CN109111400B - Preparation and application of phenylquinolinone and flavonoid derivatives - Google Patents

Preparation and application of phenylquinolinone and flavonoid derivatives Download PDF

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CN109111400B
CN109111400B CN201710488414.7A CN201710488414A CN109111400B CN 109111400 B CN109111400 B CN 109111400B CN 201710488414 A CN201710488414 A CN 201710488414A CN 109111400 B CN109111400 B CN 109111400B
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alkoxy group
phenyl
hydroxy
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CN109111400A (en
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盛荣
楼金芳
严洪兵
胡永洲
唐黎
张冯敏
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Hangzhou Bio Sincerity Pharma Tech Corp ltd
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Hangzhou Bio Sincerity Pharma Tech Corp ltd
Zhejiang University ZJU
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Abstract

The invention relates to phenyl quinolinone and flavonoid derivatives and a preparation method thereof, wherein the derivatives are histamine H3The receptor antagonist can protect and restore the normal function of the central nervous system, and has great clinical application value, especially in neurodegenerative diseases and ischemic brain injury.

Description

Preparation and application of phenylquinolinone and flavonoid derivatives
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to preparation of phenylquinolinone and flavonoid derivatives, wherein the active ingredient of the derivatives is histamine H3 receptor antagonist, and the derivatives can protect and restore normal functions of the central nervous system and can be applied to treatment of neurodegenerative diseases, ischemic and hypoxic encephalopathy, Parkinson's syndrome, hypersomnia, epilepsy and freezing-related diseases. The phenylquinolinone and flavonoid derivatives also comprise pharmaceutically acceptable salts, compounds, solvates and the like.
Background
Histamine H3The receptor is present in cerebral cortex, striatum, hippocampus, olfactory bulb, nucleus basalis of terminal striatum, thalamus, lower brainstem spinal nucleus, cerebellum, etc., and histamine H3Receptors are autoreceptors of neuronal synapses, which are stimulated to inhibit histamine or other neurotransmitter release, and antagonized to promote neurotransmitter release.
Cerebral ischemia is cerebral infarction caused by cerebral blood supply insufficiency caused by thrombosis, embolism or other reasons in cerebral vessels, and is also one of the first killers causing human disability and death. Probably due to the complex mechanisms of the pathological process, no effective drugs have been used clinically so far.
Studies have shown that histamine H3Receptor antagonists can be used for the treatment of Alzheimer's Disease (AD), Parkinson's Disease (PD), dementia (ALS), hypersomnia, etc., by promoting the synthesis and release of neurotransmitters such as histamine.
In particular, Alzheimer Disease (AD) has been found to be more than one hundred years old, and the number of patients is on an increasing trend year by year, and studies indicate that many factors such as β -amyloid peptide (a β) aggregation, tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, and neurotransmitter system dysfunction are likely to be related to their pathogenesis, and different molecular mechanisms are related and influence each other. Currently, the first-line therapeutic drugs clinically used for AD mainly include acetylcholinesterase (AChE) inhibitors donepezil, rivastigmine, galantamine and uncompetitive NMDA receptor antagonist memantine, which all act on the cognition-related neurotransmitter system, and although they can alleviate cognitive impairment of early patients, they cannot fundamentally improve the disease state or stop the disease process.
Aiming at the characteristics that the process of the occurrence and the development of AD diseases relates to a plurality of factors, the Medicine (MTDLs) which can simultaneously aim at the action of a plurality of targets has unique advantages and attracts the wide attention of people. As shown in the study, H3Receptors are important receptors for neurotransmitter regulation in the brain, H3Receptor antagonist blockade of H3Receptors are effective in promoting the release of histamine, acetylcholine, and other cognitively related neurotransmitters, and several histamine H receptors are currently available3Receptor antagonists (ABT-288, AZD5213, CEP-26401, GSK239512 and MK0249) were introduced into clinical studies for the treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, lethargy and the like, see FIG. 1.
Senile Plaques (SP) formed by amyloid peptide a β deposited at the limbus and cerebral cortex after aggregation are one of the most typical pathological features of AD. Furthermore, oligomers, fibrils and fibers formed during the aggregation of a β can be toxic to nerve cells and even lead to apoptosis of nerve cells. Therefore, Α β aggregation is widely considered to be an intrinsic cause of AD, and drugs that inhibit Α β aggregation have become an important direction for current AD drug development.
The invention can improve the target (H) of symptom on the basis of carrying out system analysis on the biological characteristics of AD related targets3Receptor) and a target point (A β aggregation) aiming at the etiology are organically combined, and a reasonable drug design method is adopted to design a drug capable of simultaneously antagonizing H3The multi-target compound can promote the release of neurotransmitter, improve the symptoms of AD patients and delay the disease condition, can inhibit the self-aggregation of A β at the same time, fundamentally prevent the progress of the disease course of AD, achieve the effects of treating both principal and secondary aspects of diseases and have unique effect on the treatment of neurodegenerative diseases such as AD and the like.
The invention also discloses a protective effect of the compound on the nerve function of ischemic brain injury.
