WO2012130153A1 - Quinolinone derivatives and use thereof as medicament against schizophrenia - Google Patents

Quinolinone derivatives and use thereof as medicament against schizophrenia Download PDF

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WO2012130153A1
WO2012130153A1 PCT/CN2012/073281 CN2012073281W WO2012130153A1 WO 2012130153 A1 WO2012130153 A1 WO 2012130153A1 CN 2012073281 W CN2012073281 W CN 2012073281W WO 2012130153 A1 WO2012130153 A1 WO 2012130153A1
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compound
salt
quinolinone derivative
hydrogen
methyl
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PCT/CN2012/073281
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French (fr)
Chinese (zh)
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李建其
辜顺林
蔡王平
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江苏恒谊药业有限公司
上海医药工业研究院
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Publication of WO2012130153A1 publication Critical patent/WO2012130153A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to quinolinone derivatives having antipsychotic activity and their use as anti-psychotic drugs. Background technique
  • Schizophrenia is a common severe psychiatric disorder, the most serious and most harmful of all mental illnesses.
  • the global incidence rate is about 1%. With the accelerated pace of social life, the incidence rate is A clear upward trend.
  • Most schizophrenic patients abandon treatment due to long treatment cycles, high costs, and high side effects, often leading to more serious social consequences.
  • Numerous studies have shown that monoamine transmitters in the brain, especially dopamine and 5-hydroxytryptamine systems, are closely related to normal mental activity in humans. Disorders in these two systems can lead to a variety of neuropsychiatric diseases such as schizophrenia and neurosis. Pain, mania, anxiety, various depressions, Parkinson's disease, etc.
  • the drugs used in clinical practice are mainly traditional antipsychotic drugs (such as dopamine D 2 receptor antagonists) and atypical antipsychotics (such as D 2 /5-HT 2a dual antagonists), among which traditional antipsychotic drugs are easy.
  • EPS extrapyramidal symptoms
  • atypical antipsychotic drugs but no drug has an absolute advantage for the improvement of the overall lineage of schizophrenia, most of them are positive or negative symptoms
  • One symptom has improved, or the side effects have decreased. Therefore, it is a hot research topic in the world pharmaceutical industry to find new anti-schizophrenic drugs with low toxicity, fast onset and wide therapeutic spectrum.
  • 5-HT 2a receptor Antagonists can improve negative symptoms, and the synergistic effect with D 2 can reduce the side effects of EPS to about 1% (the incidence of classic anti-schizophrenia drugs is about 30%), the partial agonism of 5-HT la and Its synergistic effect with 5-HT 2a can reduce EPS to an undetectable level at therapeutic doses.
  • the invention relates to the quinolinone derivative capable of stabilizing the dopaminergic and serotoninergic system in the brain, and may have an improvement and therapeutic effect on various neuropsychiatric diseases, and can be used for neuropathic pain, mania, schizophrenia , anxiety disorders, various depressions, Parkinson's disease, especially the treatment of schizophrenia. Summary of the invention
  • the quinolinone derivative according to the invention is a compound of the formula I, a racemate of the formula I, a compound optical isomer of the formula I, a free base or a formula of a compound of the formula I Salt of the compound of I:
  • ⁇ represents hydrogen or methyl
  • R 3 represents hydrogen, methyl or ethyl
  • R 2 , R 3 are divided into two cases, the first one: R 2 is methoxy, R 3 is hydrogen; the second, R 2 is hydrogen, R 3 is hydrogen or methyl;
  • quinolinone derivative when the quinolinone derivative is an optical isomer of the compound of formula I, when ⁇ is a double bond, R1 methyl, R2 is hydrogen, and R3 is methyl or ethyl;
  • R2, R3 are hydrogen, and R1 is a methyl group
  • the salt is a salt containing a pharmaceutically acceptable anion such as a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a sulfate or a hydrogen sulfate, a phosphate or an acid phosphate, an acetic acid.
  • a pharmaceutically acceptable anion such as a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a sulfate or a hydrogen sulfate, a phosphate or an acid phosphate, an acetic acid.
  • Salt lactate, citrate, tartrate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate
  • An acid salt or a p-toluenesulfonate wherein a hydrochloride, a hydrobromide, a sulfate, a trifluoroacetate, a tartrate or a methanesulfonate is preferred, and the salt preferably contains 0.5 to 3 molecules of water of crystallization. , preferably a hydrochloride, a hydrobromide, a sulfate, a trifluoroacetate or a methanesulfonate;
  • the quinolinone derivative comprises:
  • the compounds 1-1, 1-2, 1-3, 1-4, (R)-I1 and (S)-I1 are simply referred to as "the six compounds of the present invention", the same applies hereinafter.
  • the invention further relates to a composition for the treatment of schizophrenia comprising a therapeutically effective amount of a compound of the formula (I) or a free base or salt of the compound and a pharmaceutically acceptable carrier .
  • the invention also relates to a compound or a free base or salt thereof for preparing a medicament for treating schizophrenia and other neuropsychiatric diseases use.
  • the neuropsychiatric diseases include neuropathic pain, mania, schizophrenia, anxiety, or various depressions.
  • the compounds of the present invention can be synthesized by the following methods:
  • R 2 has the same meaning as above, and 1 in the structure of the compound B is a halogen; the compound A is commercially available, and the related intermediate which is not commercially available can be prepared by a general synthetic method, and the synthesis method can be found in a specific compound.
  • In vitro receptor binding assays have shown that the compounds of the present invention have high affinity for dopamine D 2 , 5-HT 2a , 5-HT la receptors, and the proportional relationship between them is in accordance with the drug-forming requirements, and has intensive research. the value of. Animal studies have shown that these compounds can ameliorate the symptoms associated with the apomorphine model, MK-801 model mice.
  • CN101302214 reports some pharmacological data of the compound ⁇ -1, such as the compound pair The efficacy of the apomorphine model (reflecting the role of anti-schizophrenia-positive symptoms), but no test results for anti-schizophrenia-negative symptoms, such as the MK-801-induced open field model
  • the ED 2Q values of the six compounds of the present invention are about 10 times their corresponding anti-schizophretic activity ED 5Q values, suggesting that the compounds of this series are less likely to induce ataxia.
  • the ED 2Q dose value is much larger than the positive drugs risperidone and 11-1. Since the anti-schizophretic positive symptom activity of this series of compounds is comparable to that of risperidone and ⁇ -1, the therapeutic window is more risperidone and ⁇ -1.
  • the derivative of the present invention can be administered to a patient in need of such treatment by oral administration, injection or the like in the form of a composition, and the dose is usually 10 to 500 mg/day of body weight, which can be determined by a physician depending on the condition, age and sex of the patient.
  • Said composition contains a therapeutically effective amount of said quinolinone derivative and a pharmaceutically acceptable carrier.
  • the carrier means a conventional carrier in the pharmaceutical field, for example: a diluent, an excipient such as water, etc.; a binder such as a cellulose derivative, gelatin, polyvinylpyrrolidone or the like; a filler such as starch, etc.; a cracking agent such as calcium carbonate , sodium bicarbonate; lubricants such as calcium stearate or magnesium stearate.
  • other adjuvants such as flavoring agents and sweeteners may also be added to the composition.
  • the quinolinone derivative of the present invention has a high affinity for the dopamine D 2 receptor, and has not only a strong antagonistic activity, but also a partial agonistic effect on the D 2 receptor.
  • the compounds of the invention improve the symptoms associated with the apomorphine model, MK-801 model mice. Since these in vitro targets and in vivo pharmacological models are closely related to schizophrenia, it is suggested that the compounds of the present invention have therapeutic effects on schizophrenia. In addition, this series of compounds is better absorbed orally, and its acute toxicity is low (LD 5()
  • Figure 1 Compound 1-1 chiral column liquid phase map.
  • Figure 2 Compound (R)-1-1 chiral column liquid chromatogram.
  • Figure 4 Compound (S)-1-1 single crystal X-Ray diffraction front view, respectively, two molecular diagrams of a unit cell.
  • Figure 5 Compound (S)-1-1 single crystal X-Ray diffraction side view, respectively, a unit cell of two Molecular map. Detailed ways
  • the two optical isomers of 1-1 are named as peck-l and peck-2 in order of retention, and the absolute configuration of peck-2 is identified as S configuration by single crystal X-ray diffraction.
  • 1 is the R configuration, as shown in detail in Figures 1 to 5.
  • the results of chiral liquid chromatography analysis are shown in Figure 1 to Figure 3.
  • Figure 1 shows the liquid phase spectrum of the racemate
  • Figure 2 shows the liquid phase of peck-1
  • Figure 3 shows the liquid phase of peck-2
  • Figure 4 shows the liquid phase of peck-2.
  • -2 Single crystal X-Ray diffraction front view
  • Fig. 5 is a Peck-2 single crystal X-Ray diffraction side view.
  • Preparation method The active ingredient is mixed with sucrose and corn starch, moistened with water, stirred uniformly, dried, pulverized and sieved, added with magnesium stearate, uniformly mixed, and tableted. Each piece weighs 250
  • HEK293 cells were transfected with a plasmid vector containing the D 2 receptor protein gene, and subjected to calcium phosphate transfection, and cultured from the transfected cells through a medium containing G418.
  • a stable cell line stably expressing the D 2 receptor protein was finally obtained.
  • Isotope ligand Spiperone (113.0 Ci / mmol); purchased from Sigma;
  • (+) spiperone purchased from RBI; GF/B glass fiber filter paper, purchased from Whatman; Tris imported package; PPO, POPOP purchased from Shanghai Reagent 1; fat-soluble scintillation solution. Beckman LS-6500 multi-function liquid scintillation counter.
  • the HEK-293 cells were infected with the recombinant virus containing the above various genes. After 48-72 hours, the receptor protein was expressed on the membrane in a large amount. After centrifuging the cells at 1000 rpm for 5 min, the culture solution was discarded, and the cells were collected and stored in a refrigerator at -20 °C. Internal backup. Resuspend in Tris-HCl reaction buffer (pH 7.5) during the experiment.
  • test compound and the radioligand 20uL and 160uL receptor protein were added to the reaction tube, and the final concentration of the test compound and the positive drug was 10umol/L. After incubating in a 30°C water bath for 50 minutes, it was immediately transferred to an ice bath to terminate it. Reaction; rapid filtration on GF/C glass fiber filter paper on Millipore cell sample collector, and eluent (50 mM Tris-HCl, pH 7.5) 3 mL*3 times, microwaved for 5-6 min, filter paper Transfer to a 0.5 mL centrifuge tube and add 500 uL of fat-soluble scintillation fluid. The light was allowed to stand for 30 minutes or more, and the radioactivity was measured by counting. Calculate the percentage inhibition of isotopic ligand binding by each compound according to the following formula:
  • Inhibition rate (1%) total combined tube cpm - compound cpm / total combined tube cpm - non-specific binding tube cpm X 100%
  • HEK293 cells were transfected with a plasmid vector containing the 5-1 ⁇ 2 ; 1 receptor protein gene, using calcium phosphate transfection method, and cultured from the transfected cells through a medium containing G418, and cells were selected. Monoclonal and radioactive permeation binding experiments resulted in stable cell lines stably expressing the 5-HT 2a receptor protein.
  • Isotope ligand [ 3 H]-Ketanserin (67.0 Ci/mmol), purchased from PerkinElmer; (+) spiperone, purchased from RBI; GF/B glass fiber filter paper, purchased from Whatman; Tris imported packaging; PPO, POPOP was purchased from Shanghai Reagent No. 1; fat-soluble scintillation fluid. Beckman LS-6500 multi-function liquid scintillation counter.
  • Inhibition rate (I %) total binding tube cpm - compound cpm / total binding tube cpm - non-specific binding tube cpm X 100%
  • 5-HT la acceptor isotopes [1H].8-OH-DPAT (purchased from PE), (+) 5-hydroxytrptamine (purchased from Sigma), GF/B glass fiber filter (purchased from Whatman) , fat-soluble scintillation fluid: ⁇ , ⁇ (purchased from Shanghai Reagent No. 1), toluene (purchased from Sinopharm Chemical Reagent Co., Ltd.), Tris imported sub-package.
  • HEK-293 cells stably expressing 5-HT 1A receptor by gene recombination were cultured in 3-5 cells cultured with DMEM + 10% serum, cells were harvested with PBS, and cells were centrifuged at -4 to 3000 rpm. After a minute, discard the supernatant, collect the cells, and store in a -80 degree refrigerator. Resuspend with Binding Buffer (PH7.4) during the experiment.
  • the coarse inhibition assay was used to determine the competitive inhibition rate of [ 3 H] 8-OH-DPAT binding to 5-HT 1A receptor at a concentration of 10 umol/L per compound.
  • Compounds with inhibition rates above 95% were subjected to a series of receptor binding assays. , determine the half-inhibition (IC50, inhibition of 50% [1H] 8-OH-DPAT and 5-HT la receptor binding required compound concentration). Two sets of tubes were tested per concentration and each compound was tested twice independently.
  • CHO-rD 2 cells were seeded at 30,000 cells/well in 96-well plates and cultured overnight; each drug was dissolved in serum-free F12 medium containing ⁇ ,, added to cells and pre-incubated at 37 ° C for 30 min; added 10 ⁇ Forskolin ⁇ 10 ⁇ Dopamine serum-free F 12 solution was reacted for 8 min, and the reaction was stopped by adding ⁇ pre-cooled IM HCIO4, and the mixture was iced for 40 min. The reaction mixture was added with 20 ⁇ l 2 ⁇ ⁇ 3 , centrifuged at 3000 rpm for 4 min at 15 ° C, and the KClO 4 precipitate was discarded.
  • the cells were removed by washing twice with 200 ⁇ l of serum-free medium, and 90 ⁇ l of serum-free medium was added to each well. The plate was incubated for 2-3 hours. 10 ⁇ serum-containing medium, vehicle (serum-free medium), negative control (antagonist) or test compound and standard in serum-free medium (positive concentration of luM) Add the lOuM solution) to each well. Return the plate to the incubator. After 18 hours, adenosine (0.5 ⁇ /well) was added to the ⁇ serum-free medium and the plate was returned to the incubator. After 4 hours, trypsin (0.25%) ( ⁇ /well) was added. Return the plate to the incubator again.
  • the test was terminated by rapid filtration through a Whatman GF IB glass fiber filter.
  • a Whatman GF IB glass fiber filter For example, using a Brandel MLR-96T cell harvester, the filter was washed with 500 mL of 50 mM Tris-HCI pH 7.0 buffer.
  • the retained radioactivity (50% effective amount) on the filter was evaluated using a Wallac 1205 Betaplate liquid scintillation counter.
  • the intrinsic activity was defined as the total uptake ( ⁇ quiziro) minus the serum-free medium, and the test compound was compared to ⁇ Quipirro (complete DA agonist) classified as 100% intrinsic activity. All tests are preferably performed in triplicate, with each drug occupying a complete column in each plate. The test results are shown in the table below: Partial agonistic results of compound D 2 of the present invention
  • the GTPyS binding assay was performed in a ⁇ buffer system with 10 ⁇ ⁇ protein per tube, and the reaction buffer was 50 mM Tris, pH 7.4, 5 mM MgCl 2 , 1 mM EDTA, 100 mM NaCl, 1 mM DTT, pH 7.5.
  • the reaction system contained 40 ⁇ of GDP, and the non-specific tube was added to ⁇ Gpp(NH)p.
  • the test tube was added with different concentrations of test drug and 10 ⁇ 5- ⁇ .
  • Each tube was added with O.lnM [ 35 S] GTPyS and placed in a water bath at 30 ° C for 30 min. The reaction was stopped on ice and filtered through a GF/C membrane. After drying, it was placed in a 0.5 ml EP tube, 500 ⁇ l of a fat-soluble scintillation fluid was added, and the radioactivity was measured by a MicroBeta liquid scintillation meter.
  • CHO cells were lysed with 50 mM Tris, pH 7.4, sterilized at 1000 x g for 10 minutes at 4 ° C, and the supernatant was again centrifuged at 36000 x g for 30 minutes at 4 ° C to retain the pellet, which was suspended in 50 mM Tris, pH 7.4, and protein was measured by BCA method. concentration.
  • GTPyS binding assay was performed in a ⁇ buffer system with 10 ⁇ ⁇ protein per tube, reaction
  • the buffer was 50 mM Tris, pH 7.4, 5 mM MgCl 2 , O.lmM EGTA, 100 mM NaCl, 1 mM DTT, pH 7.5.
  • the reaction system contained 40 ⁇ GDP, and the non-specific tube was added to ⁇ Gpp(NH)p.
  • the test tube was added with different concentrations of test drug and ⁇ 5- ⁇ . Each tube was added with O.lnM [ 35 S] GTPyS and placed in a water bath at 22 ° C for 60 min. The reaction was stopped on ice and filtered through a GF/C membrane.
  • mice male and female, were randomly divided into 8 groups according to body weight: blank control group, model control group, gradient dose group of test compound (5 doses, determined according to pre-experiment) And risperidone group (1.00 mg-kg 1 ), aripiprazole group (0.50mg/Kg), administered by intragastric administration.
