ethyl acetate extraction (2 × 200mL), then washed once respectively with water, saturated aqueous common salt, organic phase is done with anhydrous sodium sulfate It is dry overnight, filtering, the give light yellow oil that is concentrated under reduced pressure 20.8g, yield 95%.

(4) preparation (1a) of 1- (3- chloropropyls) -4- phenylpiperazines

Addition 25mL acetone in toward 50mL three-necked flasks, 1.2g (7.40mmol) 1-php (8), stirring and dissolving, then Add 2.56g (18.5mmol) potassium carbonate.The bromo- 3- chloropropanes of 1.75g (11.1mmol) 1-, Ran Houhuan are slowly added dropwise under ice-water bath It is slow to be heated to 50 DEG C of reaction 3h, then slowly heat, gentle reflux 8h, terminate reaction.Cooling, filter, rotate and steam under filtrate decompression Hair, residue is purified by column chromatography for separation, with petroleum ether：Ethyl acetate (volume ratio)=2:1 elution, finally gives light yellow Grease 1.04g, yield 59%.

2nd, the preparation (2) of 4- (2- (propylcarbamic) ethyl) Indolin-2-one

(1) preparation (10) of benzoic acid (2- chloromethyls) phenethyl ester

By compound 9 (65.0g, 484mmol) add 120mL dichloromethane in, stirring, add zinc chloride (1.95g, 14.3mmol).After reactant mixture is heated to backflow, chlorobenzoyl chloride (71.5g, 509mmol) is slowly added dropwise, drop finishes, continued back 2.5h is flowed, the fundamental reaction of raw material 9 is complete.Terminate reaction, cooling, wash (3 × 200mL), anhydrous sodium sulfate drying is overnight.Filtering, Filtrate decompression concentrates, and obtains brown crystal product 132g, yield 99%, 50 DEG C of fusing point ＜.

¹H NMR(300MHz,CDCl₃),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 benzoic acid (2- carboxaldehyde radicals) phenethyl ester

Compound 10 (2.70g, 9.83mmol) is put into 35mL dimethyl sulfoxides, stirring, adds sodium acid carbonate (1.67g, 19.9mmol), it is heated to 110 DEG C.3h is reacted, the fundamental reaction of raw material 10 finishes, and terminates reaction.Filtering, decompression Brownish red grease is concentrated to give, is diluted with water, is extracted (3 × 50mL) with dichloromethane, is washed, decompression removes solvent, obtains and slightly produces Thing.Absolute ethyl alcohol (9.2mL) is added, stirring, adds the mixing of sodium hydrogensulfite (8.64g, 83.0mmol) and water (20mL) Thing, 30min is sufficiently stirred under the conditions of 20 DEG C, there is white solid precipitation.Filtering, white is washed till with cold dichloromethane, is dried, is obtained White solid.Solid obtained above is added to the mixture of sodium acid carbonate (5.0g), water (80mL) and dichloromethane (45mL) In, 2h, stratification are stirred under normal temperature, water layer is extracted (2 × 40mL) with dichloromethane again.Merge organic layer, wash (2 × 50mL), then with saturated common salt (50mL) is washed, anhydrous sodium sulfate drying is overnight, and be concentrated under reduced pressure to obtain light green oil 1.67g, Yield 67%.

¹H NMR(300MHz,CDCl₃),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 benzoic acid (2- β-nitroethenyl group) phenethyl ester

9.33g (36.69mmol) compound 11 is weighed, is added in 30mL methanol, stirring and dissolving.Under ice-water bath successively slowly 3.32g (54.39mmol) nitromethane, 2.21g (36.80mmol) acetic acid and 2.73g (37.33mmol) n-butylamine, drop is added dropwise System temperature control is below 15 DEG C during adding.Drop finishes, and reacts 14h in 25 DEG C or so, terminates reaction.Reaction system is cooled To -5 DEG C, 2h is stood.Filtering, is washed twice with cold isopropanol, is dried in vacuo at 40 DEG C, obtain yellow solid 5.24g.Receive Rate：48%, fusing point：65-67 DEG C (66-68 DEG C of literature value).