Histamine H3The molecular structure of the receptor antagonist is mostly chain molecules and mainly comprises three parts: the western segment is a part composed of nitrogen-containing basic region of fatty tertiary amine and connecting chain, the center is liposoluble aromatic ring, and the east segment is liposoluble aromatic ring or basic group (figure 2)
The invention proceeds from H3On the other hand, earlier researches show that the N-amine propoxy phenyl-pyridine-4-ketone derivative with similar structure has good A β aggregation inhibiting activity (N-substituted phenyl pyridine-4-ketone derivative and preparation and application thereof, ZL201310511154.2) further activity tests show that the designed phenyl quinolinone and flavonoid derivative have H antagonistic activity3Receptors and dual-target compounds that inhibit aggregation of a β.
Disclosure of Invention
Description of terms: the term "alkyl" as used herein, unless a different number of atoms is indicated, refers to a straight or branched hydrocarbon chain containing from 1 to 6 carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isobutyl, isopropyl. "alkyl" also includes substituted alkyl. The alkyl group may be optionally substituted one or more times with halogen or hydroxy.
The term "alkoxy" as used herein refers to an-O-alkyl group, wherein alkyl is as defined above. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy. "alkoxy" also includes substituted alkoxy. Alkoxy groups may be optionally substituted one or more times with halo.
The pharmaceutically acceptable salt in the invention comprises inorganic acid salts, organic acid salts and amino acid salts which are commonly used in pharmacy, such as hydrochloride, sulfate, hydrobromide, (+) tartrate, (-) tartrate, fumarate, succinate and the like.
The benzoquinolinone, flavonoid and analogue thereof or pharmaceutically acceptable salt and solvate thereof provided by the invention have the following general structure (A):
Figure GDA0002385267420000021
general structure (A)
In the formula:
x is selected from N or O;
R1selected from H, C1-3Alkyl or C1-3An alkoxy group;
R2selected from H, hydroxy or C1-3An alkoxy group;
R3selected from H, hydroxy, C1-3Alkyl or C1-3An alkoxy group.
NR' R "is selected from cyclic amines and open chain alkylamines having a total of 3-6 carbon atoms, including but not limited to the following fragments:
Figure GDA0002385267420000031
further, quinolinone and flavonoid derivatives preferred in the present invention, said
Figure GDA0002385267420000032
Selected from the following two heterocycles:
Figure GDA0002385267420000033
further, quinolinone and flavonoid derivatives and analogs thereof, R, preferred in the present invention1Preferably hydrogen, methyl and ethyl; r2Preferably hydrogen, hydroxy and methoxy; r3Hydrogen, hydroxy and methoxy are preferred.
It is to be understood that the invention includes all combinations and subcombinations of the specific groups defined herein, including substituents defined in the brief description above, exemplified in various embodiments throughout the specification, and recited in the appended claims.
More specifically, the preferable compounds (or pharmaceutically acceptable salts, compounds and solvates) of the quinolinone and flavonoid derivatives with the general formula are selected from the compounds shown in Table 1
TABLE 1 Quinolinone derivatives preferred Compounds
Figure GDA0002385267420000034
Figure GDA0002385267420000041
The preparation method of the compound provided by the invention is prepared by the following steps, but is not limited to the following method.
Quinolinone derivatives of general formula (xxxv) can be synthesized by the following procedure.
Synthesis of I-1, I-2 in the series of compounds I (quinolinone derivatives) (this method is suitable when X ═ N):
Figure GDA0002385267420000042
the specific reaction process is as follows: dissolving raw materials 1, 3-bromochloropropane and potassium carbonate in acetonitrile, heating and refluxing, and then adding NaOH/CH3An intermediate 1 is obtained by reaction in an OH system, then an intermediate 2 is obtained by refluxing in a thionyl chloride solution, then the intermediate is reacted with o-aminoacetophenone at room temperature to obtain an intermediate 3, the intermediate 4 is obtained by reaction with potassium tert-butoxide in microwave, and finally the intermediate is reacted with secondary amine by refluxing to obtain the target compounds I-1 and I-2.
Synthesis of I-3 to I-6 in the series of compounds I (quinolinone derivatives) (this method is suitable when X ═ N):
Figure GDA0002385267420000051
the specific reaction process is as follows: the intermediate 4 in the embodiment 1 is dissolved in DMF, sodium hydride and halogenated hydrocarbon are added to react to obtain an intermediate 5, and finally the intermediate 5 reacts with secondary amine and triethylamine under reflux to obtain target compounds I-3 to I-6.
Synthesis of I-7, I-8 in the series of compounds I (quinolinone derivatives) (this method is suitable when X ═ N):
Figure GDA0002385267420000052
the specific reaction process is as follows: dissolving p-hydroxyacetophenone (raw material 4) in acetonitrile, adding 1, 3-bromochloropropane and potassium carbonate for reflux reaction to obtain an intermediate 6, and then reacting with bromine in an ice bath to obtain a bromoketone intermediate 7; the latter is heated and reacted with o-aminobenzoic acid and potassium carbonate in DMF to obtain an ester intermediate 8, ammonium acetate/acetic acid reflux cyclization is carried out to obtain an intermediate 9, and finally the intermediate is refluxed and reacted with secondary amine and triethylamine to obtain the target compounds I-7 and I-8.