  • the model control group was intragastrically administered with the same volume of solvent. 30 minutes after the administration of the test drug, a concentration of 10.0 mg'kg- 1 of apomorphine solution (dissolved in 0.1% ascorbic acid) was induced by intraperitoneal injection of 10.0 mL kg- 1 mouse body to establish mouse essence.
  • mice After administration of apomorphine in mice, observe records 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51- 55.
  • the mice In the first 30 seconds of 56-60 minutes, the mice showed stereotypes such as vertical tail and wall climbing, and scored according to the following criteria: 0 points, no such behavior occurred within 30 seconds (K1 seconds); 1 point The discontinuous moderate behavior (30 seconds ⁇ 3 seconds) occurred within 30 seconds; 2 points, continuous strong above behavior (t > 3 seconds) occurred within 30 seconds.
  • the total score of stereotypes such as vertical tail and wall climbing in the mice was calculated within 60 minutes.
  • the ED50 is calculated according to the formula:
  • Aripiprazole group 12 0.50 6.41 soil 4.72 76.98
  • mice Immediately after the mice were given MK-801, they were placed in a soundproof box to observe the total distance of the mice's self-activity within 60 minutes.
  • the ED 5Q is calculated according to the above formula as a regression equation.
  • Risperidone group 12 0.30 3028.00 soil 825.3 1 88.01 aripiprazole group 12 0.30 2975.00 ⁇ 814.25 88.22
  • the six compounds described in the present invention cause the mouse ataxia test ED 2Q
  • mice Seventy ICR mice were randomly divided into 7 groups, 10 in each group.
  • the six compounds and the compound ⁇ -1 according to the claims were administered to mice by intragastric administration, and one group of each compound, that is, 10 animals, at a dose of 2 mg/Kg, was subjected to pharmacokinetic experiments, and the results were as follows: Plasma major pharmacokinetic parameters
  • the LD 5() of the six compounds of the present invention is more than 1500 mg/kg in a single administration, and the LD 5Q value is much larger than 20 times of the pharmacodynamic dose (ED 5Q ), which is highly safe.
  • ED 5Q pharmacodynamic dose
  • Species Salmonella typhimurium histidine auxotrophic mutants TA 97 , TA 98 , TA 1 (K) and TA 102 .
  • RESULTS The experiment consisted of two parts, -s « ⁇ n + s 9 , in the absence of the S 9 test system in the D 98 and the S 9 test system ⁇ 97 5000 ⁇ ⁇ / dish has a bacteriostatic effect. The other doses had no bacteriostatic effect on all strains, and the growth background was good. All test doses did not cause any significant increase in colony reversion variables in either the S 9-free or S 9 experimental system, and the Ames test was negative.

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Abstract

Disclosed are quinolinone derivatives and use thereof as a medicament against schizophrenia. The quinolinone derivatives of the present invention have a high affinity to dopamine d2 receptors, not only showing a relatively strong antagonist activity, but also exhibiting partial activation of d2 receptors. The compounds have good oral absorption and exhibit low acute toxicity (LD50 > 1500 mg/kg, a single gavage in mice) that is equivalent to aripiprazole and ziprasidone and far lower than risperidone, thus having the potential to be developed into a novel medicament against schizophrenia. The general structure is as follows:

Description

喹啉酮衍生物及其作为抗精神分裂症药物的应用 技术领域  Quinolinone derivatives and their use as anti-schizophrenia drugs
本发明涉及具有抗精神病活性的喹啉酮衍生物以及它们作为抗精 神分裂症药物的应用。 背景技术  The present invention relates to quinolinone derivatives having antipsychotic activity and their use as anti-psychotic drugs. Background technique
精神分裂症是一种常见的重性精神病患， 是所有精神疾病中最严 重、 危害最大的一种， 全球范围内的发病率约为 1%， 随着社会生活节 奏的加快， 发病率呈明显上升趋势。 多数精神分裂患者由于治疗周期 长、 费用高、 副作用大而放弃治疗， 往往会导致更严重的社会后果。 大量研究表明， 脑内单胺递质， 特别是多巴胺和 5-羟基色胺系统 与人体正常精神活动密切相关， 这两类系统的紊乱可导致多种神经精 神类疾病如精神分裂症、 神经性疼痛、 躁狂症、 焦虑症、 各种抑郁症、 帕金森氏病等。 目前临床上使用的药物主要为传统抗精神病药（如多巴胺 D2受体 拮抗剂） 和非典型抗精神病药 （如 D2/5-HT2a双重拮抗剂） ， 其中， 传 统抗精神病药由于容易导致锥体外系症状 （EPS ) 而逐渐被淘汰， 非典 型抗精神病药种类繁多， 但并没有哪一个药物对于精神分裂症整体谱 系的改善有绝对的优势， 多数是对阳性或阴性症状中的某一症状有所 改善， 或副作用降低。 因此寻找毒副作用低， 起效快， 治疗谱宽的新 型抗精神分裂药一直是世界制药业的研究热点。 近年来， 科学家发现多巴胺 D2部分激动剂能在多巴胺活动过度时 减少多巴胺的传递， 而非全部阻断； 反之， 当多巴胺能活性低下时则 引起刺激作用， 对精神病阳性和阴性症状都有显著疗效。 5-HT2a受体 拮抗剂可以改善阴性症状， 同时与 D2的协同作用可以将 EPS副作用降 低到 1%左右的水平 （经典抗精神分裂症药物 EPS发生率约为 30% ) ， 5-HTla的部分激动作用及其与 5-HT2a的协同作用可以使得在治疗剂量 下 EPS降低到观测不到的水平， 因此， 具有 D2、 5-HT2a、 5HTla三靶点 协同作用的新型抗精神分裂药物是目前研发的重点和重要发展方向。 本发明涉及所述喹啉酮衍生物能稳定脑内多巴胺能、 5-羟色胺能 系统， 可能对多种神经精神类疾病具有改善和治疗作用， 可用于神经 性疼痛、 躁狂症、 精神分裂症、 焦虑症、 各种抑郁症、 帕金森氏病， 尤其是精神分裂症的治疗。 发明内容 Schizophrenia is a common severe psychiatric disorder, the most serious and most harmful of all mental illnesses. The global incidence rate is about 1%. With the accelerated pace of social life, the incidence rate is A clear upward trend. Most schizophrenic patients abandon treatment due to long treatment cycles, high costs, and high side effects, often leading to more serious social consequences. Numerous studies have shown that monoamine transmitters in the brain, especially dopamine and 5-hydroxytryptamine systems, are closely related to normal mental activity in humans. Disorders in these two systems can lead to a variety of neuropsychiatric diseases such as schizophrenia and neurosis. Pain, mania, anxiety, various depressions, Parkinson's disease, etc. Currently, the drugs used in clinical practice are mainly traditional antipsychotic drugs (such as dopamine D 2 receptor antagonists) and atypical antipsychotics (such as D 2 /5-HT 2a dual antagonists), among which traditional antipsychotic drugs are easy. Lead to extrapyramidal symptoms (EPS) and gradually eliminated, a wide variety of atypical antipsychotic drugs, but no drug has an absolute advantage for the improvement of the overall lineage of schizophrenia, most of them are positive or negative symptoms One symptom has improved, or the side effects have decreased. Therefore, it is a hot research topic in the world pharmaceutical industry to find new anti-schizophrenic drugs with low toxicity, fast onset and wide therapeutic spectrum. In recent years, scientists have found that dopamine D 2 partial agonists can reduce dopamine transmission, but not all, when dopamine hyperactivity; conversely, when dopaminergic activity is low, it causes irritation, and both psychotic positive and negative symptoms are significant. Efficacy. 5-HT 2a receptor Antagonists can improve negative symptoms, and the synergistic effect with D 2 can reduce the side effects of EPS to about 1% (the incidence of classic anti-schizophrenia drugs is about 30%), the partial agonism of 5-HT la and Its synergistic effect with 5-HT 2a can reduce EPS to an undetectable level at therapeutic doses. Therefore, a novel anti-schizophrenic drug with synergistic effects of D 2 , 5-HT 2a , and 5HT la is currently The focus of research and development and important development directions. The invention relates to the quinolinone derivative capable of stabilizing the dopaminergic and serotoninergic system in the brain, and may have an improvement and therapeutic effect on various neuropsychiatric diseases, and can be used for neuropathic pain, mania, schizophrenia , anxiety disorders, various depressions, Parkinson's disease, especially the treatment of schizophrenia. Summary of the invention
本发明需要解决的技术问题之一是公开一种喹啉酮衍生物， 以克 服现有药物锥体外系症状明显、 催乳素升高等副作用的缺陷， 以解决 临床难题和满足临床用药需求。 本发明需要解决的技术问题之二是公开上述化合物作为在制备治 疗精神分裂症及相关的神经精神类疾病药物中的应用。 本发明所述的喹啉酮衍生物为具有如下结构通式 I 的化合物、 通 式 I的化合物消旋体、 通式 I的化合物光学异构体、 通式 I的化合物的 游离碱或通式 I的化合物的盐：  One of the technical problems to be solved by the present invention is to disclose a quinolinone derivative, which overcomes the drawbacks of side effects such as obvious extrapyramidal symptoms and elevated prolactin in order to solve clinical problems and meet clinical drug demand. The second technical problem to be solved by the present invention is to disclose the use of the above compounds as a medicament for the preparation of a medicament for treating schizophrenia and related neuropsychiatric diseases. The quinolinone derivative according to the invention is a compound of the formula I, a racemate of the formula I, a compound optical isomer of the formula I, a free base or a formula of a compound of the formula I Salt of the compound of I:
Figure imgf000004_0001
Figure imgf000004_0001
通式 I  Formula I
中：  Medium:
=为单键或双键；  = single or double button;
！^代表氢或甲基；  ! ^ represents hydrogen or methyl;
代表氢或甲氧基; R3代表氢、 甲基或乙基； Represents hydrogen or methoxy; R 3 represents hydrogen, methyl or ethyl;
优选的：  Preferred:
当^为双键时， ！^为甲基， R2、 R3分为两种情况， 第一种： R2 为甲氧基， R3为氢； 第二种， R2为氢， R3为氢或甲基； When ^ is a double button, ! ^ is methyl, R 2 , R 3 are divided into two cases, the first one: R 2 is methoxy, R 3 is hydrogen; the second, R 2 is hydrogen, R 3 is hydrogen or methyl;
当^为单键时， R2、 R3为氢， ！^为甲基； When ^ is a single bond, R 2 and R 3 are hydrogen, ! ^ is methyl;
优选的： 所述的喹啉酮衍生物为通式 I 的化合物光学异构体时， 当^为双键时， R1 甲基， R2为氢， R3为甲基或乙基； Preferred: when the quinolinone derivative is an optical isomer of the compound of formula I, when ^ is a double bond, R1 methyl, R2 is hydrogen, and R3 is methyl or ethyl;
当^为单键时， R2、 R3为氢， R1为甲基；  When ^ is a single bond, R2, R3 are hydrogen, and R1 is a methyl group;
在上述结构化合物为游离碱的情况下， 它们均能够与各种无机酸 和有机酸形成各种不同的盐。 所述的盐为含有药物上可接受的阴离子的盐， 诸如盐酸盐、 氢溴 酸盐、 氢碘酸盐、 硝酸盐、 硫酸盐或硫酸氢盐、 磷酸盐或酸式磷酸盐、 乙酸盐、 乳酸盐、 柠檬酸盐、 酒石酸盐、 马来酸盐、 富马酸盐、 葡糖 酸盐、 糖二酸盐、 苯甲酸盐、 甲磺酸盐、 乙磺酸盐、 苯磺酸盐、 对甲 苯磺酸盐， 其中优选盐酸盐、 氢溴酸盐、 硫酸盐、 三氟醋酸盐、 酒石 酸盐或甲磺酸盐，所说的盐优选含 0.5-3分子的结晶水，优选为盐酸盐、 溴氢酸盐、 硫酸盐、 三氟醋酸盐或甲磺酸盐；  In the case where the above structural compounds are free bases, they are capable of forming various salts with various inorganic acids and organic acids. The salt is a salt containing a pharmaceutically acceptable anion such as a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a sulfate or a hydrogen sulfate, a phosphate or an acid phosphate, an acetic acid. Salt, lactate, citrate, tartrate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate An acid salt or a p-toluenesulfonate, wherein a hydrochloride, a hydrobromide, a sulfate, a trifluoroacetate, a tartrate or a methanesulfonate is preferred, and the salt preferably contains 0.5 to 3 molecules of water of crystallization. , preferably a hydrochloride, a hydrobromide, a sulfate, a trifluoroacetate or a methanesulfonate;
优选的， 所述喹啉酮衍生物包括：  Preferably, the quinolinone derivative comprises:
7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基 )-3，4-二氢 -3-甲 基喹啉 -2(1H)-酮、 7-( 3 -(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3,4-dihydro-3-methyl quinoline -2(1H)-ketone,
7— (3—(4-(6-氟苯并 [d]异哑唑 -3-基）哌啶 -1-基）丙氧基 )-3-甲基喹啉 -2(1H)-酮、 7 — (3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3-methylquinolin-2(1H)-one ,
7— (3— (4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基) -2-甲基丙氧基) -3-甲 基喹啉 -2(1H)-酮、 7 — (3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-2-methylpropoxy)-3-methylquinoline-2 (1H)-ketone,
7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基）哌啶 -1-基)丙氧基 )-6-甲氧基 -3- 甲基喹啉 -2(1H)-酮。  7-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-6-methoxy-3-methylquinoline- 2(1H)-ketone.
(R)- 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基） -3-甲基 喹啉 -2(1H 酮或其盐、  (R)- 7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3-methylquinolin-2 ( 1H ketone or its salt,
(S)- 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基） -3-甲基喹 啉 -2(1H)-酮或其盐。 上述化合物的结构见表 1。 表 1、 化合物结构 (S)- 7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3-methylquin Porphyrin-2(1H)-one or a salt thereof. The structure of the above compounds is shown in Table 1. Table 1, compound structure
Figure imgf000006_0001
本发明将化合物 1-1、 1-2、 1-3、 1-4、 （R)- I-l和 (S)- I-l简称为 "本 发明所述六个化合物" ， 下同。 本发明还涉及一种用于治疗精神分裂症的组合物， 所述组合物包 括治疗有效量的结构通式 (I)所示的化合物或该化合物的游离碱或盐和 医学上可接受的载体。 本发明还涉及化合物或其游离碱或盐在制备治疗精神分裂症及其 它神经精神疾病药物中的应 用。 所述的神经精神疾病包括神经性疼痛、 躁狂症、 精神分裂症、 焦 虑症或各种抑郁症等。 本发明的化合物可采用如下的方法进行合成：
Figure imgf000006_0001
In the present invention, the compounds 1-1, 1-2, 1-3, 1-4, (R)-I1 and (S)-I1 are simply referred to as "the six compounds of the present invention", the same applies hereinafter. The invention further relates to a composition for the treatment of schizophrenia comprising a therapeutically effective amount of a compound of the formula (I) or a free base or salt of the compound and a pharmaceutically acceptable carrier . The invention also relates to a compound or a free base or salt thereof for preparing a medicament for treating schizophrenia and other neuropsychiatric diseases use. The neuropsychiatric diseases include neuropathic pain, mania, schizophrenia, anxiety, or various depressions. The compounds of the present invention can be synthesized by the following methods:
Figure imgf000007_0001
其中， 、 R2的涵义同上， 化合物 B结构中的 1为卤素； 化合物 A可商购， 不易商购的相关中间体可用通用的合成方法制 备， 合成方法见具体化合物。 体外受体结合试验表明， 本发明所涉及的化合物对多巴胺 D2、 5-HT2a、 5-HTla受体具有较高的亲和力， 且相互之间的比例关系符合成 药性要求， 具有深入研究的价值。 动物试验结果显示， 这些化合物能改善阿朴吗啡模型、 MK-801 模型小鼠的相关症状。 由于这些体外作用靶点和体内药理模型与多巴 胺功能紊乱导致的神经系统疾病， 特别是精神分裂症密切相关， 因此 提示本发明涉及的化合物具有对精神分裂症的治疗作用。 动物僵住症 实验表明， 该系列化合物在治疗剂量下诱发椎体外系副作用的概率低。 动物模型研究结果表明， 本发明中所述六个化合物均具有明显抗 精神分裂症的作用， 口服吸收较好， 急性毒性与阿立哌唑和齐拉西酮 相当， 远低于利培酮， Ames试验阴性， 治疗指数较大， 药代动力学性 质符合成药性要求， 具备作为新型抗精神分裂症开发的潜在价值。
Figure imgf000007_0001
Wherein, R 2 has the same meaning as above, and 1 in the structure of the compound B is a halogen; the compound A is commercially available, and the related intermediate which is not commercially available can be prepared by a general synthetic method, and the synthesis method can be found in a specific compound. In vitro receptor binding assays have shown that the compounds of the present invention have high affinity for dopamine D 2 , 5-HT 2a , 5-HT la receptors, and the proportional relationship between them is in accordance with the drug-forming requirements, and has intensive research. the value of. Animal studies have shown that these compounds can ameliorate the symptoms associated with the apomorphine model, MK-801 model mice. Since these in vitro target and in vivo pharmacological models are closely related to neurological diseases caused by dopamine dysfunction, particularly schizophrenia, it is suggested that the compounds of the present invention have therapeutic effects on schizophrenia. Animal catalepsy experiments have shown that this series of compounds has a low probability of inducing side effects of extracorporeal body at therapeutic doses. The results of the animal model study showed that the six compounds described in the present invention have obvious anti-schizophrenia effects, and the oral absorption is better, and the acute toxicity is comparable to that of aripiprazole and ziprasidone, which is much lower than that of risperidone. The Ames test is negative, the therapeutic index is large, and the pharmacokinetic properties are consistent with the drug-forming requirements, and have potential value as a new type of anti-schizophrenia development.