(4) preparation (13) of the chloro- 1,3- dihydros -2H- indol-2-ones of 4- (2- ethyl phenylacetates) 3-

Ferric trichloride (15.9g, 98.0mmol) is added in 80mL dichloromethane, stirring, be slowly added dropwise under condition of ice bath Chloroacetic chloride (7.69g, 98.0mmol), reaction temperature are controlled at 5 DEG C or so.Drop finishes, and is slowly dropped into and is dissolved in 30mL dichloromethane Compound 12 (7.28g, 24.5mmol).3h is reacted under the conditions of 5 DEG C, then instills 100mL water, controls the temperature of reactant mixture No more than 30 DEG C.Drop finishes, and continues to stir 1h.Stratification, water layer are extracted (2 × 200mL) with dichloromethane.Merge organic layer, Wash (3 × 200mL), saturated common salt washing (2 × 200mL), anhydrous sodium sulfate drying.Filtering, is concentrated under reduced pressure into about 100mL, 55mL petroleum ethers are added, 3h is cooled down under the conditions of 0 DEG C, there is the precipitation of yellow solid particle.Filtering, with the mixed liquor (dichloro that 40mL is cold Methane：Petroleum ether=4：1, volume ratio) washing, 65 DEG C of vacuum drying, obtain pale solid 4.58g.Yield 59%, fusing point 154- 155 DEG C of (literature values：154-155℃).

¹H NMR(300MHz,DMSO-d₆),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-ones

In toward 15mL methanol add intermediate 13 (1.20g, 3.80mmol), stirring, add 10%Pd/C (0.075g, 0.070mmol), it is heated to flowing back.Hydrazine hydrate (0.38g, 7.59mmol) is slowly instilled, drop finishes, and continues the 3h that flows back.Dropwise addition is dissolved in The sodium hydroxide (8.10g, 202mmol) of 26mL water, then the 2h that flows back.Claim heat filtering, be concentrated under reduced pressure and remove most of methanol (solution In just begun with solid particle precipitation), be placed in refrigerator and cool down 2h.Filtering, cold water washing (2 × 15mL), 65 DEG C of vacuum drying, Obtain clear crystal 0.48g.Yield 71%, 146-147 DEG C of fusing point (147-149 DEG C of document).

IR(KBr)δ_max(cm^-1):3261,3166,1682,1618,1608；¹H NMR(300MHz,DMSO-d₆),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)；¹³C NMR(300MHz,DMSO-d₆),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 p-methyl benzenesulfonic acid 2- (2- oxo-dihydro -4- indoles) ethyl ester

Into 50mL reaction bulbs add compound 14 (2.00g, 11.29mmol), 13mL Py, stirring, less than 5 DEG C at drip It is subject to 3.02g (15.84mmol) TsCl of 15mL dchloromethanes.Drop finishes, and 3h is stirred at 10 DEG C, and reaction is complete.It is added dropwise 20mL water, 9mL dichloromethane, 15mL concentrated hydrochloric acids, stratification after 2h is stirred, aqueous phase is extracted (40mL × 2) with dichloromethane, is closed And organic layer, washing, anhydrous sodium sulfate drying are overnight.Filtrate is steamed to just there is solid particle, cooling crystallization, is filtered, is dried, obtain To faint yellow solid 3.22g.Yield 86%, fusing point：128-129℃.