Synthesis of I-9, I-10 in the series of compounds I (quinolinone derivatives) (this method is suitable when X ═ N):
Figure GDA0002385267420000053
the specific reaction process is as follows: the intermediate 9, dimethyl sulfate and potassium carbonate in example 3 were dissolved in acetone, and subjected to a reflux reaction to obtain an intermediate 10, which was then subjected to a reflux reaction with secondary amine NHR 'R' and triethylamine to obtain the target compounds I-9, I-10.
Method for synthesis of II-1, II-2 in the series of compounds II (flavonoid derivatives) (this method is suitable when X ═ O):
Figure GDA0002385267420000061
the specific reaction process is as follows: dissolving a raw material 6 in acetonitrile, adding 1, 3-bromochloropropane and potassium carbonate, performing reflux reaction to obtain an intermediate 11, condensing the intermediate with p-hydroxyacetophenone in potassium hydroxide to obtain an intermediate 12, performing cyclization by a hydrogen oxide/KOH system to obtain an intermediate 13, and performing reflux reaction with secondary amine and triethylamine to obtain target compounds II-1 and II-2.
Synthesis of II-3 and II-4 of Compound II (Flavonoids derivate) series (this method is suitable for X ═ O)
Figure GDA0002385267420000062
The specific reaction process is as follows: the intermediate 13, methyl iodide and potassium carbonate in example 5 were dissolved in acetone, and subjected to a reflux reaction to obtain an intermediate 14, which was then subjected to a reflux reaction with secondary amine and triethylamine to obtain the target compounds II-3, II-4.
Synthesis of compounds II (flavonoid derivatives) II-5, II-6 of the series (this method is suitable for X ═ O)
Figure GDA0002385267420000063
The specific reaction process is as follows: dissolving the intermediate 11 and 2, 6-dihydroxyacetophenone in ethanol, adding potassium hydroxide, performing reflux reaction to obtain an intermediate 15, performing cyclization reaction under the action of iodine and concentrated sulfuric acid to obtain an intermediate 16, and performing reflux reaction with secondary amine and triethylamine to obtain target compounds II-5 and II-6.
Synthesis of compounds II (flavonoid derivatives) II-7 and II-8 (this method is suitable for X ═ O)
Figure GDA0002385267420000071
The specific reaction process is as follows: in example 7, the intermediate 16, potassium iodide and potassium carbonate are dissolved in acetone, and subjected to reflux reaction to obtain an intermediate 17, and then subjected to reflux reaction with secondary amine and triethylamine to obtain target compounds II-7 and II-8.
The invention also aims to provide application of the quinolinone, the flavonoid derivative and the pharmaceutically acceptable salt and the solvate thereof in preparing a medicament, wherein the medicament is prepared from the analogue, the pharmaceutically acceptable salt and the solvate thereof and a pharmaceutically acceptable carrier or excipient.
The "pharmaceutically acceptable carrier" refers to a pharmaceutical carrier which is conventional in the pharmaceutical field and includes diluents, excipients such as water and the like, fillers such as starch and the like, binders such as cellulose derivatives, gelatin and the like, humectants such as glycerin, disintegrating agents such as agar-agar, calcium carbonate and the like, absorption promoters such as quaternary ammonium compounds, surfactants such as cetyl alcohol, adsorption carriers such as kaolin and bentonite, lubricants such as talc and the like, and if necessary, flavoring agents, sweeteners and the like.
The pharmaceutical formulations are adapted for administration by any suitable route, such as the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal) or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. These formulations may be prepared by any method known in the art of pharmacy. For example, by admixing the active ingredient with a carrier or excipient.
The invention provides the compound and a preferable compound thereof, pharmaceutically acceptable salts of the compound, solvates, prodrugs (esters or phosphate esters), stereoisomers, deuterons and application of the compound in treating neurodegenerative related diseases by combining with other medicines. The neurodegenerative diseases are selected from Alzheimer's disease, Parkinson's disease, lethargy, epilepsy, gradually freezing disease and the like, and particularly discloses a compound and a preferable compound thereof of the invention, which have the protection effect on ischemic brain injury, are beneficial to recovery of nerve functions and effectively reduce the cerebral infarction volume.
Drawings
Figure 1 is a partial H3 receptor antagonist that entered clinical studies.
FIG. 2 shows the design concept of target molecules.
Figure 3 is a graph of the effect of compounds on Α β self-aggregation.
In FIG. 3, [ A β ]1-42]＝25μM；[compd.]＝20μM；a.Aβ1-42alone,0h；b.a.Aβ1-42alone,24h；c.Aβ1-42+I-6,24h；d.Aβ1-42+II-1,24h.PBS pH 7.4。
Figure 4 is a graph of the effect of compounds on a β depolymerization.