CN101302214报道了化合物 Π-1的一些药理数据， 如该化合物对 阿扑吗啡模型的药效 （反映抗精神分裂症阳性症状的作用） ， 但没有 抗精神分裂症阴性症状的试验结果，如对 MK-801诱导的旷场运动模型 的研
Figure imgf000008_0001
CN101302214 reports some pharmacological data of the compound Π-1, such as the compound pair The efficacy of the apomorphine model (reflecting the role of anti-schizophrenia-positive symptoms), but no test results for anti-schizophrenia-negative symptoms, such as the MK-801-induced open field model
Figure imgf000008_0001
II- 1 本发明所涉及的六个化合物较 Π-1 具有更好的抗精神分裂症活性 和更高的安全性， 具备突出的成药性优点。 具体阐述如下： 按照 II-1 The six compounds involved in the present invention have better anti-schizophrenia activity and higher safety than Π-1, and have outstanding drug-forming advantages. The details are as follows:
CN101302214说明书中方法合成了 11-1，与本发明所述六个化合物进行 了药效、 药代及安全性的比对实验 （结果见实施例 15〜实施例 25 ) ， 结果表明： The method of the specification of CN101302214 synthesizes 11-1, and performs the comparison test of pharmacodynamics, pharmacokinetics and safety with the six compounds of the present invention (the results are shown in Example 15 to Example 25), and the results show that:
1、 阿扑吗啡诱导的刻板运动模型中， 说明本发明所述六个化合物 具有较强的抗精神分裂症阳性症状作用， 与 Π-1 相比在该模型下活性 相当。  1. Apomorphine-induced stereotypic exercise model, indicating that the six compounds of the present invention have strong anti-schizophrenia positive symptoms, and have comparable activity in this model compared to Π-1.
2、 MK-801诱导的旷场运动模型中， 本发明中所述六个化合物显 示出较强的抗精神分裂症阴性症状作用， 活性均远强于 11-1。  2. In the MK-801 induced open field exercise model, the six compounds described in the present invention showed strong anti-schizophrenia negative symptoms, and the activities were much stronger than 11-1.
3、 本发明所述六个化合物 ED2Q值为其对应的抗精神分裂活性 ED5Q值 10倍左右， 提示该系列化合物诱发共济失调的可能性较小。 其 ED2Q剂量值远大于阳性药利培酮及 11-1，由于该系列化合物抗精神分裂 阳性症状活性与利培酮、 Π-1相当， 所以其治疗窗较利培酮、 Π-1更宽， 又鉴于本发明所述化合物对精神分裂症阴性症状、 药代特性显著优于 化合物 Π-1， 因此， 本发明所述六个化合物比 Π-1具有更强的抗精神分 裂症活性和更好的安全性， 成药性更好， 显示了本发明所述六个化合 物较 CN101302214, 具有技术优势、 创造性、 深入开发的价值及显著 的科学进步。 本发明的衍生物可以组合物的形式通过口服、 注射等方式施用于 需要这种治疗的患者， 剂量一般为 10〜500mg/天体重， 具体可根据患 者的病情、 年龄和性别由医师决定。 所说的组合物含有治疗有效量的所说的喹啉酮衍生物和医学上可 接受的载体。 所说的载体是指药学领域常规的载体， 例如： 稀释剂、 赋形剂如 水等； 粘合剂如纤维素衍生物、 明胶、 聚乙烯吡咯烷酮等； 填充剂如 淀粉等； 崩裂剂如碳酸钙、 碳酸氢钠； 润滑剂如硬脂酸钙或硬脂酸镁 等。 另外， 还可以在组合物中加入其他辅助剂如香味剂和甜味剂。 用 于口服时， 可将其制备成常规的固体制剂如片剂、 粉剂或胶囊等； 用 于注射时， 可将其制备成注射液。 本发明的组合物的各种剂型可以采用医学领域常规的方法进行制 备， 其中活性成分的含量为 0.1%〜99.5% (重量比） 。 综上所述， 本发明的喹啉酮衍生物对多巴胺 D2 受体具有较高的 亲和力， 不仅具有较强的拮抗活性， 且体现出对 D2 受体的部分激动 作用。 体内试验表明， 本发明的化合物能改善阿朴吗啡模型、 MK-801 模型小鼠的相关症状。 由于这些体外作用靶点和体内药理模型与精神 分裂症密切相关， 因此提示本发明涉及的化合物具有对精神分裂症的 治疗作用。 另外该系列化合物口服吸收较好， 其急性毒性较低 （LD5() 3. The ED 2Q values of the six compounds of the present invention are about 10 times their corresponding anti-schizophretic activity ED 5Q values, suggesting that the compounds of this series are less likely to induce ataxia. The ED 2Q dose value is much larger than the positive drugs risperidone and 11-1. Since the anti-schizophretic positive symptom activity of this series of compounds is comparable to that of risperidone and Π-1, the therapeutic window is more risperidone and Π-1. Width, and in view of the fact that the compound of the present invention is significantly superior to the compound Π-1 in the negative symptoms and pharmacological properties of schizophrenia, the six compounds of the present invention have stronger anti-schizophretic activity than Π-1 and Better safety and better drug-taking, showing that the six compounds of the present invention have technical advantages, creativity, in-depth development value and significant scientific progress compared with CN101302214. The derivative of the present invention can be administered to a patient in need of such treatment by oral administration, injection or the like in the form of a composition, and the dose is usually 10 to 500 mg/day of body weight, which can be determined by a physician depending on the condition, age and sex of the patient. Said composition contains a therapeutically effective amount of said quinolinone derivative and a pharmaceutically acceptable carrier. The carrier means a conventional carrier in the pharmaceutical field, for example: a diluent, an excipient such as water, etc.; a binder such as a cellulose derivative, gelatin, polyvinylpyrrolidone or the like; a filler such as starch, etc.; a cracking agent such as calcium carbonate , sodium bicarbonate; lubricants such as calcium stearate or magnesium stearate. In addition, other adjuvants such as flavoring agents and sweeteners may also be added to the composition. For oral administration, it can be prepared into a conventional solid preparation such as a tablet, a powder or a capsule, etc.; when it is used for injection, it can be prepared as an injection. The various dosage forms of the compositions of the present invention can be prepared by conventional methods in the medical field, wherein the active ingredient is present in an amount of from 0.1% to 99.5% by weight. In summary, the quinolinone derivative of the present invention has a high affinity for the dopamine D 2 receptor, and has not only a strong antagonistic activity, but also a partial agonistic effect on the D 2 receptor. In vivo tests have shown that the compounds of the invention improve the symptoms associated with the apomorphine model, MK-801 model mice. Since these in vitro targets and in vivo pharmacological models are closely related to schizophrenia, it is suggested that the compounds of the present invention have therapeutic effects on schizophrenia. In addition, this series of compounds is better absorbed orally, and its acute toxicity is low (LD 5()
> 1500mg/Kg，小鼠单次灌服） 与阿立哌唑和齐拉西酮相当， 远远低于 利培酮， 具备作为一类新型抗神经精神疾病药物开发的潜在价值。 附图说明 > 1500mg/Kg, single-dose in mice) is comparable to aripiprazole and ziprasidone, far below risperidone, and has potential value as a new class of anti-neuropsychiatric drugs. DRAWINGS
图 1 化合物 1-1手性柱液相图谱。  Figure 1 Compound 1-1 chiral column liquid phase map.
图 2 化合物 (R)- 1-1手性柱液相图谱。  Figure 2 Compound (R)-1-1 chiral column liquid chromatogram.
图 3 化合物 (S)- 1-1手性柱液相图谱。  Figure 3. Compound (S)-1-1 chiral column liquid chromatogram.
图 4 化合物 (S)- 1-1单晶 X-Ray衍射正视图，分别为一个晶胞的两 个分子图。  Figure 4 Compound (S)-1-1 single crystal X-Ray diffraction front view, respectively, two molecular diagrams of a unit cell.
图 5 化合物 (S)- 1-1单晶 X-Ray衍射侧视图，分别为一个晶胞的两 个分子图。 具体实施方式 Figure 5 Compound (S)-1-1 single crystal X-Ray diffraction side view, respectively, a unit cell of two Molecular map. Detailed ways
本发明按下列方法制备。 除非另外说明， 取代基 、 R2、 R3、 的 定义同上。 实施例 1 The present invention was prepared in the following manner. Unless otherwise stated, the substituents, R 2 , R 3 , are as defined above. Example 1
1-1 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基 )-3，4-二氢 -3-甲基喹啉 -2(1H)-酮的制备  1-1 7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3,4-dihydro-3-methyl Preparation of quinolin-2(1H)-one
1 ) N-(3-甲氧基苯基)丙酰胺  1) N-(3-methoxyphenyl)propanamide
将 3-甲氧基苯胺 (0.1mol)、 二氯甲烷 (30mL)、 三乙胺 (0.2mol)， 加 入到 lOOmL三口瓶中， 冰浴下滴加丙酰氯 (0.12mol)的二氯甲烷溶液 30 mL， 控温不超过 5 °C， 加毕， 撤去冰浴， 室温搅拌 0.5h， 体系依次用 水、 稀盐酸、 饱和食盐水洗涤， 无水硫酸镁干燥， 蒸干得白色粉末状 固体 17.01g， 收率 95%。  3-methoxyaniline (0.1 mol), dichloromethane (30 mL), and triethylamine (0.2 mol) were added to a 100 mL three-necked flask, and a solution of propionyl chloride (0.12 mol) in dichloromethane was added dropwise thereto in an ice bath. 30 mL, the temperature control is not more than 5 °C, after the addition, the ice bath is removed, and the mixture is stirred at room temperature for 0.5 h. The system is washed with water, dilute hydrochloric acid and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. , yield 95%.
2) 2-氯 -7-甲氧基 -3-甲基喹啉 2) 2-Chloro-7-methoxy-3-methylquinoline
将 DMF(20mL)加入到 250mL 三口瓶中， 冰盐浴下滴加 POCl3(100mL)， 控温不超过 0°C， 加毕搅拌 0.5h， 分批加入 N-(3-甲氧 基苯基)丙酰胺粉末 (31.0g)， 缓慢升温至 50°C， 剧烈反应， 待放热缓和 后， 缓慢升温至回流， 保温反应 2h， 冷至室温， 将体系倒入 800 g碎 冰中， 以碳酸钠调节体系 pH至 7， 析出黄色固体， 以石油醚-乙酸乙酯 重结晶得纯品 20.86g， 收率 58%。 3 ) 7-甲氧基 -3-甲基喹啉 -2(1H)-酮 Add DMF (20mL) to a 250mL three-necked bottle, add POCl 3 (100mL) under ice salt bath, control temperature does not exceed 0 °C, add 0.5h after stirring, add N-(3-methoxybenzene in batches Propylamide powder (31.0g), slowly warmed to 50 ° C, violent reaction, after the heat release is alleviated, slowly warming to reflux, heat preservation reaction for 2h, cooled to room temperature, the system was poured into 800 g of crushed ice, The sodium carbonate was adjusted to pH 7 to give a yellow solid which was crystallized from petroleum ether-ethyl acetate to yield a pure product of 20.86 g, yield 58%. 3) 7-Methoxy-3-methylindolequinoline-2(1H)-one
将 2-氯 -7-甲氧基 -3-甲基喹啉 (20.76g)、冰醋酸 (150mL)置于 250mL 单口瓶中， 加热回流 24h， 回收醋酸， 残余物以 95%乙醇重结晶， 得白 色针状结晶 16.08g， 收率 85%。  2-Chloro-7-methoxy-3-methylquinoline (20.76 g) and glacial acetic acid (150 mL) were placed in a 250 mL single-necked flask, heated under reflux for 24 h, acetic acid was recovered, and the residue was recrystallized from 95% ethanol. White needle crystals were obtained in 16.08 g, and the yield was 85%.
4) 7-甲氧基 -3，4-二氢 -3-甲基喹啉 -2(1H)-酮 将 7-甲氧基 -3-甲基喹啉 -2(1H)-酮（18.92g)、 冰醋酸（150mL)、 10%Pd/C(lg)加入到 250mL三口瓶中， 以氮气置换体系中的空气， 再以 氢气置换氮气， 然后加热至 80°C反应过夜， 冷至室温， 过滤， 滤液蒸 干得白色粉末， 水洗涤一次， 50°C真空干燥 4h， 得白色粉末状固体 18.91g，收率 98.95%。 4) 7-Methoxy-3,4-dihydro-3-methylquinoline-2(1H)-one Add 7-methoxy-3-methylquinolin-2(1H)-one (18.92g), glacial acetic acid (150mL), 10% Pd/C (lg) to a 250mL three-necked flask, replace the system with nitrogen The air in the air was replaced with hydrogen gas, then heated to 80 ° C overnight, cooled to room temperature, filtered, and the filtrate was evaporated to dryness to give a white powder, which was washed once with water and dried at 50 ° C for 4 h to give a white powdery solid 18.91 g The yield was 98.95%.
5 ) 7-羟基 -3，4-二氢 -3-甲基喹啉 -2(1H)-酮 5) 7-Hydroxy-3,4-dihydro-3-methylquinoline-2(1H)-one
将 7-甲氧基 -3，4-二氢 -3-甲基喹啉 -2(1H)-酮 （19.12g)、 40%氢溴酸 (150mL)置于 250mL单口瓶中， 加热回流 12h，冷却至室温， 析出固体， 过滤， 滤饼依次以氢溴酸、 水洗涤， 50°C真空干燥 4h， 得白色粉末状 固体 14.60g， 收率 82.4%。  7-Methoxy-3,4-dihydro-3-methylquinolin-2(1H)-one (19.12g), 40% hydrobromic acid (150mL) was placed in a 250mL single-mouth bottle, heated to reflux for 12h The mixture was cooled to room temperature, and the solid was separated and filtered. The filter cake was washed with hydrobromic acid and water, and dried under vacuum at 50 ° C for 4 h to give a white powdery solid 14.60 g, yield: 82.4%.
6 ) 3-(1-(3-氯丙基)哌啶 -4-基) -6-氟苯并 [d]异哑唑 6) 3-(1-(3-Chloropropyl)piperidin-4-yl)-6-fluorobenzo[d]isodazole
将 6-氟 -3- (哌啶 -4-基）苯并 [d]异哑唑（22.00g)、 1-溴 -3-氯丙烷 (40mL)、 无水碳酸钾 (40g)、 丙酮 (250mL)加入到 500mL单口瓶中， 回 流过夜， 冷却至室温， 过滤， 滤饼用热的丙酮洗涤两次， 合并滤液， 滴加入无水氯化氢的乙醇溶液， 析出白色固体， 过滤， 滤饼用丙酮洗 涤一次后， 溶解于 200mL水中， 用碳酸钠调 pH值至 9， 过滤， 得白色 粉末状固体 15.94g， 收率 48.0%  6-Fluoro-3-(piperidin-4-yl)benzo[d]isodazole (22.00 g), 1-bromo-3-chloropropane (40 mL), anhydrous potassium carbonate (40 g), acetone ( 250mL) was added to a 500mL single-mouth bottle, refluxed overnight, cooled to room temperature, filtered, the filter cake was washed twice with hot acetone, the filtrate was combined, and an anhydrous hydrogen chloride solution was added dropwise to precipitate a white solid, which was filtered, and the filter cake was acetone. After washing once, it was dissolved in 200 mL of water, adjusted to pH 9 with sodium carbonate, and filtered to give a white powdery solid 15.94 g, yield 48.0%
7) 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基 )-3，4-二氢 -3- 甲基喹啉 -2(1H)-酮 7) 7-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3,4-dihydro-3-methyl Quinoline-2(1H)-one
将 3-(1-(3-氯丙基)哌啶 -4-基) -6-氟苯并 [d]异哑唑 (lmmol)、 7-羟基 —3，4-二氢 -3-甲基喹啉 -2(1H)-酮（1.0mmol)、无水碳酸钾 (3.0mmol)加入到 lOmLDMF中， 60°C反应过夜， 滤除碳酸钾， 母液蒸干， 得淡黄色固体， 滤饼以 95%乙醇重结晶， 50°C真空干燥 4h， 得白色粉末状固体 0.30g， 收率 69%。  3-(1-(3-Chloropropyl)piperidin-4-yl)-6-fluorobenzo[d]isodazole (1 mmol), 7-hydroxy-3,4-dihydro-3-methyl The quinolinol-2(1H)-one (1.0 mmol) and anhydrous potassium carbonate (3.0 mmol) were added to 10 mL of DMF, and reacted at 60 ° C overnight, the potassium carbonate was filtered off, and the mother liquid was evaporated to give a pale yellow solid. The crystals were recrystallized from 95% ethanol, and dried under vacuum at 50 ° C for 4 h to give a white powdery solid 0.30 g, yield 69%.