(7) preparation (2) of 4- (2- (propylcarbamic) ethyl) Indolin-2-one

65mL absolute ethyl alcohols, 9.08g (27.40mmol) compound 15, stirring and dissolving, N are added into reaction bulb₂Protection, 85mL (1.03mol) n-propylamine is added under ice-water bath.Drop finishes, and continues to stir 10min, then slowly heats, and flow back 2.5h, terminates Reaction.Be concentrated under reduced pressure (<30 DEG C), 150mL water is added into residue, pH to 11 is adjusted with 40%NaOH.Extracted with dichloromethane (250mL × 3), merge organic layer, washing, anhydrous sodium sulfate drying is overnight, filters, concentration.Purified through column chromatography, with dichloromethane Alkane：Methanol：Triethylamine=150:3:2 are eluted as eluent, obtain viscous brown shape compound 3.59g, yield 60%.

¹H NMR(300MHz,DMSO-d₆),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]⁺.

3rd, the preparation of 4- (2- ((3- (4- phenylpiperazine -1- bases) propyl group) (propyl group) amino) ethyl) Indolin-2-one (3a)

Toward addition 30mL acetonitriles, 0.70g (3.21mmol) compound 2,0.77g (3.24mmol) in reaction bulb under ice-water bath Compound 1a, stirring and dissolving, 0.89g (6.44mmol) potassium carbonate is added, 0.54g (3.25mmol) KI, is slowly heated up To 60 DEG C, raw material fundamental reaction is complete after 11h.Filter while hot, filtrate decompression concentration, residue is purified with column chromatography for separation, with two Chloromethanes：Methanol：Triethylamine=200:0.5:1 elution, obtains viscous brown shape compound 0.86g, yield 64%.

¹H NMR(300MHz,CDCl₃),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,CDCl₃),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]⁺.

The 3- of embodiment 2 (3- (4- (4- chlorphenyls) piperazine -1- bases) propyl group) -10- methoxies -2,3,4,4a, 5,6- Hexahydro -1H-

The preparation (3b) of pyrazine [1,2-a] and quinoline

Reference compound 3a preparation method, prepare compound 1b, input intermediate 2 (0.70g, 3.21mmol), reaction Viscous brown shape compound 0.93g, yield 67% are obtained after end.

¹H NMR(300MHz,CDCl₃),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,CDCl₃),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 4- of embodiment 3 (2- ((3- (4- (2,3- 3,5-dimethylphenyls) piperazine -1- bases) propyl group) (propyl group) amino) ethyl) two The preparation (3c) of hydrogen indoles -2- ketone

Reference compound 3a preparation method, prepare compound 1c, input intermediate 2 (0.70g, 3.21mmol), reaction Viscous brown shape compound 0.89g, yield 62% are obtained after end.

¹H NMR(300MHz,CDCl₃),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,CDCl₃),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 4- of embodiment 4 (2- (propyl group (3- (4- (o-tolyl) piperazine -1- bases) propyl group) amino) ethyl) indoline - The preparation (3d) of 2- ketone

Reference compound 3a preparation method, prepare compound 1d, input intermediate 2 (0.70g, 3.21mmol), reaction Viscous brown shape compound 0.92g, yield 66% are obtained after end.

¹H NMR(300MHz,CDCl₃),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,CDCl₃),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 4- of embodiment 5 (2- (propyl group (3- (4- (4- (trifluoromethoxy) phenyl) piperazine -1- bases) propyl group) amino) ethyl) The preparation (3e) of Indolin-2-one

Reference compound 3a preparation method, prepare compound 1e, input intermediate 2 (0.70g, 3.21mmol), reaction Viscous brown shape compound 1.13g, yield 70% are obtained after end.

¹H NMR(300MHz,CDCl₃),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,CDCl₃),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 4- of embodiment 6 (2-((3- (4- (3- methoxyphenyls) piperazine-1- bases) propyl group) (propyl group) amino) ethyl) dihydro The preparation (3f) of indol-2-one

Reference compound 3a preparation method, prepare compound 1f, input intermediate 2 (0.70g, 3.21mmol), reaction Viscous brown shape compound 0.94g, yield 65% are obtained after end.