In FIG. 4, [ A β ]1-42]＝25μM,[compd.]＝20μM；a.Aβ1-42alone,24h；b.Aβ1-42fibrils+I-6,24h；c.Aβ1-42fibrils+II-1,24h；d.Aβ1-42fibrils+Curcumin,24h.PBS pH 7.4,50,000x。
Detailed Description
The following specific examples are included for purposes of illustration and are not to be construed as limiting the scope of the invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
Example 1: synthesis of I-1 and I-2 in the compounds (quinolinones) in the class I.
The method comprises the following steps: 4- (3-chloropropyloxy) benzoic acid (intermediate 1).
Ethyl p-hydroxybenzoate II-1(12g,72mmol) and 1, 3-bromochloropropane (14) were added.2mL,144mmol) and K2CO3(20g,144mmol) was dissolved in 100mL acetonitrile and heated at reflux for 12 h. Suction filtration to remove excess K2CO3The solvent was distilled off under reduced pressure to give a colorless oily liquid. 15mL of 6N NaOH solution and 30mL of CH were added directly3OH, refluxing for 1 h. After the reaction solution became clear, it was cooled, acidified with 2N hydrochloric acid to pH 2, and a large amount of white solid was precipitated, filtered by suction, washed with water, and dried to obtain 14.5g of white solid powder. The yield is 94%;1H NMR(500MHz,CDCl3):8.08(d,J＝8.5Hz,2H),6.96(d,J＝8.5Hz,2H),4.21(t,J＝6.0Hz,2H),3.77(t,J＝6.5Hz,2H),2.30-2.25(m,2H)；ESI-MS:m/z＝215[M+H]+。
step two: n- (2-acetylphenyl) -4- (3-chloropropoxy) benzamide (intermediate 3).
Intermediate 1(5.0g, 23mmol) in 10mL SOCl2Refluxing for 1h, and adding 1-2 drops of DMF into the reaction system. After the reaction was complete, excess SOCl was removed under reduced pressure2To obtain a colorless liquid intermediate 2. O-aminoacetophenone (2.83g, 21mmol) was dissolved in 15mL of anhydrous CH2Cl2And 6.5mL of anhydrous TEA, intermediate 2 was slowly added dropwise at 0 deg.C, the reaction was continued at room temperature for 2h, suction filtration was carried out, the filtrate was dried by spinning, and the resulting residue was separated by column chromatography (petroleum ether: EtOAc 10:1) to give 5.0g of a white solid. The yield is 72 percent;1H NMR(500MHz,CDCl3):12.65(s,1H),8.11(d,J＝9.0Hz,1H),8.05(d,J＝9.0Hz,2H),7.97(dd,J＝8.0,1.5Hz,1H),7.64(t,J＝8.0Hz,1H),7.16(t,J＝8.0Hz,1H),7.02(d,J＝9.0Hz,2H),4.21(t,J＝6.0Hz,2H),3.78(t,J＝6.5Hz,2H),2.73(m,3H),2.31-2.26(m,2H)；ESI-MS:m/z＝332[M+H]+。
step three: 2- (4- (3-chloropropoxy) phenyl) quinolin-4 (1H) -one (intermediate 4).
Intermediate 3(995mg,3.0mmol) and potassium tert-butoxide (1.68g,15mmol) were dissolved in 15mL of THF and reacted in a closed vessel with a microwave at 110 ℃ for 20 min. After the reaction is finished, cooling to room temperature, pouring into 100mL of ice water, adding 2N HCl to adjust the pH value to 5-6, separating out a large amount of yellow solid, washing with water, and adding a small amount of glacial acetone and CH2Cl2(1:1) to give intermediate 4, 750 mg. The yield is 80%;1H NMR(500MHz,CDCl3):11.63(s,1H),8.10(dd,J＝8.0,1.0Hz,1H),7.83(d,J＝9.0Hz,2H),7.78(d,J＝8.0,1H),7.68(t,J＝7.5Hz,1H),7.35(t,J＝7.5Hz,1H),7.17(d,J＝9.0Hz,2H),6.33(s,1H),4.21(t,J＝6.0Hz,2H),3.84(t,J＝6.5Hz,2H),2.24-2.18(m,2H)；ESI-MS:m/z＝314[M+H]+。
step four: 2- (4- (3- (pyrrolidin-1-yl) propoxy) phenyl) quinolin-4 (1H) -one (I-1).
Intermediate 4(60mg,0.19mmol) was dissolved in 3mL acetonitrile, 41mg (0.57mmol) pyrrolidine and 96mg (0.96mmol) TEA were added dropwise and the reaction was warmed to reflux overnight. After completion of the reaction, the reaction mixture was cooled, the solvent was distilled off under reduced pressure, and the residue was separated by column chromatography (petroleum ether: EtOAc: TEA ═ 1:5:0.1) to obtain 40mg of a yellow solid. The yield is 60 percent;1H NMR(500MHz,CDCl3):8.33(d,J＝9.0Hz,1H),7.86(d,J＝8.0Hz,1H),7.62(t,J＝7.5Hz,1H),7.55(t,J＝8.5Hz,2H),7.34(t,J＝7.5Hz,1H),6.76(d,J＝8.5Hz,2H),6.38(s,1H),3.91(t,J＝6.0Hz,2H),2.95-2.88(m,6H),2.12-2.07(m,2H),1.98-1.93(m,2H)；13C NMR(125MHz,CDCl3):174.19,155.44,146.00,136.03,127.08,124.08,122.23,120.66,120.41,118.90,113.92,109.83,102.77,60.93,48.61,47.68,22.01,18.61；ESI-MS:m/z＝349[M+H]+。
2- (4- (3- (piperidin-1-yl) propoxy) phenyl) quinolin-4 (1H) -one (I-2).