1H NMR(DMSO-d6):l .27(d,3H,J=9.2Hz),2.06-2.32(m,9H),2.67-2.69 (t,2H),2.95(d*d,lH,J=3.2Hz,12.8Hz),3.15-3.17(m,2H),4.05(t,2H,J=6Hz),6. 37(d，lH，J=2.4Hz)，6.56(d*d，lH，J=2.4Hz，8.0Hz)，7.05-7.11(m，2H)，7.25-7.29 (m,lH),7.73-7.76(m,lH),7.98(s,lH),11.43(brs,lH) 1H NMR (DMSO-d 6 ): 1.27 (d, 3H, J = 9.2 Hz), 2.06-2.32 (m, 9H), 2.67-2.69 (t, 2H), 2.95 (d*d, lH, J =3.2 Hz, 12.8 Hz), 3.15-3.17 (m, 2H), 4.05 (t, 2H, J = 6 Hz), 6.37 (d, lH, J = 2.4 Hz), 6.56 (d*d, lH, J=2.4Hz, 8.0Hz), 7.05-7.11(m, 2H), 7.25-7.29 (m, lH), 7.73-7.76 (m, lH), 7.98 (s, lH), 11.43 (brs, lH)
ESI-MS:438(M+1) 实施例 2  ESI-MS: 438 (M+1) Example 2
1-1盐酸盐的制备  Preparation of 1-1 hydrochloride
将 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基 )-3，4-二氢 -3- 甲基喹啉 -2(1H)-酮 (lmmol)溶解与乙酸乙酯 (50mL)中， 缓慢滴加无水氯 化氢的乙酸乙酯溶液 (lmol/L，5mL)， 搅拌 2h， 析出固体， 过滤， 滤饼 以乙酸乙酯洗涤， 50°C真空干燥 4h， 得白色粉末状固体 0.436g， 收率 92%。  7-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3,4-dihydro-3-methylquin The porphyrin-2(1H)-one (1 mmol) was dissolved in ethyl acetate (50 mL). EtOAc (EtOAc m. The organic layer was washed with ethyl acetate and dried at 50 &lt
ESI-MS:438(M+1) ESI-MS: 438 (M+1)
元素分析结果：  Elemental analysis results:
计算值： C， 63.35%; H, 6.17%; Cl， 7.48%; F， 4.01%; N, 8.87%; O， 10.13%  Calculated: C, 63.35%; H, 6.17%; Cl, 7.48%; F, 4.01%; N, 8.87%; O, 10.13%
实验值： C， 63.29%;H, 6.24%; CI, 7.43%; F， 4.05%; N, 8.82%; O， 10.17% 实施例 3  Found: C, 63.29%; H, 6.24%; CI, 7.43%; F, 4.05%; N, 8.82%; O, 10.17% Example 3
1-1 甲磺酸盐的制备  Preparation of 1-1 methanesulfonate
将 1-1 (lmmol)溶解与乙酸乙酯 (50mL)中， 缓慢滴加甲磺酸的乙酸 乙酯溶液 (lmol/L，5mL)， 搅拌 2h， 析出固体， 过滤， 滤饼以乙酸乙酯 洗涤， 50°C真空干燥 4h， 得白色粉末状固体 0.487g， 收率 91.3%。  1-1 (1 mmol) was dissolved in ethyl acetate (50 mL), and ethyl acetate (1 mol/L, 5 mL) was slowly added dropwise, and the mixture was stirred for 2 h to precipitate a solid. The mixture was dried under vacuum at 50 ° C for 4 h to give a white powdery solid, 0.487 g, yield 91.3%.
ESI-MS:438(M+1, 正离子模式）， 95(CH3SO3—， 负离子模式） 元素分析结果： ESI-MS: 438 (M+1, positive ion mode), 95 (CH 3 SO 3 —, negative ion mode) Elemental analysis results:
计算值： C, 58.52%; H, 6.04%; F, 3.56%; N, 7.87%; 0， 17.99%; S, 6.01%  Calculated: C, 58.52%; H, 6.04%; F, 3.56%; N, 7.87%; 0, 17.99%; S, 6.01%
实验值： C, 58.49%; H, 6.09%; F, 3.50%; N, 7.81%; 0， 18.02%; S, 6.09% 实施例 4 Found: C, 58.49%; H, 6.09%; F, 3.50%; N, 7.81%; 0, 18.02%; S, 6.09% Example 4
1-2 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基）哌啶 -1-基)丙氧基 )-3-甲基 喹啉 -2(1H)-酮的制备  1-2 7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3-methylquinoline-2 (1H )- Preparation of ketone
1 ) 7-羟基 -3-甲基喹啉 -2(1H)-酮  1) 7-Hydroxy-3-methylquinoline-2(1H)-one
将 7-甲氧基 -3-甲基喹啉 -2(1H)-酮 （O.lmol, 按照 1-1方法制备） 、 7 -Methoxy- 3 -methylquinolin-2(1H)-one (0.1 mol, prepared according to the method of 1-1),
40%氢溴酸（lOOmL)置于 250mL单口瓶中，加热回流 12h，冷却至室温， 析出固体， 过滤， 滤饼依次以氢溴酸、 水洗涤， 50°C真空干燥 4h， 得 白色粉末状固体 14.35g， 收率 82%。 2 ) 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基 )-3-甲基喹啉40% hydrobromic acid (100 mL) was placed in a 250 mL single-necked flask, heated to reflux for 12 h, cooled to room temperature, solids were precipitated, filtered, and the filter cake was washed with hydrobromic acid, water, and dried under vacuum at 50 ° C for 4 h to give a white powder. The solid was 14.35 g, and the yield was 82%. 2) 7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3-methylquinoline
-2(1H)-酮 -2(1H)-ketone
将 7-羟基 -3-甲基喹啉 -2(1H)-酮 (0.1mol)、 3-(1-(3-氯丙基）哌啶 -4- 基）-6-氟苯并 [d]异哑唑（0.105mol)， 无水碳酸钾（0.3mol)加入到 250mLDMF 中， 60°C反应过夜， 滤除碳酸钾， 母液蒸干， 得淡黄色固 体， 以 95%乙醇热洗涤， 50°C真空干燥 4h， 得白色粉末状固体 26.97g， 收率 62%。  7-Hydroxy-3-methylquinolin-2(1H)-one (0.1 mol), 3-(1-(3-chloropropyl)piperidin-4-yl)-6-fluorobenzo[d Iso-doxazole (0.105 mol), anhydrous potassium carbonate (0.3 mol) was added to 250 mL of DMF, and reacted at 60 ° C overnight. Potassium carbonate was filtered off, and the mother liquid was evaporated to give a pale yellow solid, which was washed with 95% ethanol, 50 After drying at 0<0>C for 4 h, a white powdery solid, 26.97 g, yield 62%.
1H NMR(DMSO-d6): 1.82-2.00(m,6H),2.02(s,3H),2.10-2.13(m,2H), 2.45-2.50(m,2H),2.936-2.965(m,2H),3.07-3.11(m,lH),4.03(t,2H,J=6.4Hz), 6.76(d*d，lH，J=2.4Hz，8.8Hz)，6.805(d，lH，2.0Hz)，7.22-7.27(m，lH)，7.45(d，l H，J=8.8Hz)，7.64-7.65(m，lH)，7.973(d*d，lH，J=6.4Hz，8.4Hz)， 11.49(brs,lH)1H NMR (DMSO-d 6 ): 1.82-2.00 (m, 6H), 2.02 (s, 3H), 2.10-2.13 (m, 2H), 2.45-2.50 (m, 2H), 2.936-2.965 (m, 2H) ), 3.07-3.11 (m, lH), 4.03 (t, 2H, J = 6.4 Hz), 6.76 (d*d, lH, J = 2.4 Hz, 8.8 Hz), 6.805 (d, lH, 2.0 Hz), 7.22-7.27(m,lH), 7.45(d,l H,J=8.8Hz), 7.64-7.65(m,lH), 7.973(d*d,lH,J=6.4Hz,8.4Hz), 11.49( Brs,lH)
ESI-MS:436(M+1)。 实施例 5 ESI-MS: 436 (M+1). Example 5
1-2硫酸一氢盐的制备  Preparation of 1-2 monohydrogen sulfate
将 I-2(lmmol)溶解于 50mL乙酸乙酯中， 缓慢滴加 0.5MH2SO4的 乙酸乙酯溶液 (20mL)， 析出固体， 过滤， 滤饼以 10mL乙酸乙酯洗涤， 50°C真空干燥 4h， 得白色粉末状固体 0.42g。 I-2 (1 mmol) was dissolved in 50 mL of ethyl acetate, and a solution of 0.5 MH 2 SO 4 in ethyl acetate (20 mL) was slowly added dropwise to precipitate a solid, which was filtered, and the filter cake was washed with 10 mL of ethyl acetate. After drying for 4 h, 0.42 g of a white powdery solid was obtained.
ESI-MS+: 436(M+1); ESI-MS—： 97(硫酸氢根）  ESI-MS+: 436 (M+1); ESI-MS-: 97 (hydrogen sulfate)
元素分析结果：  Elemental analysis results:
计算值： C, 56.38%; H, 5.11%; F, 3.57%; N, 7.89%; 0， 21.03%; S, 6.02% Calculated: C, 56.38%; H, 5.11%; F, 3.57%; N, 7.89%; 0, 21.03%; S, 6.02%
实验值： C， 56.33%; H， 5.15%; F， 3.54%; N, 7.91%; O， 21.01%; S， 6.06%。 实施例 6  Found: C, 56.33%; H, 5.15%; F, 3.54%; N, 7.91%; O, 21.01%; S, 6.06%. Example 6
1-2氢溴酸盐的制备  Preparation of 1-2 hydrobromide salt
将 I-2(lmmol)溶解于 50mL乙酸乙酯中， 缓慢滴加 0.5MHBr的乙 酸乙酯溶液 (20mL)， 析出固体， 过滤， 滤饼以 10mL乙酸乙酯洗涤， 50 °C真空干燥 4h， 得白色粉末状固体 0.41g。  I-2 (1 mmol) was dissolved in 50 mL of ethyl acetate, and a solution of 0.5 MHBr of ethyl acetate (20 mL) was slowly added dropwise, and the solid was precipitated, filtered, and the filter cake was washed with 10 mL of ethyl acetate and dried under vacuum at 50 ° C for 4 h. 0.41 g of a white powdery solid was obtained.
ESI-MS:436(M+1, 正离子模式）， 79， 81 (Br", 负离子模式） 元素分析结果：  ESI-MS: 436 (M+1, positive ion mode), 79, 81 (Br", negative ion mode) Elemental analysis results:
计算值： C， 58.15%; H, 5.27%; Br, 15.47%; F， 3.68%; N, 8.14%; 0， 9.29%  Calculated: C, 58.15%; H, 5.27%; Br, 15.47%; F, 3.68%; N, 8.14%; 0, 9.29%
实验值： C， 58.10%; H， 5.29%; Br, 15.43%; F， 3.62%; N, 8.19%; 0， 9.37%。 实施例 7  Found: C, 58.10%; H, 5.29%; Br, 15.43%; F, 3.62%; N, 8.19%; 0, 9.37%. Example 7
1-3 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基）哌啶 - 1 -基 )-2-甲基丙氧 基) -3-甲基喹啉 -2(1H)-酮的制备  1-3 7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-2-methylpropoxy)-3-methylquin Preparation of porphyrin-2(1H)-one
1 ) 3-(1-(3-氯 -2-甲基丙基)哌啶 -4-基) -6-氟苯并 [d]异哑唑  1) 3-(1-(3-Chloro-2-methylpropyl)piperidin-4-yl)-6-fluorobenzo[d]isodazole
将 6-氟 -3- (哌啶 -4-基)苯并 [d]异哑唑 (O.lmol)、 2-甲基 -1-溴 -3-氯丙 烷 (0.4mol)、无水碳酸钾 (0.3mol)、丙酮 (300mL)加入到 500mL单口瓶中， 回流过夜， 冷却至室温， 过滤， 滤饼用热的丙酮洗涤两次， 合并滤液， 滴加入无水氯化氢的乙醇溶液， 析出白色固体， 过滤， 滤饼用丙酮洗 涤一次后， 溶解于 200mL水中， 用碳酸钠调 pH值至 9， 过滤， 得白色 粉末状固体 19.36g， 收率 62.3%。  6-Fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (0.1 mol), 2-methyl-1-bromo-3-chloropropane (0.4 mol), anhydrous carbonic acid Potassium (0.3 mol) and acetone (300 mL) were added to a 500 mL single-mouth bottle, refluxed overnight, cooled to room temperature, filtered, and the filter cake was washed twice with hot acetone. The filtrate was combined, and an aqueous solution of anhydrous hydrogen chloride was added dropwise to precipitate white. The solid was filtered, and the filter cake was washed once with acetone, dissolved in water (200 mL), adjusted to pH 9 with sodium carbonate, and filtered to give a white powdery solid, 19.36 g, yield 62.3%.
2 ) 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基) -2-甲基丙氧基) -3- 甲基喹啉 -2(1H)-酮 2) 7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-2-methylpropoxy)-3-methylquinoline -2(1H)-ketone
将 3-(1-(3-氯 -2-甲基丙基)哌啶 -4-基) -6-氟苯并 [d]异哑唑（10mmol)、 7-羟基 -3-甲基喹啉 -2(1H)-酮（lOmmol)、 无水碳酸钾（30mmol)、 DMF(60mL)加入到 lOOmL单口瓶中， 60°C反应过夜， 滤除碳酸钾， 滤 液蒸干， 得淡黄色固体， 以 95%乙醇重结晶， 得白色粉末状固体 3.25g， 收率 72.4%。 3-(1-(3-Chloro-2-methylpropyl)piperidin-4-yl)-6-fluorobenzo[d]isodazole (10 mmol), 7-Hydroxy-3-methylquinolin-2(1H)-one (10 mmol), anhydrous potassium carbonate (30 mmol), DMF (60 mL) was added to a 100 mL single-necked flask, and reacted at 60 ° C overnight to remove potassium carbonate. The filtrate was evaporated to dryness to give a pale-yellow solid, which was crystallised from 95% ethanol to yield 3.25 g of white powdery solid.
1H NMR(DMSO-d6):1.02(d,3H,J=6.4Hz),1.81-1.88(m,2H),2.00-2.03 (m,2H),2.037(s,3H),2.11-2.28(m,2H),2.39-2.44(m,lH),2.90-3.01(m,2H),3. l l-3.19(m,lH),3.826-3.865(m,lH),4.004-4.038(m,lH),6.772(d*d,lH,J=9.6 Hz，2.4Hz)，6.805(d，lH，J=2.4Hz)，7.225-7.276(m，lH)，7.46(d，lH，J=8.8Hz)，7. 63(s，lH)，7.64(d，lH，J=8.8Hz)，7.968(d*d，lH，J=8.8Hz，4.2Hz)，11.47(brs，lH)1H NMR (DMSO-d 6 ): 1.02 (d, 3H, J = 6.4 Hz), 1.81-1.88 (m, 2H), 2.00-2.03 (m, 2H), 2.037 (s, 3H), 2.11-2.28 ( m, 2H), 2.39-2.44 (m, lH), 2.90-3.01 (m, 2H), 3. l l-3.19 (m, lH), 3.826-3.865 (m, lH), 4.004-4.038 (m, lH), 6.772 (d*d, lH, J = 9.6 Hz, 2.4 Hz), 6.805 (d, lH, J = 2.4 Hz), 7.225-7.276 (m, lH), 7.46 (d, lH, J = 8.8 Hz), 7. 63 (s, lH), 7.64 (d, lH, J = 8.8 Hz), 7.968 (d*d, lH, J = 8.8 Hz, 4.2 Hz), 11.47 (brs, lH)
ESI-MS:450(M+1)。 实施例 8 ESI-MS: 450 (M+1). Example 8
1-3盐酸盐的制备  Preparation of 1-3 hydrochloride
将 I-3(lmmol)溶解与乙酸乙酯 (50mL)中， 缓慢滴加无水氯化氢的 乙酸乙酯溶液 (lmol/L，5mL)， 搅拌 2h， 析出固体， 过滤， 滤饼以乙酸 乙酯洗涤， 50°C真空干燥 4h， 得白色粉末状固体 0.44g。  The solution was dissolved in ethyl acetate (50 mL). Washing, vacuum drying at 50 ° C for 4 h gave a white powdery solid, 0.44 g.