¹H NMR(300MHz,CDCl₃),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,CDCl₃),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 4- of embodiment 7 (2- ((3- (4- (3,4- 3,5-dimethylphenyls) piperazine -1- bases) propyl group) (propyl group) amino) ethyl) two The preparation (3g) of hydrogen indoles -2- ketone

Reference compound 3a preparation method, prepare compound 1g, input intermediate 2 (0.70g, 3.21mmol), reaction Viscous brown shape compound 0.91g, yield 63% are obtained after end.

¹H NMR(300MHz,CDCl₃),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,CDCl₃),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 4- of embodiment 8 (2- ((2- (4- (3- methoxyphenyls) piperazine -1- bases) ethyl) (propyl group) amino) ethyl) dihydro The preparation (3h) of indol-2-one

Reference compound 3a preparation method, prepare compound 1h, input intermediate 2 (0.70g, 3.21mmol), reaction Viscous brown shape compound 0.91g, yield 65% are obtained after end.

¹H NMR(300MHz,CDCl₃),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,CDCl₃),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]⁺.

The 4- of embodiment 9 (2- ((2- (4- (4- chlorphenyls) piperazine -1- bases) ethyl) (propyl group) amino)) ethyl) dihydro Yin The preparation (3i) of diindyl -2- ketone

Reference compound 3a preparation method, prepare compound 1i, input intermediate 2 (0.70g, 3.21mmol), reaction Gray solid 0.96g, yield 68%, fusing point are obtained after end：136-137℃.

¹H NMR(300MHz,CDCl₃),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,CDCl₃),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 4- of embodiment 10 (2- (propyl group (2- (4- (4- (trifluoromethoxy) phenyl) piperazine -1- bases) ethyl) amino) second Base) Indolin-2-one preparation (3j)

Reference compound 3a preparation method, prepare compound 1j, input intermediate 2 (0.70g, 3.21mmol), reaction Viscous brown shape compound 0.93g, yield 59% are obtained after end.

¹H NMR(300MHz,CDCl₃),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,CDCl₃),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 4- of embodiment 11 (2- ((2- (4- phenylpiperazine -1- bases) ethyl) (propyl group) amino) ethyl) Indolin-2-one Preparation (3k)

Reference compound 3a preparation method, prepare compound 1k, input intermediate 2 (0.70g, 3.21mmol), reaction Gray solid 0.93g is obtained after end.Yield 71%, fusing point：113-114℃.

¹H NMR(300MHz,CDCl₃),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,CDCl₃),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 4- of embodiment 12 (2- ((2- (4- (3,4- 3,5-dimethylphenyls) piperazine -1- bases) ethyl) (propyl group) amino) ethyl) The preparation (3l) of Indolin-2-one

Reference compound 3a preparation method, prepare compound 1l, input intermediate 2 (0.70g, 3.21mmol), reaction Viscous brown shape compound 0.98g, yield 70% are obtained after end.

¹H NMR(300MHz,CDCl₃),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,CDCl₃),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 D₃Acceptor and D₂The affinity test of acceptor

The research of bioactivity is carried out to compound of the present invention, with the D of stable transfection₃R-HEK-293 cell lines are Carrier, by radioligand [³H] Spiperone competion experiments, the experiment of a series of receptors combination concentration is carried out, really Compound is determined to D₃Acceptor and D₂The K of acceptor_iValue.

Medicine and reagent:

[³H] Spiperone (98Ci/mmol) is purchased from PE companies；(+) Butaclamol, purchased from RBI companies；GF/C glass Glass fiber filter paper, purchased from Whatman companies；Fat-soluble scintillation solution Tris, is dispensed by Ji Tai Science and Technology Ltd.s.

Experimental method:

D₃R-HEK-293 cells, receptor protein great expression on film after 48-72 hours, cell 1000rpm is centrifuged Supernatant is abandoned after 5min, precipitation is resuspended in 5mM Tris, 5mM EDTA^.In 2Na, 5mM EGTA lysates (pH=7.4), on ice Place 30min.Mediate and shake 5-10 times, 4 DEG C, 40000g centrifugations 20min.Supernatant is abandoned, precipitation is resuspended in ice-cold 50mM Tris- In HCl (pH=7.4) buffer solution, syringe needle 5-10 times, 4 DEG C, 40000g centrifugations 20min are crossed.Coomassie brilliant G-250 method surveys albumen Concentration.