The preparation method is the same as the compound I-1, and piperidine is used for replacing pyrrolidine to obtain yellow solid. The yield is 75%;1H NMR(500MHz,CDCl3):8.33(d,J＝8.5Hz,1H),7.79(d,J＝8.5Hz,1H),7.62(t,J＝7.5Hz,1H),7.59(t,J＝8.5Hz,2H),7.34(t,J＝7.5Hz,1H),6.84(d,J＝8.5Hz,2H),6.39(s,1H),3.95(t,J＝6.0Hz,2H),2.59-2.54(m,6H),2.04-1.99(m,2H),1.70-1.66(m,4H),1.51-1.48(m,2H)；13C NMR(125MHz,CDCl3):174.16,155.86,145.64,135.72,127.17,123.84,121.89,120.82,120.43,118.94,113.68,110.07,102.82,61.52,50.78,49.56,21.23,20.50,19.15；ESI-MS:m/z＝363[M+H]+。
example 2: synthesis of I-3-I-6 in the I class of compounds (quinolinones).
The method comprises the following steps: 2- (4- (3-Chloropropoxy) phenyl) -1-methylquinolin-4 (1H) -one (intermediate 5 a).
Intermediate 4(276mg,0.88mmol) was dissolved in 5mL of DMF, 42mg of NaH (60%, 1.05mmol) was added, and after stirring at room temperature for 30min, iodomethane (138mg,0.97mmol) was added, and the reaction was allowed to proceed at 35 ℃ for 30 min. The reaction solution was poured into 50mL of H2In O, extracting with EtOAc, washing with water, washing with saturated NaCl, and washing with anhydrous Na2SO4And (5) drying. After recovery of the solvent, column chromatography separation (petroleum ether: EtOAc: 10:1) gave 250mg of a white solid. The yield is 87%;1H NMR(500MHz,CDCl3):8.17(d,J＝8.0Hz,1H),8.10-8.08(m,3H),7.71(d,J＝8.0,1H),7.48(t,J＝7.5Hz,1H),7.14(s,1H),7.05(d,J＝9.0Hz,2H),4.21(t,J＝6.0Hz,2H),4.12(s,3H),3.79(t,J＝6.5Hz,2H),2.31-2.26(m,2H)；ESI-MS:m/z＝328[M+H]+。
2- (4- (3-Chloropropoxy) phenyl) -1-ethylquinolin-4 (1H) -one (intermediate 5 b).
The preparation method uses a compound intermediate 5a, and uses ethyl bromide to replace methyl iodide to obtain yellow solid. The yield is 67%;1HNMR(500MHz,CDCl3):8.21(d,J＝8.0Hz,1H),8.09-8.07(m,3H),7.71(d,J＝8.0,1H),7.48(t,J＝7.5Hz,1H),7.12(s,1H),7.05(d,J＝9.0Hz,2H),4.37(q,J＝7.0Hz,2H),4.21(t,J＝6.0Hz,2H),3.79(t,J＝6.5Hz,2H),2.31-2.26(m,2H),1.62(s,3H)；ESI-MS:m/z＝342[M+H]+。
step two, 2- (4- (3- (pyrrolidine-1-yl) propoxy) phenyl) -1-methylquinoline-4 (1H) -ketone (I-3).
The preparation method is the same as the compound I-1, the intermediate 5a is used for replacing the intermediate 4, the secondary amine is pyrrolidine, and the white solid I-3 is prepared with the yield of 74 percent;1H NMR(500MHz,CDCl3):8.17(d,J＝8.0Hz,1H),8.09-8.06(m,3H),7.70(t,J＝8.0,1H),7.47(t,J＝7.5Hz,1H),7.14(s,1H),7.04(d,J＝9.0Hz,2H),4.13(t,J＝6.0Hz,2H),4.12(s,3H),2.71(t,J＝6.5Hz,2H),2.61-2.57(m,4H),2.10-2.05(m,2H),1.85-1.80(m,4H)；13C NMR(100MHz,CDCl3):162.70,160.18,158.36,149.15,132.72,129.87,128.95,128.79,125.01,121.57,120.15,114.66,97.40,66.51,55.59,54.28,53.17,28.82,23.44；ESI-MS:m/z＝363[M+H]+。
2- (4- (3- (piperidin-1-yl) propoxy) phenyl) -1-methylquinolin-4 (1H) -one (I-4).