元素分析结果：  Elemental analysis results:
计算值： C, 69.47%; H, 6.28%; F, 4.23%; N, 9.35%; 0， 10.68% 实验值： C, 69.42%; H, 6.30%; F, 4.29%; N, 9.31%; 0， 10.69%
Figure imgf000015_0001
实施例 9 Calculated: C, 69.47%; H, 6.28%; F, 4.23%; N, 9.35%; 0, 10.68% Found: C, 69.42%; H, 6.30%; F, 4.29%; N, 9.31%; 0, 10.69%
Figure imgf000015_0001
Example 9
1-3三氟甲磺酸盐的制备  Preparation of 1-3 trifluoromethanesulfonate
将化合物 I-3(lmmol)溶解于 50mL乙酸乙酯中， 缓慢滴加 0.5M三 氟甲磺酸的乙酸乙酯溶液 20mL， 搅拌 0.5h后， 析出固体， 过滤， 滤饼 以 10mL乙酸乙酯洗涤， 50°C真空干燥 4h， 得白色粉末状固体 0.49g。  Compound I-3 (1 mmol) was dissolved in 50 mL of ethyl acetate, and a solution of 0.5 M trifluoromethanesulfonic acid in ethyl acetate (20 mL) was slowly added dropwise. After stirring for 0.5 h, solids were separated and filtered, and filtered cake Washing, vacuum drying at 50 ° C for 4 h gave a white powdery solid, 0.49 g.
元素分析结果：  Elemental analysis results:
计算值： C, 54.08%; H, 4.88%; F, 12.67%; N, 7.01%; 0， 16.01%; S, 5.35%  Calculated: C, 54.08%; H, 4.88%; F, 12.67%; N, 7.01%; 0, 16.01%; S, 5.35%
实验值： C, 54.03%; H, 4.90%; F, 12.64%; N, 7.03%; 0， 15.96%; S, 5.44% Found: C, 54.03%; H, 4.90%; F, 12.64%; N, 7.03%; 0, 15.96%; S, 5.44%
ESI-MS:450(M+1, 正离子模式）， 149(CF3SO3—， 负离子模式）。 实施例 10 ESI-MS: 450 (M+1, positive ion mode), 149 (CF 3 SO 3 —, negative ion mode). Example 10
1-4 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基 )-6-甲氧基 -3-甲基喹啉 -2(1H)-酮的制备  1-4 7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-6-methoxy-3-methyl Preparation of quinoline-2(1H)-one
1 ) 2- (苄氧基) -1-甲氧基 -4-硝基苯  1) 2-(Benzyloxy)-1-methoxy-4-nitrobenzene
将 5-硝基愈创木酚钠 (20mmol)、 氯化苄（19.5mmol)、 无水碳酸钾 (30mmol)、 DMF(250mL)加入到 500mL 单口瓶中， 50°C反应过夜， 滤 除碳酸钾， 母液蒸干， 用少量水洗涤后， 以 95%乙醇重结晶， 得淡黄 色固体 (4.29g)， 收率 85%。  Add 5-nitroguaiacol sodium (20mmol), benzyl chloride (19.5mmol), anhydrous potassium carbonate (30mmol), DMF (250mL) to a 500mL single-mouth bottle, react at 50 ° C overnight, filter out carbonic acid Potassium, the mother liquor was evaporated to dryness, washed with a small portion of water and then recrystallized from 95% ethanol to give a pale yellow solid (4.29 g).
2) 3-苄氧基 -4-甲氧基苯胺 2) 3-benzyloxy-4-methoxyaniline
2- (苄氧基) -1-甲氧基 -4-硝基苯（10mmol)、 无水乙醇 (60mL)、 乙酸 乙酯 (60mL)、 加入到 250mL 四口瓶中， 加热到 70°C， 分批缓慢加入 2-(Benzyloxy)-1-methoxy-4-nitrobenzene (10mmol), absolute ethanol (60mL), ethyl acetate (60mL), added to a 250mL four-necked flask, heated to 70 ° C , join slowly in batches
SnCl2-H2O(40mmol),加毕保温反应 4h，蒸除溶剂，所得粘稠状物以 10% 氢氧化钠溶液 (200mL)、乙酸乙酯 (200mL)分配，水层以乙酸乙酯 (lOOmL) 萃取一次， 合并有机层， 依次用水（100mL*2)、 饱和食盐水（100mL*2) 洗涤， 无水硫酸钠干燥， 蒸干得黑色固体 (1.66g)， 收率 72.5%。 SnCl 2 -H 2 O (40 mmol), the reaction mixture was stirred for 4h, then evaporated to dryness crystals crystals crystals crystals crystals (100 mL), the organic layer was combined, washed sequentially with water (100 mL*2), brine (100 mL*2), dried over anhydrous sodium sulfate and evaporated to give a white solid (1.66 g).
3 ) N-(3- (苄氧基) -4-甲氧基苯基)丙酰胺 3) N-(3-(Benzyloxy)-4-methoxyphenyl)propanamide
3-苄氧基 -4-甲氧基苯胺（10mmol)、 CH2Cl2(20mL)、三乙胺 (20mmol) 加入到 lOOmL三口瓶中， 降温至 0°C， 缓慢滴加溶有丙酰氯（15mmol) 的 CH2C12溶液 20mL， 控温不超过 5°C， 加毕室温搅拌 2h， 反应液依 次以水、 稀盐酸、 饱和食盐水洗涤， 无水硫酸镁干燥， 蒸干得白色粉 末状固体 (2.63g)， 收率 92.3%。 3-benzyloxy-4-methoxyaniline (10mmol), CH 2 Cl 2 (20mL), triethylamine (20mmol) was added to a 100mL three-necked flask, cooled to 0 ° C, slowly added with propionyl chloride (15mmol) 20 ml of CH 2 C1 2 solution, the temperature control is not more than 5 ° C, and the mixture is stirred at room temperature for 2 h. The reaction liquid is washed with water, dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and evaporated. Solid (2.63 g), yield 92.3%.
4) 7- (苄氧基) -2-氯 -6-甲氧基 -3-甲基喹啉 4) 7-(Benzyloxy)-2-chloro-6-methoxy-3-methylquinoline
将 DMF(20mL)加入到 250mL 三口瓶中， 冰盐浴下滴加 POCl3(100mL), 控温不超过 0°C， 加毕搅拌 0.5h， 分批加入 N-(3- (苄氧 基) -4-甲氧基苯基)丙酰胺粉末 (lOmmol), 缓慢升温至 50°C， 剧烈反应， 待放热缓和后， 缓慢升温至回流， 保温反应 2h， 蒸除大部分三氯氧磷， 冷至室温， 将体系倒入 500g碎冰中， 以碳酸钠调节体系 pH至 7， 析 出黄色固体， 以石油醚-乙酸乙酯重结晶得氮黄色粉末状固体 (1.60g)， 收率 56.4%。 Add DMF (20mL) to a 250mL three-necked bottle, add POCl 3 (100mL) under ice salt bath, control temperature does not exceed 0 °C, add 0.5h after stirring, add N-(3-(benzyloxy) in batches Base -4-methoxyphenyl)propanamide powder (10 mmol), slowly warming to 50 ° C, violent reaction, after the heat release is moderate, slowly warming to reflux, keeping the reaction for 2 h, distilling off most of the trichloroox Phosphorus, cooled to room temperature, the system was poured into 500 g of crushed ice, and the pH of the system was adjusted to 7 with sodium carbonate to precipitate a yellow solid, which was crystallized from petroleum ether-ethyl acetate to give a yellow-yellow powdery solid (1.60 g). 56.4%.
5 ) 7- (苄氧基) -6-甲氧基 -3-甲基喹啉 -2(1H)-酮 5) 7-(Benzyloxy)-6-methoxy-3-methylquinoline-2(1H)-one
将 7- (苄氧基） -2-氯 -6-甲氧基 -3-甲基喹啉 （10mmol)、 冰醋酸 (150mL)置于 250mL单口瓶中，加热回流 24h，回收醋酸，残余物以 95% 乙醇重结晶， 得白色粉末状固体 (2.23g)， 收率 84.2%。  7-(Benzyloxy)-2-chloro-6-methoxy-3-methylquinoline (10 mmol) and glacial acetic acid (150 mL) were placed in a 250 mL single-necked flask and heated to reflux for 24 h to recover acetic acid. Recrystallization from 95% ethanol gave white powdery solid (2.23 g).
6) 7-羟基 -6-甲氧基 -3-甲基喹啉 -2(1H)-酮 6) 7-Hydroxy-6-methoxy-3-methylquinoline-2(1H)-one
将 7- (苄氧基) -6-甲氧基 -3-甲基喹啉 -2(1H)-酮（10mmol)、 甲酸铵 (40mmol)、 10%Pd/C(lg)、 无水乙醇 (80mL)加入到 250mL单口瓶中， 加 热回流过夜， 滤除 Pd/C， 滤液浓缩至干， 以水洗涤 (20mL*2)， 自然晾 干， 得白色粉末状固体 (1.69g)， 收率 96.3%。  7-(Benzyloxy)-6-methoxy-3-methylquinolin-2(1H)-one (10 mmol), ammonium formate (40 mmol), 10% Pd/C (lg), absolute ethanol (80 mL) was added to a 250 mL single-necked flask, heated to reflux overnight, filtered, and filtered to dryness. The filtrate was concentrated to dryness, washed with water (20mL*2), and dried to give a white powdery solid (1.69 g). 96.3%.
7 ) 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基 )-6-甲氧基 -3-甲基喹啉 -2(1H)-酮 7) 7-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-6-methoxy-3-methylquin Porphyrin-2(1H)-one
将 7-羟基 -6-甲氧基 -3-甲基喹啉 -2(1H)-酮（10mmol)、3-(l-(3-氯丙基) 哌啶 -4-基）-6-氟苯并 [d]异哑唑（lOmmol)、 无水碳酸钾（30mmol)、 DMF(50mL)加入到 lOOmL单口瓶中， 60°C反应过夜， 滤除碳酸钾， 滤 液蒸干， 以 10mL95%的乙醇搅拌洗涤， 过滤， 滤饼 50°C真空干燥， 得 白色粉末状固体 (3.51g)，收率 75.3%。  7-Hydroxy-6-methoxy-3-methylquinolin-2(1H)-one (10 mmol), 3-(l-(3-chloropropyl)piperidin-4-yl)-6- Fluorobenzo[d]isodazole (10 mmol), anhydrous potassium carbonate (30 mmol), DMF (50 mL) was added to a 100 mL single-necked flask, reacted at 60 ° C overnight, filtered off potassium carbonate, and the filtrate was evaporated to dryness to 10 mL 95% The ethanol was stirred and washed, filtered, and the filter cake was dried under vacuum at 50 ° C to give a white powdery solid (3.51 g).
1H NMR(DMSO-d6):2.10-.46(m,l lH),2.71-2.92(m,2H),3.16-3.381H NMR (DMSO-d 6 ): 2.10-.46 (m, l lH), 2.71-2.92 (m, 2H), 3.16-3.38
(m,2H),3.91(s,3H),4.24(t,2H,J=6Hz),6.898(s,lH),6.917(s,lH),7.048-7.098( m，lH)，7.253(d*d，lH，J=8.8Hz，1.6Hz)，7.536(s，lH)，7.781(s，lH)，11.47(brs，l H) (m, 2H), 3.91 (s, 3H), 4.24 (t, 2H, J = 6 Hz), 6.988 (s, lH), 6.917 (s, lH), 7.048-7.098 (m, lH), 7.253 (d *d, lH, J = 8.8 Hz, 1.6 Hz), 7.536 (s, lH), 7.78 (s, lH), 11.47 (brs, l H)
ESI-MS:466(M+1)。 实施例 11 ESI-MS: 466 (M+1). Example 11
1-4盐酸盐的制备  Preparation of 1-4 hydrochloride
将 I-4(lmmol)溶解与乙酸乙酯 (50mL)中， 缓慢滴加无水氯化氢的 乙酸乙酯溶液 (lmol/L，5mL)， 搅拌 2h， 析出固体， 过滤， 滤饼以乙酸 乙酯洗涤， 50°C真空干燥 4h， 得白色粉末状固体 0.437g。  I-4 (1 mmol) was dissolved in ethyl acetate (50 mL). EtOAc (EtOAc m. Washing, vacuum drying at 50 ° C for 4 h gave 0.437 g of a white powdery solid.
元素分析结果：  Elemental analysis results:
计算值： C, 62.21%; H, 5.82%; C1, 7.06%; F, 3.78%; N, 8.37%; 0， 12.75%  Calculated: C, 62.21%; H, 5.82%; C1, 7.06%; F, 3.78%; N, 8.37%; 0, 12.75%
实验值： C， 62.14%; H, 5.88%; Cl， 7.12%; F， 3.76%; N, 8.33%; O， 12.76%  Found: C, 62.14%; H, 5.88%; Cl, 7.12%; F, 3.76%; N, 8.33%; O, 12.76%
ESI-MS:466 o 实施例 12  ESI-MS: 466 o Example 12
1-4甲磺酸盐的制备  Preparation of 1-4 mesylate
将 I-4(lmmol)溶解与乙酸乙酯 (50mL)中， 缓慢滴加甲磺酸的乙酸 乙酯溶液 (lmol/L，5mL)， 搅拌 2h， 析出固体， 过滤， 滤饼以乙酸乙酯 洗涤， 50°C真空干燥 4h， 得白色粉末状固体 0.49g。  The solution was dissolved in ethyl acetate (50 mL). Washing, vacuum drying at 50 ° C for 4 h gave a white powdery solid, 0.49 g.
元素分析结果：  Elemental analysis results:
计算值： C, 57.74%; H, 5.74%; F, 3.38%; N, 7.48%; 0， 19.94%; S, 5.71%  Calculated: C, 57.74%; H, 5.74%; F, 3.38%; N, 7.48%; 0, 19.94%; S, 5.71%
实验值： C, 57.69%; H, 5.70%; F, 3.43%; N, 7.53%; 0， 19.91%; S, 5.73%  Found: C, 57.69%; H, 5.70%; F, 3.43%; N, 7.53%; 0, 19.91%; S, 5.73%
ESI-MS:446(M+1正离子模式）， 95(CH3SO3—，负离子模式）。 实施例 13 ESI-MS: 446 (M + 1 positive ion mode), 95 (CH 3 SO 3 -, negative mode). Example 13
(R)-7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基 )-3，4-二氢 -3-甲基喹啉 -2(1H)-酮和 (S)- 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基) 丙氧基 )-3，4-二氢 -3-甲基喹啉 -2(1H)-酮的制备  (R)-7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3,4-dihydro-3- Methylquinoline-2(1H)-one and (S)-7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy Of 3-(3-dihydro-3-methylquinolin-2(1H)-one
将化合物 I-l(20g)进行手性色谱分离， 色谱柱为 CHIRALPAK IA, 以甲醇： 二氯甲烷： 二乙胺 =95:5:0.1 (体积比） 为流动相， 分别得到 1-1 的两个光学异构体， 按保留出峰先后顺序， 依次命名为 peck-l、 peck-2 , peck-2的绝对构型经单晶 X衍射鉴定为 S构型， 则 peck-1为 R构型， 具体见图 1〜图 5。 手性液相色谱分析结果如图 1〜图 3所示， 图 1 为消旋体液相图 谱， 图 2为 peck-1液相图谱， 图 3为 peck-2液相图谱， 图 4为 peck-2 单晶 X-Ray衍射正视图， 图 5为 peck-2单晶 X-Ray衍射侧视图。 实施例 14 The compound Il (20 g) was subjected to chiral chromatography, and the column was CHIRALPAK IA, with methanol: dichloromethane: diethylamine = 95:5: 0.1 (volume ratio) as mobile phase, respectively The two optical isomers of 1-1 are named as peck-l and peck-2 in order of retention, and the absolute configuration of peck-2 is identified as S configuration by single crystal X-ray diffraction. 1 is the R configuration, as shown in detail in Figures 1 to 5. The results of chiral liquid chromatography analysis are shown in Figure 1 to Figure 3. Figure 1 shows the liquid phase spectrum of the racemate, Figure 2 shows the liquid phase of peck-1, Figure 3 shows the liquid phase of peck-2, and Figure 4 shows the liquid phase of peck-2. -2 Single crystal X-Ray diffraction front view, Fig. 5 is a Peck-2 single crystal X-Ray diffraction side view. Example 14
片剂： 本发明的化合物 25mg  Tablets: Compounds of the invention 25 mg
蔗糖 155mg  Sucrose 155mg
玉米淀粉 65mg  Corn Starch 65mg
硬脂酸镁 5mg  Magnesium stearate 5mg
制备方法： 将活性成分与蔗糖、 玉米淀粉混合， 加水润湿， 搅拌 均匀， 干燥， 粉碎过筛， 加入硬脂酸镁， 混合均匀， 压片。 每片重 250  Preparation method: The active ingredient is mixed with sucrose and corn starch, moistened with water, stirred uniformly, dried, pulverized and sieved, added with magnesium stearate, uniformly mixed, and tableted. Each piece weighs 250
实施例 15 Example 15
针剂： 本发明的化合物 10mg  Injection: Compound of the invention 10 mg
注射用水 90mg  Water for injection 90mg
制备方法： 将活性成分溶解于注射用水， 混合均匀， 过滤， 将所 获得的溶液在无菌条件下分装于安瓿瓶中， 每瓶 10mg， 活性成分含量 为 lmg/瓶。 实施例 16  Preparation method: The active ingredient is dissolved in water for injection, uniformly mixed, filtered, and the obtained solution is dispensed into an ampoule under aseptic conditions, 10 mg per bottle, and the active ingredient content is 1 mg/bottle. Example 16
多巴胺 D2受体结合试验 Dopamine D 2 receptor binding assay
1、 实验材料：  1. Experimental materials:
(1) D2受体细胞转染： (1) D 2 receptor cell transfection:
本实验用含有 D2受体蛋白基因的质粒载体转染 HEK293细胞，使 用磷酸钙转染法， 并从转染后的细胞中， 通过含 G418的培养液培养， 以及挑选细胞单克隆和放射性配基结合实验， 最终获得能稳定表达 D2 受体蛋白的稳定细胞株。 In this experiment, HEK293 cells were transfected with a plasmid vector containing the D 2 receptor protein gene, and subjected to calcium phosphate transfection, and cultured from the transfected cells through a medium containing G418. As well as the selection of cell monoclonal and radioligand binding experiments, a stable cell line stably expressing the D 2 receptor protein was finally obtained.