A certain amount of testing compound and radioactive ligand and receptor protein are added in reaction tube, 30 DEG C of water-baths are incubated After 50min, ice bath is moved at once and terminates its reaction.Then, on Millipore cell sample collection devices, by GF/C glass Fiber filter paper rapid filtration under suction, and with eluent (50mM Tris-HCl, PH=7.5) 3ml × 3 time, dried with 3~4min of micro-wave oven It is dry, filter paper is moved into 0.5ml centrifuge tubes, adds the fat-soluble scintillation solutions of 500ul.Lucifuge stands more than 30min, counts measure and puts Penetrating property intensity.

A certain amount of tested compound sample is respectively asked for, the experiment of a series of receptors combination concentration is carried out, determines compound To D₃Acceptor and D₂The K of acceptor_iValue.Compounds against dopamine D₃Acceptor and D₂Affinity (the K of acceptor_iValue) measurement result is shown in Table 2.

The compounds against dopamine D of table 2₃Acceptor and D₂The K of acceptor_iValue

* positive control is represented

Test 2 the experiment of environmental conditioned place preference

It is preferred that above-claimed cpd 3g (code name ZBH-II-A-8), studies it to morphine induced rat conditioned place preference Influence.

Experimental principle the experiment of environmental conditioned place preference (Conditioned Place Preference, CPP) is to comment at present The Classic Experiments of valency Drug psychological dependence, experimental animal (rat) is placed in the white observation area of conditioned place preference case, Psychic dependence medicine morphine is injected, observation experiment animal is in the black region of conditioned place preference case and the activity feelings of white area Condition (has wicket to be available for animal to pass freely through) between white area, black region and grey area therein.Because of the psychological dependence of medicine Effect, animal will be produced on position in administration area in the presence of drug reward effect to black and white region every time Preference.

Instrument and material Conditioned Place Preference in Rats instrument；Wistar rats, male, 200 ± 20g of body weight；

Reagent：Morphine hydrochloride；Compound ZBH-II-A-8, is synthesized by inventor.

Experimentation is divided into four-stage：Medicine prepares, time span of forecast, training period, tests the phase.

1) medicine prepares

Morphine solution：10mg/kg, 1mg morphines are claimed to be dissolved in 100mL distilled waters；Compound sample ZBH-II-A-8 solution： 1.0mg/kg, claim 0.1mg compounds ZBH-II-A-8 to be first dissolved in a small amount of DMSO, then add distilled water to 100mL；5.0mg/kg Claim 0.5mg compounds ZBH-II-A-8 to be first dissolved in a small amount of DMSO, then add distilled water to 100mL；10.0mg/kg, claim 1mg compounds ZBH-II-A-8 is 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, allows it freely to be run in three casees 15min.Residence time of the rat in each case is determined, judges rat to black, white box preference situation.

3) training period

The 4-11 days, dividing plate is plugged, prevents rat from being passed freely through between case.Every morning 9:00 and afternoon 14:00 starts Experiment.Daily with respectively training 1 time of salt solution and medicine, co-continuous 8 day time.ZBH-II-A-8 3 dosage groups, abdominal cavity is to ZBH- Morphine 10mg/kg is subcutaneously injected after 20 minutes in each dosage of II-A-8, is put into white box (with medicine-chest) 45min immediately after, subcutaneously Black box (non-with medicine-chest) 45min, daily circulation primary are immediately placed in after pump pickle.Give solvent 30 minutes in morphine group abdominal cavity Afterwards, white box (with medicine-chest) 45min is immediately placed in after morphine (10mg/kg) is subcutaneously injected, it is (non-to be immediately placed in black box after pump pickle With medicine-chest) 45min, daily circulation primary.After salt solution is given 30 minutes in solvent group abdominal cavity, it is immediately placed in after hypodermic injection solvent white Case 45min, 45min in black box, daily circulation primary are put into after pump pickle.