The preparation method is the same as the compound I-1, the intermediate 5a is used for replacing the intermediate 4, the secondary amine is used for replacing pyrrolidine, and the white solid I-4 is prepared with the yield of 71 percent;1H NMR(500MHz,CDCl3):8.17(d,J＝8.0Hz,1H),8.09-8.06(m,3H),7.70(d,J＝8.0,1H),7.47(t,J＝7.5Hz,1H),7.14(s,1H),7.04(d,J＝9.0Hz,2H),4.12(s,3H),4.11(t,J＝6.0Hz,2H),2.58-2.52(m,2H),2.50-2.44(m,4H),2.08-2.03(m,2H),1.66-1.62(m,4H),1.47-1.45(m,2H)；13C NMR(100MHz,CDCl3):162.70,160.22,158.41,149.18,132.75,129.92,128.99,128.83,125.06,121.61,120.18,114.69,97.46,66.65,56.04,55.64,54.69,26.80,25.97,24.43；ESI-MS:m/z＝377[M+H]+。
2- (4- (3- (pyrrolidin-1-yl) propoxy) phenyl) -1-ethylquinolin-4 (1H) -one (I-5).
The preparation method is the same as the compound I-1, the intermediate 5b is used for replacing the intermediate 4, and the secondary amine is pyrrolidine, so that the light yellow solid I-5 is prepared. The yield is 74 percent;1H NMR(500MHz,CDCl3):8.21(d,J＝8.0Hz,1H),8.07-8.05(m,3H),7.70(t,J＝8.0,1H),7.47(t,J＝7.5Hz,1H),7.12(s,1H),7.04(d,J＝9.0Hz,2H),4.37(q,J＝7.0Hz,2H),4.13(t,J＝6.0Hz,2H),2.77-2.75(m,2H),2.71-2.64(m,4H),2.14-2.10(m,2H),1.89-1.85(m,4H),1.62(t,J＝7.0Hz,3H)；13C NMR(100MHz,CDCl3):161.98,160.17,158.35,149.25,132.85,129.77,128.96,128.78,124.86,121.69,120.26,114.67,97.95,66.53,63.97,54.27,53.16,28.82,23.46,14.54；ESI-MS:m/z＝377[M+H]+。
2- (4- (3- (piperidin-1-yl) propoxy) phenyl) -1-ethylquinolin-4 (1H) -one (I-6).
The preparation method is the same as the compound I-1, the intermediate 5b is used for replacing the intermediate 4, and the secondary amine is piperidine to prepare light yellow solid I-6. The yield is 85 percent;1H NMR(500MHz,CDCl3):8.21(d,J＝8.0Hz,1H),8.07-8.05(m,3H),7.70(t,J＝8.0,1H),7.47(t,J＝7.5Hz,1H),7.12(s,1H),7.04(d,J＝9.0Hz,2H),4.37(q,J＝7.0Hz,2H),4.11(t,J＝6.0Hz,2H),2.60-2.52(m,2H),2.51-2.44(m,4H),2.10-2.05(m,2H),1.68-1.63(m,4H),1.62(t,J＝7.0Hz,3H),1.50-1.45(m,2H)；13C NMR(100MHz,CDCl3):162.00,160.18,158.40,149.25,132.85,129.83,128.96,128.81,124.91,121.73,120.26,114.68,98.00,66.63,64.01,56.00,54.66,26.77,25.93,24.41,14.59；ESI-MS:m/z＝391[M+H]+。
example 3: synthesis of I-7 and I-8 in the I compounds (quinolinones).
The method comprises the following steps: 4- (3-chloropropyloxy) acetophenone (intermediate 6).
P-hydroxyacetophenone (5.0g,36.7mmol), 1, 3-bromochloropropane (7.3mL,73.5mmol) and K2CO3(10g,73.5mmol) was dissolved in 30mL acetonitrile and heated at reflux for 10 h. Suction filtration to remove excess K2CO3The solvent was evaporated under reduced pressure and separated by column chromatography (petroleum ether: EtOAc: 10:1) to give 7.6g of a colorless liquid. The yield is 98 percent;1H NMR(500MHz,CDCl3):7.95(d,J＝9.0Hz,2H),6.95(d,J＝9.0Hz,2H),4.20(t,J＝6.0Hz,2H),3.77(t,J＝6.0Hz,2H),2.56(s,3H),2.29-2.24(m,2H)；ESI-MS:m/z＝213[M+H]+。
step two, 2-bromo-1- (4- (3-chloropropoxy) phenyl) ethanone (intermediate 7).
Intermediate 6(2.12g,10mmol) was dissolved in 20mL of diethyl ether and Br was slowly added dropwise at 0 deg.C2(0.51mL,10mmol) and stirred at room temperature for 16h after dropping. The reaction solution was poured into saturated NaHCO3Extracting with diethyl ether, and passing the organic layer through anhydrous Na2SO4Drying, and separating by column chromatography (petroleum ether: CH)2Cl23:1) to give 2.45g of a pale yellow solid. 84% of intermediate;1H NMR(500MHz,CDCl3):7.97(d,J＝9.0Hz,2H),6.97(d,J＝9.0Hz,2H),4.40(s,2H),4.22(t,J＝6.0Hz,2H),3.77(t,J＝6.0Hz,2H),2.30-2.25(m,2H)；ESI-MS:m/z＝291[M+H]+。
step three, 2- (4- (3-chloropropoxy) phenyl) -2-oxoethyl-2-aminobenzoate (intermediate 8).