(2) 受体结合实验材料： (2) Receptor binding experimental materials:
同位素配基 Spiperone(113.0Ci/mmol) ; 购自 Sigma 公司； Isotope ligand Spiperone (113.0 Ci / mmol); purchased from Sigma;
(+) spiperone, 购自 RBI公司； GF/B玻璃纤维滤纸， 购自 Whatman公 司； Tris进口分装； PPO、 POPOP购自上海试剂一厂； 脂溶性闪烁液。 Beckman LS-6500型多功能液体闪烁计数仪。 2、 实验方法： (+) spiperone, purchased from RBI; GF/B glass fiber filter paper, purchased from Whatman; Tris imported package; PPO, POPOP purchased from Shanghai Reagent 1; fat-soluble scintillation solution. Beckman LS-6500 multi-function liquid scintillation counter. 2. Experimental method:
(1) 细胞：  (1) Cells:
用含以上各种基因的重组病毒分别感染 HEK-293细胞， 48-72小 时后受体蛋白在膜上大量表达， 将细胞 lOOOrpm离心 5min后弃培液， 收胞体， 保存于 -20 °C冰箱内备用。 实验时用 Tris-HCl 反应缓冲液 ( PH7.5 ) 重悬。  The HEK-293 cells were infected with the recombinant virus containing the above various genes. After 48-72 hours, the receptor protein was expressed on the membrane in a large amount. After centrifuging the cells at 1000 rpm for 5 min, the culture solution was discarded, and the cells were collected and stored in a refrigerator at -20 °C. Internal backup. Resuspend in Tris-HCl reaction buffer (pH 7.5) during the experiment.
(2) 受体竞争结合实验： (2) Receptor competition binding experiments:
将待测化合物与放射性配基各 20uL及 160uL受体蛋白加入反应试 管中， 使受试化合物及阳性药物终浓度均为 10umol/L， 30°C水浴孵育 50min后， 即刻移至冰浴终止其反应； 在 Millipore细胞样品收集器上， 经过 GF/C玻璃纤维滤纸快速抽滤， 并用洗脱液 (50mMTris-HCl， PH7.5) 3mL*3次， 用微波 5~6 min烘干， 将滤纸移入 0.5mL离心管中， 加入 500uL脂溶性闪烁液。 避光静置 30min以上， 计数测定放射性强度。 按 以下公式计算各化合物对同位素配基结合的抑制率百分率：  The test compound and the radioligand 20uL and 160uL receptor protein were added to the reaction tube, and the final concentration of the test compound and the positive drug was 10umol/L. After incubating in a 30°C water bath for 50 minutes, it was immediately transferred to an ice bath to terminate it. Reaction; rapid filtration on GF/C glass fiber filter paper on Millipore cell sample collector, and eluent (50 mM Tris-HCl, pH 7.5) 3 mL*3 times, microwaved for 5-6 min, filter paper Transfer to a 0.5 mL centrifuge tube and add 500 uL of fat-soluble scintillation fluid. The light was allowed to stand for 30 minutes or more, and the radioactivity was measured by counting. Calculate the percentage inhibition of isotopic ligand binding by each compound according to the following formula:
抑制率 (1%)=总结合管 cpm—化合物 cpm/总结合管 cpm—非特异结 合管 cpm X 100%  Inhibition rate (1%) = total combined tube cpm - compound cpm / total combined tube cpm - non-specific binding tube cpm X 100%
化合物每次实验做双复管， 进行两次单独实验。 实施例 17  The compound was double-tubed in each experiment and two separate experiments were performed. Example 17
5-HT2a受体结合试验 1、 实验材料： 5-HT 2a receptor binding assay 1. Experimental materials:
(1) 5-HT2a细胞转染： (1) 5-HT 2a cell transfection:
本实验用含有 5-1^2；1受体蛋白基因的质粒载体转染 HEK293 细 胞， 使用磷酸钙转染法， 并从转染后的细胞中， 通过含 G418的培养液 培养， 以及挑选细胞单克隆和放射性培基结合实验， 最终获得能稳定 表达 5-HT2a受体蛋白的稳定细胞株。 In this experiment, HEK293 cells were transfected with a plasmid vector containing the 5-1^ 2 ; 1 receptor protein gene, using calcium phosphate transfection method, and cultured from the transfected cells through a medium containing G418, and cells were selected. Monoclonal and radioactive permeation binding experiments resulted in stable cell lines stably expressing the 5-HT 2a receptor protein.
(2) 受体结合实验材料： (2) Receptor binding experimental materials:
同位素配基 [3H]-Ketanserin(67.0Ci/mmol) , 购自 PerkinElmer 公 司； （+)spiperone， 购自 RBI公司； GF/B玻璃纤维滤纸， 购自 Whatman 公司； Tris 进口分装； PPO、 POPOP 购自上海试剂一厂； 脂溶性闪烁 液。 Beckman LS-6500型多功能液体闪烁计数仪。 Isotope ligand [ 3 H]-Ketanserin (67.0 Ci/mmol), purchased from PerkinElmer; (+) spiperone, purchased from RBI; GF/B glass fiber filter paper, purchased from Whatman; Tris imported packaging; PPO, POPOP was purchased from Shanghai Reagent No. 1; fat-soluble scintillation fluid. Beckman LS-6500 multi-function liquid scintillation counter.
2、 实验方法： 2. Experimental method:
受体竞争结合实验：  Receptor competition binding experiments:
用含以上各种基因的重组病毒分别感染 HEK-293细胞， 48-72小 时后受体蛋白在膜上大量表达， 将细胞 lOOO rpm离心 5min后弃培液， 收胞体，保存于 -20°C冰箱内备用。实验时用 Tris-HCl反应缓冲液（PH= 7.7 ) 重悬。 将待测化合物与放射性配基各 10 uL及 80 ul受体蛋白加入反应试 管中， 使受试化合物及阳性药物终浓度均为 10 umol/L， 37°C水浴孵育 15 min后， 即刻移至冰浴终止其反应； 在 Millipore细胞样品收集器上， 经过 GF/B玻璃纤维滤纸快速抽滤，并用洗脱液 (50 mM Tris-HCl, PH 7.7) 3 mL * 3次， 用微波炉 8~9 min烘干， 将滤纸移入 0.5 mL离心管中， 加入 500 uL脂溶性闪烁液。 避光静置 30min以上， 计数测定放射性强 度。 按以下公式计算各化合物对同位素配基结合的抑制率百分率：  HEK-293 cells were infected with recombinant viruses containing the above various genes. After 48-72 hours, the receptor protein was expressed in a large amount on the membrane. The cells were centrifuged at 1000 rpm for 5 min, and the culture solution was discarded. The cells were harvested and stored at -20 °C. Spare in the refrigerator. The experiment was resuspended in Tris-HCl reaction buffer (pH = 7.7). The test compound and the radioligand 10uL and 80 ul of the receptor protein were added to the reaction tube, and the final concentration of the test compound and the positive drug was 10 umol/L. After incubating for 15 min in a 37 ° C water bath, it was immediately moved to The reaction was terminated by ice bath; rapidly filtered through a GF/B glass fiber filter on a Millipore cell sample collector, and eluent (50 mM Tris-HCl, pH 7.7) 3 mL * 3 times, using a microwave oven 8-9 Min dry, transfer the filter paper into a 0.5 mL centrifuge tube and add 500 uL of fat-soluble scintillation fluid. The light was allowed to stand for more than 30 minutes, and the radioactivity was measured by counting. Calculate the percentage inhibition rate of each compound for isotope ligand binding according to the following formula:
抑制率 (I %)=总结合管 cpm—化合物 cpm/总结合管 cpm—非特异 结合管 cpm X 100% Inhibition rate (I %) = total binding tube cpm - compound cpm / total binding tube cpm - non-specific binding tube cpm X 100%
化合物每次实验做两复管， 进行两次单独实验。 实施例 18 Compounds were subjected to two replicates per experiment and two separate experiments were performed. Example 18
5-HTla受体结合试验 5-HT la receptor binding assay
1、 实验材料：  1. Experimental materials:
5-HTla 受 体 同 位 素 配 基 [1H].8-OH-DPAT(购 自 PE 公 司）， (+)5-hydroxytrptamine (购自 Sigma公司）， GF/B玻璃纤维滤纸 （购自 Whatman 公司） ， 脂溶性闪烁液： ΡΡΟ,ΡΟΡΟΡ (购自上海试剂一厂）， 甲苯 （购自国药集团化学试剂有限公司） ， Tris进口分装。 5-HT la acceptor isotopes [1H].8-OH-DPAT (purchased from PE), (+) 5-hydroxytrptamine (purchased from Sigma), GF/B glass fiber filter (purchased from Whatman) , fat-soluble scintillation fluid: ΡΡΟ, ΡΟΡΟΡ (purchased from Shanghai Reagent No. 1), toluene (purchased from Sinopharm Chemical Reagent Co., Ltd.), Tris imported sub-package.
细胞： 用基因重组稳定表达 5-HT1A受体的 HEK-293 细胞， 用 DMEM+10%血清的细胞培养液培养 3-5后， 用 PBS收细胞， 将细胞用 -4度 3000转离心 10分钟后弃上清液， 收胞体， 存于 -80度冰箱保存。 实验时用 Binding Buffer ( PH7.4 ) 重悬。 Cells: HEK-293 cells stably expressing 5-HT 1A receptor by gene recombination were cultured in 3-5 cells cultured with DMEM + 10% serum, cells were harvested with PBS, and cells were centrifuged at -4 to 3000 rpm. After a minute, discard the supernatant, collect the cells, and store in a -80 degree refrigerator. Resuspend with Binding Buffer (PH7.4) during the experiment.
2、 实验方法： 2. Experimental method:
粗筛测定每个化合物 10umol/L浓度对 [3H] 8-OH-DPAT与 5-HT1A 受体结合的竞争抑制率； 抑制率高于 95%的化合物进行一系列浓度的 受体结合试验， 确定半数抑制量 （IC50, 抑制 50%[1H] 8-OH-DPAT与 5-HTla受体结合所需化合物浓度） 。 每浓度测定两副管， 每个化合物 进行两次独立试验。 The coarse inhibition assay was used to determine the competitive inhibition rate of [ 3 H] 8-OH-DPAT binding to 5-HT 1A receptor at a concentration of 10 umol/L per compound. Compounds with inhibition rates above 95% were subjected to a series of receptor binding assays. , determine the half-inhibition (IC50, inhibition of 50% [1H] 8-OH-DPAT and 5-HT la receptor binding required compound concentration). Two sets of tubes were tested per concentration and each compound was tested twice independently.
总结合管 8-OH-DPAT 20ul  Total combined tube 8-OH-DPAT 20ul
Di Binding Buffer 20ul  Di Binding Buffer 20ul
细胞 160ul  Cell 160ul
非特异管 8-OH-DPAT 20ul  Non-specific tube 8-OH-DPAT 20ul
5-HT do-4) ) 20ul 5-HT do- 4 ) ) 20ul
细胞 160ul  Cell 160ul
待测物管 8-OH-DPAT 20ul  Test tube 8-OH-DPAT 20ul
待测物 20ul  Test object 20ul
细胞 160ul  Cell 160ul
以上反应管混匀后， 转移至 30度水浴 （1小时） ， 取出立即置于 冰浴中， 用 Harvest抽滤 （冰冷的 Tris淋洗液抽 5次） ， 滤膜用中火 8 分钟烘干， 移入 0.5mL离心管中， 加闪烁液， 静置 30分钟后测数据。 After the above reaction tube is mixed, transfer to a 30-degree water bath (1 hour), take it out and place it in an ice bath immediately, and draw it with Harvest (5 times of ice-cold Tris eluent), and filter medium with medium heat 8 Dry for a minute, transfer to a 0.5 mL centrifuge tube, add scintillation fluid, and let stand for 30 minutes before measuring the data.
1%= (总结合 CPM - 待测物 CPM ) /(总结合 CPM - 非特异 CPM)* 100% 表 2 本发明化合物对 D2、 5-HT2a、 5-HTla受体亲和力 1% = (total binding CPM - analyte CPM) / (total binding CPM - non-specific CPM) * 100% Table 2 Affinity of compounds of the invention for D 2 , 5-HT 2a , 5-HT la receptor
Figure imgf000023_0001
实施例 19
Figure imgf000023_0001
Example 19
D2受体拮抗作用试验 D 2 receptor antagonism test
1、 实验材料：  1. Experimental materials:
稳定表达 rD2R 的 CHO 细胞； Forskolin、 IBMX、 Dopamine、 Haloperidol购自 Sigma; 其余试剂购自国药集团上海化学试剂公司。 CHO cells stably expressing rD 2 R; Forskolin, IBMX, Dopamine, Haloperidol were purchased from Sigma; the remaining reagents were purchased from Sinopharm Shanghai Chemical Reagent Company.
