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WO2012130153A1 - Dérivés de quinolinone et leur utilisation comme médicament contre la schizophrénie - Google Patents

Dérivés de quinolinone et leur utilisation comme médicament contre la schizophrénie Download PDF

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Publication number
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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Prior art keywords
compound
salt
quinolinone derivative
hydrogen
methyl
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Ceased
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PCT/CN2012/073281
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English (en)
Chinese (zh)
Inventor
李建其
辜顺林
蔡王平
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Shanghai Institute of Pharmaceutical Industry
Jiangsu Hengyi Pharmaceutical Co Ltd
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Shanghai Institute of Pharmaceutical Industry
Jiangsu Hengyi Pharmaceutical Co Ltd
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Publication of WO2012130153A1 publication Critical patent/WO2012130153A1/fr
Anticipated expiration legal-status Critical
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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

L'invention concerne des dérivés de quinolinone et leur utilisation comme médicament contre la schizophrénie. Les dérivés de quinolinone de la présente invention ont une affinité élevée pour les récepteurs d2 de la dopamine, lesquels présentent non seulement une activité antagoniste relativement puissante, mais encore manifestant une activation partielle de récepteurs d2. Les composés ont une bonne absorption par voie orale et présentent une faible toxicité aiguë (DL50 > 1 500 mg/kg, un simple gavage chez les souris) qui est équivalente à l'aripiprazole et à la ziprasidone et de loin inférieure à la rispéridone, ayant ainsi le potentiel d'être élaborés sous la forme d'un nouveau médicament contre la schizophrénie. La structure générale est la suivante :
PCT/CN2012/073281 2011-03-31 2012-03-30 Dérivés de quinolinone et leur utilisation comme médicament contre la schizophrénie Ceased WO2012130153A1 (fr)

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CN2011100799044A CN102718758A (zh) 2011-03-31 2011-03-31 喹啉酮衍生物及其作为抗精神分裂症药物的应用
CN201110079904.4 2011-03-31

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CN115850242B (zh) * 2022-11-28 2024-02-06 烟台大学 喹啉-2(1h)-酮衍生物及其制备方法和用途

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CN101302214A (zh) * 2007-05-11 2008-11-12 江苏国华投资有限公司 芳烷基哌啶(嗪)衍生物及在治疗精神神经疾病中的应用
CN101607959A (zh) * 2009-06-18 2009-12-23 上海医药工业研究院 二氢喹啉酮衍生物,其制备方法和以该化合物为活性成分的药物组合物

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WO2001017993A1 (fr) * 1999-09-09 2001-03-15 EGIS Gyógyszergyár Rt. Derives d'alkypiperidi nylbenzo [d] isoxazole presentant une activite psychotrope, compositions pharmaceutiques contenant ces derniers, et procede de preparation de l'ingredient actif
CN1701072A (zh) * 2002-09-17 2005-11-23 沃纳-兰伯特公司 用于治疗精神分裂症的杂环取代的哌嗪
JP2011529090A (ja) * 2008-07-28 2011-12-01 江蘇国華投資有限公司 アラルキルピペリジン（又はピペラジン）誘導体及びその統合失調症治療のための使用

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Publication number Priority date Publication date Assignee Title
CN101302214A (zh) * 2007-05-11 2008-11-12 江苏国华投资有限公司 芳烷基哌啶(嗪)衍生物及在治疗精神神经疾病中的应用
CN101607959A (zh) * 2009-06-18 2009-12-23 上海医药工业研究院 二氢喹啉酮衍生物,其制备方法和以该化合物为活性成分的药物组合物

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