Anthranilic acid (720mg,5.25mmol) and K2CO3(760mg,5.5mmol) was dissolved in 10mL DMF and stirred at room temperature for 30min, then intermediate 7(1.46g,5.0mmol) was added, the temperature was raised to 50 ℃ and reaction was carried out for 3h, then the reaction was poured into 100mL water and extracted with EtOAc and the organic layer was washed with 1N NaOH solution, saturated NaCl solution was washed, dried, the solvent was distilled off under reduced pressure and purified by column chromatography (petroleum ether: EtOAc: 3:1) to obtain 1.6g of a white solid. The yield is 92 percent;1H NMR(500MHz,CDCl3):8.02(dd,J＝8.0,1.0Hz,1H),7.96(d,J＝8.5Hz,2H),7.32(t,J＝7.5Hz,1H),6.98(d,J＝8.5Hz,2H),6.72-6.68(m,2H),5.49(s,2H),4.22(t,J＝6.0Hz,2H),3.77(t,J＝6.0Hz,2H),2.30-2.25(m,2H)；ESI-MS:m/z＝348[M+H]+。
step four, 2- (4- (3-chloropropoxy) phenyl) -3-hydroxyquinolin-4 (1H) -one (intermediate 9).
Intermediate 8(1.6g,4.6mmol) and ammonium acetate (5.3g,69mmol) were dissolved in 30mL of acetic acid and heated to reflux for 3 h. After the reaction is finished, the reaction solution is poured into 250mL of water, a large amount of solid is separated out, filtered, washed to be neutral, and dried to obtain 1.02g of light yellow solid. The yield is 67%;1H NMR(500MHz,CDCl3):8.32(d,J＝8.5Hz,1H),7.80-7.76(m,2H),7.61-7.57(m,2H),7.32(t,J＝7.5Hz,1H),6.97-6.95(m,2H),6.72-6.68(m,2H),4.12(t,J＝6.0Hz,2H),3.76(t,J＝6.0Hz,2H),2.26-2.23(m,2H)；ESI-MS:m/z＝330[M+H]+。
step five, 2- (4- (3- (pyrrolidin-1-yl) propoxy) phenyl) -3-hydroxyquinolin-4 (1H) -one (I-7).
The preparation method is the same as the compound I-1, and the intermediate 9 is used for replacing the intermediate 4 to obtain beige solid. The yield is 59 percent;1H NMR(500MHz,DMSO-d6):11.48(s,1H),8.29(s,1H),8.13(dd,J＝8.0,1.0Hz,1H),7.78(d,J＝9.0Hz,2H),7.73(d,J＝8.5Hz,1H),7.60(t,J＝7.5Hz,1H),7.28(t,J＝7.5Hz,1H),7.13(d,J＝9.0Hz,2H),4.12(t,J＝6.5Hz,2H),2.56(t,J＝7.0Hz,2H),2.46-2.42(m,4H),1.95-1.89(m,2H),1.70-1.67(m,4H)；13C NMR(125MHz,DMSO-d6):170.22,159.80,138.42,138.01,131.81,131.11,130.85,124.85,124.80,122.24,122.15,118.84,114.66,66.54,54.13,52.68,28.63,23.58；ESI-MS:m/z＝365[M+H]+。
2- (4- (3- (pyrrolidin-1-yl) propoxy) phenyl) -3-hydroxyquinolin-4 (1H) -one (I-8).
The preparation method is the same as the compound I-1, the intermediate 9 is used for replacing the intermediate 4, and piperidine is used for replacing pyrrolidine, so that yellow solid is obtained. The yield is 67%;1H NMR(500MHz,DMSO-d6):11.47(s,1H),8.28(s,1H),8.12(dd,J＝8.0,1.0Hz,1H),7.77(d,J＝9.0Hz,2H),7.72(d,J＝8.5Hz,1H),7.59(t,J＝7.5Hz,1H),7.27(t,J＝7.5Hz,1H),7.12(d,J＝9.0Hz,2H),4.12(t,J＝6.5Hz,2H),2.56(t,J＝7.0Hz,2H),2.46-2.42(m,4H),1.95-1.89(m,2H),1.70-1.67(m,4H),1.51-1.48(m,2H)；13C NMR(125MHz,DMSO-d6):170.25,159.49,138.43,138.03,131.75,131.17,130.84,125.04,124.83,122.26,122.14,118.88,114.67,65.99,54.29,53.08,28.58,24.19,23.74；ESI-MS:m/z＝379[M+H]+。
example 4: synthesis of I-9 and I-10 in the I compounds (quinolinones).
Step one, 2- (4- (3-chloropropoxy) phenyl) -3-methoxy-1-methylquinolin-4 (1H) -one (intermediate 10).