2、 实验方法： 2. Experimental method:
CHO-rD2细胞以 30000个 /孔接种于 96孔板， 培养过夜； 各药物 溶解于含 ΙΟΟμΜ ΙΒΜΧ的无血清 F12培液， 加入细胞中于 37°C预孵育 30min; 加入含 10μΜ Forskolin 禾卩 10μΜ Dopamine 的无血清 F12培液 反应 8min， 加入 ΙΟΟμΙ预冷的 IM HCIO4终止反应， 置冰 40min， 加入 20μ1 2Μ Κ^Ο3中和反应液， 3000rpm 4°C离心 15min， 弃 KClO4沉淀， 取一定量的上清稀释于 0.05M 醋酸缓冲液中， 用放射免疫方法测定 cAMP生成量。 [125I]cAMP放免试剂盒购自上海中医药大学核医学实验 中心， 具体步骤可参见其说明书。 各化合物每浓度测定两副管， 每个 化合物至少进行两次独立试验， 试验结果见下表: 本发明化合物对02受体拮抗作用结果 CHO-rD 2 cells were seeded at 30,000 cells/well in 96-well plates and cultured overnight; each drug was dissolved in serum-free F12 medium containing ΙΟΟμΜ ,, added to cells and pre-incubated at 37 ° C for 30 min; added 10 μΜ Forskolin 卩10μΜ Dopamine serum-free F 12 solution was reacted for 8 min, and the reaction was stopped by adding ΙΟΟμΙ pre-cooled IM HCIO4, and the mixture was iced for 40 min. The reaction mixture was added with 20 μl 2Μ Κ^Ο 3 , centrifuged at 3000 rpm for 4 min at 15 ° C, and the KClO 4 precipitate was discarded. A certain amount of the supernatant was diluted in 0.05 M acetate buffer, and the amount of cAMP production was measured by radioimmunoassay. The [ 125 I]cAMP radioimmunoassay kit was purchased from the Nuclear Medicine Experimental Center of Shanghai University of Traditional Chinese Medicine. The specific steps can be found in the instructions. Two tubes per concentration for each compound, each The compound was tested at least twice independently, and the results are shown in the following table: Results of the antagonistic effect of the compound of the present invention on the 02 receptor
Figure imgf000024_0001
实施例 20
Figure imgf000024_0001
Example 20
D2内在激动活性的 腺苷摄取试验 D 2 intrinsic agonistic activity of adenosine uptake assay
通过使用 200μ1 不含血清的培养基洗涤两次对细胞除去血清， 将 90μ1不含血清的培养基加入到各孔中. 将平板保温 2-3 小时。 将作为 阳性对照的 10μ含有血清的培养基、 载体 （不含血清的培养基） 、 阴 性对照（拮抗剂）或在不含血清的培养基中的测试化合物和标准品（终 浓度为 luM 的 ΙΟμΙ的 lOuM 溶液） 加入到各孔中. 使平板返回到保 温箱中。 18小时后， 加入 腺苷 （0.5μα /孔） 在 ΙΟμΙ不含血清 的培养基中， 并使平板返回到保温箱中。 4 小时后， 加入胰蛋白酶 (0.25 %) (ΙΟΟμΙ/孔）。 再次使平板返回到保温箱中。 1 小时后， 通过经 Whatman GF I B 玻璃纤维滤器进行快速过滤终止试验。 例如使用 Brandel MLR -96T 细胞收集器，用 500 mL 50 mM Tris-HCI pH7.0缓冲 液洗涤滤器。 例如， 使用 Wallac 1205 Betaplate 液体闪烁计数器评估 滤器上的保留的放射性 （50 %有效量） 。 将内在活性定义为总摄取量 ( ΙμΜ 奎吡罗） 减去不含血清的培养基， 将测试化合物与分类为 100 %内在活性的 ΙμΜ奎吡罗（完全 DA 激动剂） 比较。 所有试验均优选 按照一式三份进行， 其中每种药物在每个平板中占完整的一列， 试验 结果见下表： 本发明化合物 D2部分激动作用结果 The cells were removed by washing twice with 200 μl of serum-free medium, and 90 μl of serum-free medium was added to each well. The plate was incubated for 2-3 hours. 10μ serum-containing medium, vehicle (serum-free medium), negative control (antagonist) or test compound and standard in serum-free medium (positive concentration of luM) Add the lOuM solution) to each well. Return the plate to the incubator. After 18 hours, adenosine (0.5 μα /well) was added to the ΙΟμΙ serum-free medium and the plate was returned to the incubator. After 4 hours, trypsin (0.25%) (ΙΟΟμΙ/well) was added. Return the plate to the incubator again. After 1 hour, the test was terminated by rapid filtration through a Whatman GF IB glass fiber filter. For example, using a Brandel MLR-96T cell harvester, the filter was washed with 500 mL of 50 mM Tris-HCI pH 7.0 buffer. For example, the retained radioactivity (50% effective amount) on the filter was evaluated using a Wallac 1205 Betaplate liquid scintillation counter. The intrinsic activity was defined as the total uptake (ΙμΜ quiziro) minus the serum-free medium, and the test compound was compared to ΙμΜQuipirro (complete DA agonist) classified as 100% intrinsic activity. All tests are preferably performed in triplicate, with each drug occupying a complete column in each plate. The test results are shown in the table below: Partial agonistic results of compound D 2 of the present invention
Figure imgf000025_0001
实施例 21
Figure imgf000025_0001
Example 21
5-HT2a受体拮抗作用试验 5-HT 2a receptor antagonism test
1、 实验材料  1. Experimental materials
[35S] GTPyS ; GF/C玻璃纤维滤纸； 脂溶性闪烁液； CHO细胞表 达的 5-HT2a受体蛋白。 Gpp(NH)p， GDP, RB缓冲液。 2、 实验方法 [ 35 S] GTPyS ; GF/C glass fiber filter paper; fat-soluble scintillation fluid; 5-HT 2a receptor protein expressed by CHO cells. Gpp(NH)p, GDP, RB buffer. 2, the experimental method
CHO细胞用 50mM Tris， H =7.4, 破细胞， 1000xg， 4°C离心 10 分钟，上清再 36000xg， 4°C离心 30分钟，保留沉淀即细胞膜，用 50mM Tris，pH 7.4悬浮， BCA法测蛋白浓度。 GTPyS结合实验在 ΙΟΟμΙ缓冲体系中进行， 每管 10μ§蛋白， 反应 缓冲液为 50mM Tris, pH7.4, 5mM MgCl2， ImM EDTA, lOOmM NaCl, ImM DTT, pH7.5。 反应体系含 40μΜ GDP , 非特异管加入 ΙΟΟμΜ Gpp(NH)p , 测试管加入不同浓度受试药物及 10μΜ 5-ΗΤ。 各管加入 O.lnM [35S] GTPyS, 置于 30°C水浴反应 30min。 取出置冰上中止反应， 经 GF/C膜过滤，烘干后置于 0.5ml EP管中，加入 500μ1脂溶性闪烁液， 用 MicroBeta液闪仪测放射强度。每个浓度三复管， 进行至少 2次独立 计算公式为： [35S] GTPyS Bound ( % above basal) = 100x (样品 dpm—基础 dpm)/ (基础 dpm—非特异 dpm) % 用软件拟合浓度-效应曲线并得出 IC5Q值， 具体结果见下表: 表 5 本发明化合物 5-HT2a受体拮抗作用结果 CHO cells were incubated with 50 mM Tris, H = 7.4, ruptured cells, 1000 x g, centrifuged at 4 ° C for 10 minutes, and the supernatant was again centrifuged at 36000 x g for 30 minutes at 4 ° C. The pellet was retained, suspended in 50 mM Tris, pH 7.4, BCA assay. Protein concentration. The GTPyS binding assay was performed in a ΙΟΟμΙ buffer system with 10 μ § protein per tube, and the reaction buffer was 50 mM Tris, pH 7.4, 5 mM MgCl 2 , 1 mM EDTA, 100 mM NaCl, 1 mM DTT, pH 7.5. The reaction system contained 40 μΜ of GDP, and the non-specific tube was added to ΙΟΟμΜ Gpp(NH)p. The test tube was added with different concentrations of test drug and 10 μΜ 5-ΗΤ. Each tube was added with O.lnM [ 35 S] GTPyS and placed in a water bath at 30 ° C for 30 min. The reaction was stopped on ice and filtered through a GF/C membrane. After drying, it was placed in a 0.5 ml EP tube, 500 μl of a fat-soluble scintillation fluid was added, and the radioactivity was measured by a MicroBeta liquid scintillation meter. Three tubes per concentration, at least 2 independent The formula is: [ 35 S] GTPyS Bound ( % above basal) = 100x (sample dpm - base dpm) / (base dpm - non-specific dpm) % Fit the concentration-effect curve with software and get the IC 5Q value, specific The results are shown in the following table: Table 5 Results of 5-HT 2a receptor antagonism of the compound of the present invention
Figure imgf000026_0001
实施例 22
Figure imgf000026_0001
Example 22
5-111^受体部分激动作用试验  5-111^ receptor partial agonistic test
1、 实验材料：  1. Experimental materials:
[35S]GTPyS (1200 Ci/mmol)、 [1H]8-OH-DPAT (124.9Ci/mmol) 及 5-HTla受体表达的 CHO细胞， GF/C玻璃纤维滤纸； 脂溶性闪烁液； Gpp(NH)p, GDP, RB缓冲液。 [ 35 S]GTPyS (1200 Ci/mmol), [1H]8-OH-DPAT (124.9 Ci/mmol) and 5-HT la receptor-expressing CHO cells, GF/C glass fiber filter paper; fat-soluble scintillation fluid; Gpp(NH)p, GDP, RB buffer.
2、 实验方法： 2. Experimental method:
CHO细胞用 50mM Tris, pH 7.4， 破细胞， 1000xg， 4°C离心 10 分钟，上清再 36000xg， 4°C离心 30分钟，保留沉淀即细胞膜，用 50mM Tris, pH 7.4悬浮， BCA法测蛋白浓度。  CHO cells were lysed with 50 mM Tris, pH 7.4, sterilized at 1000 x g for 10 minutes at 4 ° C, and the supernatant was again centrifuged at 36000 x g for 30 minutes at 4 ° C to retain the pellet, which was suspended in 50 mM Tris, pH 7.4, and protein was measured by BCA method. concentration.
GTPyS结合实验在 ΙΟΟμΙ缓冲体系中进行， 每管 10μ§蛋白， 反应 缓冲液为 50mM Tris, pH7.4, 5mM MgCl2， O.lmM EGTA, lOOmM NaCl, ImM DTT, pH7.5。 反应体系含 40μΜ GDP , 非特异管加入 ΙΟΟμΜ Gpp(NH)p , 测试管加入不同浓度受试药物及 ΙΟμΜ 5-ΗΤ。 各管加入 O.lnM [35S] GTPyS, 置于 22°C水浴反应 60min。 取出置冰上中止反应， 经 GF/C膜过滤， 烘干后置于 0.5mL EP管中， 加入 500μί脂溶性闪烁 液， 用 MicroBeta液闪仪测放射强度。 每个浓度三复管， 进行至少 2次 独立实验。 计算公式为： [35S] GTPyS Bound ( % above basal) = 100x (样品 dpm—基础 dpm)/ (基础 dpm—非特异 dpm) % 用软件拟合浓度-效应曲线并得出 IC5Q值， 结果如表 5 表 6 本发明化合物 5-111 ^受体部分激动作用结果 GTPyS binding assay was performed in a ΙΟΟμΙ buffer system with 10 μ § protein per tube, reaction The buffer was 50 mM Tris, pH 7.4, 5 mM MgCl 2 , O.lmM EGTA, 100 mM NaCl, 1 mM DTT, pH 7.5. The reaction system contained 40 μΜ GDP, and the non-specific tube was added to ΙΟΟμΜ Gpp(NH)p. The test tube was added with different concentrations of test drug and ΙΟμΜ 5-ΗΤ. Each tube was added with O.lnM [ 35 S] GTPyS and placed in a water bath at 22 ° C for 60 min. The reaction was stopped on ice and filtered through a GF/C membrane. After drying, it was placed in a 0.5 mL EP tube, 500 μί of a fat-soluble scintillation fluid was added, and the radioactivity was measured by a MicroBeta liquid scintillation meter. At least 2 independent experiments were performed with each concentration of three tubes. The formula is: [ 35 S] GTPyS Bound ( % above basal) = 100x (sample dpm - base dpm) / (base dpm - non-specific dpm) % Fit the concentration-effect curve with software and get the IC 5Q value, the result Table 5 Table 6 Compounds 5-111 ^ Receptor partial agonistic results
Figure imgf000027_0001
实施例 23
Figure imgf000027_0001
Example 23
本发明中所述六个化合物体内抗精神分裂活性试验  In vivo anti-schizophrenia activity test of the six compounds described in the present invention
1、 阿扑吗啡模型：  1. Apomorphine model:
(1) 阿扑吗啡诱导小鼠精神分裂症实验模型建立  (1) Establishment of experimental model of schizophrenia induced by apomorphine in mice
近交系 C57BL/6小鼠 108只， 雌雄各半， 按体重均衡随机分为 8组： 空白对照组， 模型对照组， 受试化合物梯度剂量组 （5个剂量， 具体根 据预实验情况确定） 和利培酮组（1.00 mg-kg 1) , 阿立哌唑组 (0.50mg/Kg), 灌胃给药。 模型对照组灌胃给予相同体积的溶剂。 给予 受试药后 30分钟， 用浓度为 10.0 mg'kg- 1的阿扑吗啡溶液 （溶于 0.1%的 抗坏血酸中） ， 按 10.0 mLkg-1小鼠体重进行腹腔注射诱导建立小鼠精 108 inbred C57BL/6 mice, male and female, were randomly divided into 8 groups according to body weight: blank control group, model control group, gradient dose group of test compound (5 doses, determined according to pre-experiment) And risperidone group (1.00 mg-kg 1 ), aripiprazole group (0.50mg/Kg), administered by intragastric administration. The model control group was intragastrically administered with the same volume of solvent. 30 minutes after the administration of the test drug, a concentration of 10.0 mg'kg- 1 of apomorphine solution (dissolved in 0.1% ascorbic acid) was induced by intraperitoneal injection of 10.0 mL kg- 1 mouse body to establish mouse essence.
(2) 刻板行为学观察 (2) Stereotype behavior observation
小鼠给予阿扑吗啡后，分别观察记录第 6-10、 11-15、 16-20、 21-25、 26-30、 31-35、 36-40、 41-45、 46-50、 51-55、 56-60分钟时的前 30秒 内小鼠是否出现竖尾和爬壁等刻板行为，并按以下标准进行评分：0分， 在 30秒内无上述行为出现 （K1秒） ； 1分， 在 30秒内出现不连续的 中度的上述行为 （1秒 <3秒） ； 2分， 在 30秒内出现连续的强的上 述行为 （t > 3秒） 。 计算 60分钟内小鼠出现竖尾和爬壁等刻板行为的 总 分 。 ED50 计 算 按 照 公 式 ：  After administration of apomorphine in mice, observe records 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51- 55. In the first 30 seconds of 56-60 minutes, the mice showed stereotypes such as vertical tail and wall climbing, and scored according to the following criteria: 0 points, no such behavior occurred within 30 seconds (K1 seconds); 1 point The discontinuous moderate behavior (30 seconds <3 seconds) occurred within 30 seconds; 2 points, continuous strong above behavior (t > 3 seconds) occurred within 30 seconds. The total score of stereotypes such as vertical tail and wall climbing in the mice was calculated within 60 minutes. The ED50 is calculated according to the formula:
(3) 统计方法 (3) Statistical methods
全部数据以 ±SD表示， 用 SPSS17.0软件统计包处理， 进行两个样 本均数比较的 t检验及单因素方差分析， 以 PO.05为显著性差异。  All data were expressed as ±SD, and were processed by SPSS 17.0 software statistical package. The t test and one-way ANOVA of the two sample means were compared, and PO.05 was used as the significant difference.
(4) 实验结果 (4) Experimental results
具体结果见表 7和表 8 The specific results are shown in Table 7 and Table 8.
表 7 化合物 1-1 单次口服给药对阿扑吗啡诱导的小鼠精神分裂症 模型总刻板运动的影响 Table 7 Effect of single oral administration of compound 1-1 on total stereotypic exercise in apomorphine-induced mouse schizophrenia model
组别 n 剂量 (mg_kg— ^ 刻板运动评分 改善率 （％)  Group n dose (mg_kg-^ Stereotype exercise score improvement rate (%)
空白对照组 12 - 0.50 土 0.80  Blank control group 12 - 0.50 soil 0.80
模型对照组 12 - 27.83 土 5.10**  Model control group 12 - 27.83 soil 5.10**
利培酮组 12 1.00 5.42 土 4.01 80.54  Risperidone group 12 1.00 5.42 soil 4.01 80.54
阿立哌唑组 12 0.50 6.41 土 4.72 76.98  Aripiprazole group 12 0.50 6.41 soil 4.72 76.98
1-1 组 12 0.12 24.17 土 4.65 13.17  1-1 group 12 0.12 24.17 soil 4.65 13.17
1- 1组 12 0.18 15.75 土 4.96## 43.41 1- 1 group 12 0.18 15.75 soil 4.96 ## 43.41
1-1 组 12 0.25 1 1.58 土 2.84## 58.38 1-1 group 12 0.25 1 1.58 soil 2.84 ## 58.38
1- 1组 12 0.35 7.42 土 5.71## 73.35 1- 1 group 12 0.35 7.42 soil 5.71 ## 73.35
1-1 组 12 0.50 0.75 土 1.48## 97.31 1-1 group 12 0.50 0.75 soil 1.48 ## 97.31
与空白对照组比较： P<0.05， P<0.01 ; 与模型对照组比较： # P<0.05 , ## P<0.01 表 8单次口服给药对阿扑吗啡诱导的小鼠精神分裂症模型总刻板 运动 ED5o Compared with the control group: P <0.05, P <0.01 ; with model control group: # P <0.05, ## P < 0.01 Table 8 mouse models of schizophrenia single oral administration of apomorphine induced increases in total Stereotype ED 5 o
Figure imgf000029_0001
Figure imgf000029_0001
注： Π-1为专利 CN101302214中的优势化合物  Note: Π-1 is the dominant compound in patent CN101302214
2、 MK-801模型： 2. MK-801 model:
(1) MK-801诱导小鼠精神分裂症实验模型建立  (1) Establishment of experimental model of mouse schizophrenia induced by MK-801
近交系 C57BL/6小鼠 108只， 雌雄各半， 按性别和体重均衡随机分 为 9组： 空白对照组， 模型对照组， 阿立哌唑组 （0.3mg/Kg) 、 利培酮 阳性对照组 （0.3mg/kg) 、 受试化合物梯度剂量组 （5个剂量， 具体根 据预实验情况确定） 。 每只动物于实验前一天放入隔音箱适应 30min， 第二天给予受试物后 30分钟， 用浓度为 0.04 mg/mL的 MK-801溶液， 按 10.0 mL/kg小鼠体重进行腹腔注射诱导建立小鼠精神分裂症实验模型， 空白对照组和模型对照组腹腔注射同体积受试物溶媒。 108 inbred C57BL/6 mice, male and female, randomly divided by sex and weight For 9 groups: blank control group, model control group, aripiprazole group (0.3 mg/Kg), risperidone positive control group (0.3 mg/kg), test compound gradient dose group (5 doses, based on Pre-experimental situation is determined). Each animal was placed in a soundproof box for 30 minutes on the day before the experiment, and 30 minutes after the administration of the test substance on the next day, the MK-801 solution at a concentration of 0.04 mg/mL was used for intraperitoneal injection of 10.0 mL/kg of mouse body weight. An experimental model of mouse schizophrenia was established. The blank control group and the model control group were intraperitoneally injected with the same volume of test substance.