4) phase is tested

12nd day, extract dividing plate out, rat is put into intermediate box position, allow its 15min that freely run in three chests, use Computer remembers residence time of the rat in white box (with medicine-chest).

Whole experiment is divided into five groups：(a) solvent+physiological saline (NS)；(b) morphine+solvent (Mor-10mg/kg)；(c) Coffee+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, contrast each group rat is in medicine-chest Residence time.Test result indicates that in the Conditioned Place Preference in Rats experiment of morphine induction, ZBH-II-A-8 exists The generation of the conditioned place preference of morphine induction can be significantly reduced during two dosage of 5.0mg/kg and 10.0mg/kg.As a result see Figure of description 1.

In the experiment of conditions above Place Preference, the compound of other embodiments of the present invention all has and ZBH-II-A-8 Substantially similar result of the test, the generation of the conditioned place preference of morphine induction can be significantly reduced in doses.

Claims (10)

1. Indolin-2-one class D3 receptors ligands, as shown in compound of formula I：

Or its pharmaceutical salts,

Wherein, n=2 or 3；R represents H, 4-CH₃、2,3-diCH₃、2-CH₃、4-OCF₃、3-OCH₃、3,4-di CH₃Or 4-Cl.

2. Indolin-2-one class D3 receptors ligands according to claim 1, it is characterised in that during the n=2, R is 3-OCH₃、4-Cl、4-OCF₃, H or 3,4-di CH₃；During n=3, R H, 4-CH₃、2,3-diCH₃、2-CH₃、4-OCF₃、3-OCH₃ Or 3,4-di CH₃。

3. Indolin-2-one class D3 receptors ligands or its pharmaceutical salts described in claim any one of 1-2 prepare treatment or Prevention Nervous and mental diseases, protection nerve, treatment and D3 receptor dysfunctions have the application in the medicine of related disorders.

4. the application of Indolin-2-one class D3 receptors ligands according to claim 3 or its pharmaceutical salts, its feature exists In the Nervous and mental diseases are Parkinson's, schizophrenia, pharmacological dependence or not peaceful restless leg syndrome；It is described with D3 receptor dysfunctions have related disorders for schizophrenia, Parkinson's, pharmacological dependence or drug habit, various forms of spirit Anxiety, anxiety, sleep-disorder or male sexual disfunction.

5. the Indolin-2-one class D3 receptors ligands or its pharmaceutical salts described in claim any one of 1-2 are being prepared for grinding Study carefully D3 receptor structures, function and have application in the instrument medicine of related disorders with D3 receptor dysfunctions.

6. a kind of pharmaceutical composition, it is characterised in that contain any one of at least one claim 1-2 indoline -2- Ketone D3 receptors ligands or its pharmaceutical salts, and pharmaceutical carrier or excipient.

7. pharmaceutical composition according to claim 6, it is characterised in that described pharmaceutical composition is injection, infusion solution, drop Ball, tablet, capsule, granule or oral liquid.

8. the preparation method of any one of the claim 1-2 Indolin-2-one class D3 receptors ligands, it is characterised in that institute It is to react made by compound 3 and compound 2 to state Indolin-2-one class D3 receptors ligands, and reaction equation is as follows：

9. the preparation method of Indolin-2-one class D3 receptors ligands according to claim 8, it is characterised in that describedization Compound 3 is as made by compound 4 through following series reaction：

Wherein, in compound 6, R H, 4-CH₃、2,3-diCH₃、2-CH₃、4-OCF₃、3-OCH₃、3,4-diCH₃Or 4-Cl.

10. the preparation method of Indolin-2-one class D3 receptors ligands according to claim 8, it is characterised in that describedization Compound 2 is to be finally separating by compound 9 through following series reaction made by purifying：