(2) 旷场跑动行为学观察 (2) Behavioral behavior observation in the market
小鼠给予 MK-801后， 立即放入隔音箱， 观察记录 60分钟内小鼠 自主活动的总路程。  Immediately after the mice were given MK-801, they were placed in a soundproof box to observe the total distance of the mice's self-activity within 60 minutes.
改善率 = (模型对照组活动总路程给药组活动总路程） I (模型对 照组活动总路程） * 100%  Improvement rate = (the total distance of the model control group activity total distance administration group activity) I (the total distance of the model control group activity) * 100%
ED5Q根据上述公式， 作回归方程， 计算得到。 The ED 5Q is calculated according to the above formula as a regression equation.
(3) 统计方法 (3) Statistical methods
全部数据以 ±SD表示， 用 SPSS17.0软件统计包处理， 进行两个样 本均数比较的 t检验及单因素方差分析， 以 PO.05为显著性差异。  All data were expressed as ±SD, and were processed by SPSS 17.0 software statistical package. The t test and one-way ANOVA of the two sample means were compared, and PO.05 was used as the significant difference.
(4)实验结果 (4) Experimental results
具体结果见表 9与表 10 The specific results are shown in Table 9 and Table 10.
表 9 单次口服给予 I-l对 MK-801诱导小鼠精神分裂症模型旷场运 动总路程的影响 （ ±SD ) Table 9 Effect of a single oral administration of I-l on the total distance of MK-801-induced schizophrenia model in mice (±SD)
动物数 剂量 自主活动总路程  Number of animals dose total distance of autonomous activities
改善率 （％) (只） (mg/kg) (cm)  Improvement rate (%) (only) (mg/kg) (cm)
正常对照组 12 - 8580.12 ± 3069.84  Normal control group 12 - 8580.12 ± 3069.84
模型对照组 12 - 25256.73土 7129.47**  Model control group 12 - 25256.73 soil 7129.47**
利培酮组 12 0.30 3028.00土 825.3 1 88.01 阿立哌唑组 12 0.30 2975.00±814.25 88.22 Risperidone group 12 0.30 3028.00 soil 825.3 1 88.01 aripiprazole group 12 0.30 2975.00 ± 814.25 88.22
1- 1 组 12 0.07 27887.03±9385.58 - 10.411- 1 group 12 0.07 27887.03±9385.58 - 10.41
1-1组 12 0.10 2021 1.47土 9785.36 19.981-1 group 12 0.10 2021 1.47 soil 9785.36 19.98
1-1组 12 0.14 16632.34土 7646.37 # 34.151-1 group 12 0.14 16632.34 soil 7464.37 # 34.15
1-1组 12 0.20 9730.62土 1865.34 ## 61.471-1 group 12 0.20 9730.62 soil 1865.34 ## 61.47
1-1组 12 0.28 7951.01±3339.76## 68.52 与正常对照组比较： P<0.05， P<0.01 ; 与模型对照组比较:1-1 group 12 0.28 7951.01±3339.76 ## 68.52 Compared with the normal control group: P<0.05, P<0.01; compared with the model control group:
P<0.05 , 冊 P<0 表 10单次口服给药对 MK-801诱导小鼠精神分裂症模型旷场运动 总路程的影响 ED50 P<0.05, P<0 Table 10 Effect of single oral administration on MK-801-induced total sacral motion of mouse schizophrenia model ED 50
Figure imgf000031_0001
实施例 24
Figure imgf000031_0001
Example 24
本发明中所述六个化合物引起小鼠共济失调试验 ED2Q The six compounds described in the present invention cause the mouse ataxia test ED 2Q
1、 抗精神分裂药物导致的小鼠共济失调实验模型建立 雄性 C57 BL/6小鼠 110只， 每组 10只， 共 11组， 空白对照组、 利培酮组 (1.0， 1.25， 1.56， 1.95，2.44mg/Kg)、受试物梯度剂量组（五个剂 量组， 具体剂量根据预实验结果确定） ， 口服灌药 0.5h后观察小鼠共 济失调情况， 空白对照组灌服同体积受试物溶媒。 1. Establishment of an experimental model of mouse ataxia induced by anti-schizophrenic drugs 110 male C57 BL/6 mice, 10 rats in each group, 11 groups in total, blank control group, risperidone group (1.0, 1.25, 1.56, 1.95, 2.44 mg/Kg), gradient dose group (5 One dose group, the specific dose was determined according to the pre-experiment results), the mice were observed to have ataxia after oral administration for 0.5 h, and the blank control group was given the same volume of test substance.
2、 共济失调行为观察  2, ataxia behavior observation
对小鼠录像采用盲法评定。共济失调行为程度评分标准：0 =正常， 1 =身体略有摇晃、 后肢未伸出或略有伸出， 2 =身体摇晃明显、 后肢 伸出明显或后肢略有拖地走， 3 =后肢伸出明显、 后肢无力拖地走， 4 =小鼠呆在一个地方基本不能动、 身体 (头和后肢)颤抖， 5=小鼠完全静 止不动  The mouse video was assessed blindly. Ataxia behavior degree scoring criteria: 0 = normal, 1 = the body is slightly shaken, the hind limbs are not extended or slightly extended, 2 = the body is shaking, the hind limbs are prominent or the hind limbs are slightly mopped, 3 = hind limbs Outstanding, the hind limbs are unable to drag, 4 = the mouse stays in one place is basically unable to move, the body (head and hind legs) trembles, 5 = the mouse is completely still
3、 统计方法  3. Statistical methods
全部数据以 ±SD表示， 用 SPSS 17.0软件统计包处理， 进行两个 样本均数比较的 t检验及单因素方差分析， 以 PO.05为显著性差异。 用 曲线下面积 （AUC) 对小鼠的共济失调行为进行评价：  All data were expressed as ±SD, and were processed by SPSS 17.0 software statistical package. The t-test and one-way ANOVA of two sample mean comparisons were performed, with PO.05 being a significant difference. The area under the curve (AUC) was used to evaluate the ataxia behavior of mice:
共 济 失 调 行 为 ED2Q 计 算 按 照 公 式 ： 失调率 =空白对 给纖 X 100O/O， 作回归方程， 计算得到。 The ataxia behavior ED 2Q is calculated according to the formula: Offset rate = blank vs. fiber X 100O/O, regression equation, calculated.
4、 实验结果 表 11 单次口服给予本发明化合物导致小鼠共济失调 ED 4. Experimental results Table 11 Single oral administration of the compounds of the present invention results in ataxia in mice ED
化合物 ED20(mg/Kg) Compound ED 20 (mg/Kg)
利培酮 1.58  Risperidone 1.58
1-1 3.87  1-1 3.87
1-2 3.95  1-2 3.95
1-3 3.56  1-3 3.56
1-4 3.43  1-4 3.43
(R)- 1-1 4.05  (R)- 1-1 4.05
(S)- 1-1 3.93  (S)- 1-1 3.93
(Π-1) 1.50 实施例 25 (Π-1) 1.50 Example 25
小鼠药代动力学试验  Mouse pharmacokinetic test
取 ICR小鼠 70只， 随机分为 7组， 每组 10只。 将权利要求所述 六个化合物及化合物 Π-1 进行小鼠灌胃给药， 每个化合物对应一组， 即 10只动物， 剂量均为 2mg/Kg， 进行药代动力学实验， 结果如下： 血浆主要药代动力学参数  Seventy ICR mice were randomly divided into 7 groups, 10 in each group. The six compounds and the compound Π-1 according to the claims were administered to mice by intragastric administration, and one group of each compound, that is, 10 animals, at a dose of 2 mg/Kg, was subjected to pharmacokinetic experiments, and the results were as follows: Plasma major pharmacokinetic parameters
Figure imgf000033_0001
脑脊液主要药代动力学参数
Figure imgf000033_0001
Main pharmacokinetic parameters of cerebrospinal fluid
Figure imgf000033_0002
Figure imgf000033_0002
结果表明： 本发明所述六个化合物在吸收、 血脑屏障透过率方面 远优于化合物 π-ΐ。 实施例 26  The results showed that the six compounds of the present invention are far superior to the compound π-ΐ in absorption and blood-brain barrier permeability. Example 26
本发明书中所述六个化合物的急性毒性研究 用 Bliss法统计， 小鼠分别单次灌服本发明所述六个化合物 LD5() 均大于 1500mg/kg， 其 LD5Q数值远大于药效剂量 (ED5Q)的 20倍， 属于 高度安全的化合物。 实施例 27 Acute toxicity study of the six compounds described in the present invention According to the Bliss method, the LD 5() of the six compounds of the present invention is more than 1500 mg/kg in a single administration, and the LD 5Q value is much larger than 20 times of the pharmacodynamic dose (ED 5Q ), which is highly safe. Compound. Example 27
本发明中所述六个化合物的细菌回复突变试验  Bacterial back mutation test of the six compounds described in the present invention
菌种： 鼠沙门氏菌组氨酸营养缺陷突变株 TA97， TA98， TA1(K)和 TA102。 结果： 实验包括 -s«^n + s9两个部分， 在无 S9测试系统中丁 98和 加 S9测试系统中 ΤΑ97 5000μ§/皿有抑菌作用。 其它剂量对所有菌株均 无抑菌作用， 生长背景良好。 所有测试剂量无论在无 S9或加 S9实验系 统中， 均未引起任何菌落回变数明显增加， Ames试验阴性。 Species: Salmonella typhimurium histidine auxotrophic mutants TA 97 , TA 98 , TA 1 (K) and TA 102 . RESULTS: The experiment consisted of two parts, -s«^n + s 9 , in the absence of the S 9 test system in the D 98 and the S 9 test system ΤΑ 97 5000 μ § / dish has a bacteriostatic effect. The other doses had no bacteriostatic effect on all strains, and the growth background was good. All test doses did not cause any significant increase in colony reversion variables in either the S 9-free or S 9 experimental system, and the Ames test was negative.

Claims

权 利 要 求 书 Claim
1. 喹啉酮衍生物， 其特征在于， 为具有如下结构通式 I的化合物、 通式 I的化合物消旋体、 通式 I的化合物光学异构体、 通式 I的化合物 的游
Figure imgf000035_0001
A quinolinone derivative characterized by being a compound having the following structural formula I, a racemate of a compound of formula I, an optical isomer of a compound of formula I, a compound of formula I
Figure imgf000035_0001
通式 I  Formula I
中：  Medium:
=为单键或双键；  = single or double button;
！^代表氢或甲基；  ! ^ represents hydrogen or methyl;
R2代表氢或甲氧基； R 2 represents hydrogen or methoxy;
R3代表氢、 甲基或乙基。 R 3 represents hydrogen, methyl or ethyl.
2. 根据权利要求 1所述的喹啉酮衍生物， 其特征在于， 当=为 双键时， ！^为甲基， R2为甲氧基， R3为氢。 The quinolinone derivative according to claim 1, wherein when = is a double bond, ! ^ is methyl, R 2 is methoxy, and R 3 is hydrogen.
3. 根据权利要求 1所述的喹啉酮衍生物， 其特征在于， 当=为 双键时， R2为氢， R3为氢或甲基。 The quinolinone derivative according to claim 1, wherein when = is a double bond, R 2 is hydrogen, and R 3 is hydrogen or methyl.
4. 根据权利要求 1所述的喹啉酮衍生物， 其特征在于， 当^为 单键时， R2、 R3为氢， ！^为甲基。 The quinolinone derivative according to claim 1, wherein, when ^ is a single bond, R 2 and R 3 are hydrogen, ! ^ is methyl.
5. 根据权利要求 1所述的喹啉酮衍生物， 其特征在于， 所述的喹 啉酮衍生物为通式 I的化合物光学异构体，当 为双键时， R1为甲基， R2为氢， R3为甲基； 当^为单键时， R2、 R3为氢， R1为甲基。 The quinolinone derivative according to claim 1, wherein the quinolinone derivative is an optical isomer of the compound of the formula I, and when it is a double bond, R1 is a methyl group, R2 Is hydrogen, R3 is methyl; when ^ is a single bond, R2, R3 are hydrogen, and R1 is methyl.
6. 根据权利要求 1〜5任一项所述的喹啉酮衍生物， 其特征在于， 所述的盐为含有药物上可接受的阴离子的盐。 The quinolinone derivative according to any one of claims 1 to 5, wherein the salt is a salt containing a pharmaceutically acceptable anion.
7. 根据权利要求 6所述的喹啉酮衍生物， 其特征在于， 所述的为 盐酸盐、 氢溴酸盐、 氢碘酸盐、 硝酸盐、 硫酸盐或硫酸氢盐、 磷酸盐 或酸式磷酸盐、 乙酸盐、 乳酸盐、 柠檬酸盐、 酒石酸盐、 马来酸盐、 富马酸盐、 葡萄糖酸盐、 糖二酸盐、 苯甲酸盐、 甲磺酸盐、 乙磺酸盐、 苯磺酸盐或对甲苯磺酸盐。 The quinolinone derivative according to claim 6, wherein the salt is a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a sulfate or a hydrogen sulfate, a phosphate or Acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, gluconate, saccharide, benzoate, methanesulfonate, B Sulfonate, besylate or p-toluenesulfonate.
8. 根据权利要求 6所述的喹啉酮衍生物， 其特征在于， 所述盐含 0.5-3分子的结晶水。 The quinolinone derivative according to claim 6, wherein the salt contains 0.5 to 3 molecules of water of crystallization.
9. 根据权利要求 1所述的喹啉酮衍生物， 其特征在于， 所述喹啉 酮衍生物选自： The quinolinone derivative according to claim 1, wherein the quinolinone derivative is selected from the group consisting of:
7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基 )-3，4-二氢 -3-甲 基喹啉 -2(1H 酮或其盐、  7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3,4-dihydro-3-methylquinoline -2 (1H ketone or its salt,
7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基） -3-甲基喹啉 -2(1H)-酮或其盐、  7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3-methylquinolin-2(1H)-one Or its salt,
7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基）丙氧基 )-6-甲氧基 -3- 甲基喹啉 -2(1H)-酮或其盐、  7-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-6-methoxy-3-methylquinoline- 2(1H)-ketone or a salt thereof,
7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基） 哌啶 -1-基) -2-甲基丙氧基) -3-甲 基喹啉 -2(1H 酮或其盐、  7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-2-methylpropoxy)-3-methylquinoline-2 (1H ketone or its salt,
(S)- 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基） -3-甲基喹 啉 -2(1H)-酮或其盐、  (S)- 7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3-methylquinolin-2 ( 1H)-ketone or a salt thereof,
(R)- 7-(3-(4-(6-氟苯并 [d]异哑唑 -3-基)哌啶 -1-基)丙氧基） -3-甲基 喹啉 -2(1H 酮或其盐。  (R)- 7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3-methylquinolin-2 ( 1H ketone or a salt thereof.
10. 一种用于治疗精神分裂症的组合物， 所述组合物包括治疗有 效量的权利要求 1〜9任一项所述的化合物或该化合物的游离碱或盐以 及医学上可接受的载体。 A composition for treating schizophrenia, the composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 9 or a free base or salt of the compound and a pharmaceutically acceptable carrier .
11. 权利要求 1〜9任一项所述的喹啉酮衍生物在制备治疗精神分 裂症及其它神经精神疾病药物中的应用。 The use of the quinolinone derivative according to any one of claims 1 to 9 for the preparation of a medicament for treating schizophrenia and other neuropsychiatric diseases.
12. 根据权利要求 11所述的应用， 其特征在于， 所述的神经精神 病包括神经性疼痛、 躁狂症、 精神分裂症、 焦虑症或各种抑郁症。 12. The use according to claim 11, wherein the neuropsychiatric disorder comprises neuropathic pain, mania, schizophrenia, anxiety or various depressions.
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Publication number Priority date Publication date Assignee Title
CN101302214A (en) * 2007-05-11 2008-11-12 江苏国华投资有限公司 Aralkyl piperidine (piperazidine) derivate and use thereof in mental disease treatment
CN101607959A (en) * 2009-06-18 2009-12-23 上海医药工业研究院 The dihydroquinoline ketone derivatives, its preparation method and be the pharmaceutical composition of activeconstituents with this compound

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AU7547100A (en) * 1999-09-09 2001-04-10 Egis Gyogyszergyar Rt. Alkylpiperidi nylbenzo [d] isoxazole derivatives having psychotropic activity, pharmaceutical compositions containing the same, and a process for the preparation of the active ingredient
CN1701072A (en) * 2002-09-17 2005-11-23 沃纳-兰伯特公司 Heterocyclic substituted piperazines for the treatment of schizophrenia
WO2010012121A1 (en) * 2008-07-28 2010-02-04 江苏国华投资有限公司 Aralkyl substituted piperidine or piperazine derivatives and their use for treating schizophrenia

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101302214A (en) * 2007-05-11 2008-11-12 江苏国华投资有限公司 Aralkyl piperidine (piperazidine) derivate and use thereof in mental disease treatment
CN101607959A (en) * 2009-06-18 2009-12-23 上海医药工业研究院 The dihydroquinoline ketone derivatives, its preparation method and be the pharmaceutical composition of activeconstituents with this compound

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