Intermediate 9(660mg,2.0mmol), dimethyl sulfate (0.75mL,8.0mmol) and K2CO3(1.1g, 8.0mmol) was dissolved in 10mL of acetone and heated to reflux for 4 h. After the reaction, the reaction mixture was cooled and filtered, and the filtrate was purified by column chromatography (petroleum ether: EtOAc 1:2) after recovering the solvent under reduced pressure to obtain 558mg of a yellow solid. The yield is 78 percent;1H NMR(500MHz,CDCl3):8.59(dd,J＝8.0,1.0Hz,1H),7.71(t,J＝7.5Hz,1H),7.53(d,J＝8.5Hz,1H),7.42(t,J＝7.5Hz,1H),7.31(d,J＝8.5Hz,2H),7.07(d,J＝8.5Hz,2H),4.22(t,J＝6.0Hz,2H),3.81(t,J＝6.0Hz,2H),3.65(s,3H),3.54(s,3H),2.36-2.24(m,2H)；ESI-MS:m/z＝358[M+H]+。
step two, 2- (4- (3- (pyrrolidine-1-yl) propoxy) phenyl) -3-methoxy-1-methylquinoline-4 (1H) -ketone (I-9).
The preparation method is the same as the compound I-1, and the intermediate 10 is used for replacing the intermediate 4 to obtain an off-white solid. The yield is 65 percent;1HNMR(500MHz,CDCl3):8.59(dd,J＝8.0,1.5Hz,1H),7.70(t,J＝8.0Hz,1H),7.53(d,J＝8.5Hz,1H),7.40(t,J＝7.5Hz,1H),7.28(d,J＝8.0Hz,2H),7.05(d,J＝8.5Hz,2H),4.12(t,J＝6.0Hz,2H),3.65(s,3H),3.53(s,3H),2.70(t,J＝7.5Hz,2H),2.61-2.55(m,4H),2.13-2.05(m,2H),1.85-1.81(m,4H)；13C NMR(125MHz,CDCl3):172.96,159.69,147.31,141.26,140.20,131.85,130.38,127.14,126.79,124.35,122.99,115.78,114.67,66.46,59.89,54.30,53.15,37.12,28.74,23.47；ESI-MS:m/z＝393[M+H]+。
2- (4- (3- (piperidin-1-yl) propoxy) phenyl) -3-methoxy-1-methylquinolin-4 (1H) -one (I-10).
The preparation method is the same as the compound I-1, the intermediate 10 is used for replacing the intermediate 4, and piperidine is used for replacing pyrrolidine, so that an off-white solid is obtained. The yield is 67 percent;1H NMR(500MHz,CDCl3):8.58(d,J＝8.0Hz,1H),7.70(t,J＝7.5Hz,1H),7.53(d,J＝8.5Hz,1H),7.41(t,J＝7.5Hz,1H),7.29(d,J＝8.5Hz,2H),7.05(d,J＝8.5Hz,2H),4.10(t,J＝6.0Hz,2H),3.65(s,3H),3.53(s,3H),2.57-2.51(m,2H),2.47-2.43(m,4H),2.08-2.03(m,2H),1.66-1.58(m,4H),1.48-1.44(s,2H)；13C NMR(125MHz,CDCl3):172.95,159.72,147.28,141.27,140.21,131.82,130.38,127.15,126.79,124.36,122.97,115.77,114.68,66.60,59.88,55.96,54.66,37.10,26.77,25.92,24.39；ESI-MS:m/z＝407[M+H]+。
example 5: synthesis of II-1 and II-2 in II compounds (flavonoids).
The method comprises the following steps: 4- (3-chloropropyloxy) benzaldehyde (intermediate 11).
The preparation method is the same as the intermediate 6, and the p-hydroxybenzaldehyde is used for replacing the p-hydroxyacetophenone to obtain a light yellow solid. The yield is 98 percent;1H NMR(500MHz,CDCl3):9.89(s,1H),7.85(d,J＝9.0Hz,2H),7.02(d,J＝9.0Hz,2H),4.22(t,J＝6.0Hz,2H),3.77(t,J＝6.0Hz,2H),2.30-2.25(m,2H)；ESI-MS:m/z＝199[M+H]+。
step two: 1- (2-hydroxyphenyl) -3- (4- (3-chloropropoxy) phenyl) prop-2-en-1-one (intermediate 12).
P-hydroxyacetophenone (1.36g,10mmol), intermediate 11(1.98g,10mmol) was dissolved in 15mL of C2H5To OH, 1.68g KOH (30mmol) was added and the reaction was refluxed for 2 h. After cooling, part of the solvent was removed under reduced pressure, 200mL of ice water was added to the remaining residue, the pH was adjusted to 4-5 with 2N HCl, and a large amount of solid was precipitated and dried by suction filtration to give 2.82g of a yellow solid. The yield is 89%;1HNMR(500MHz,CDCl3):12.92(s,1H),7.94-7.89(m,2H),7.63(d,J＝8.5Hz,2H),7.57and7.54(s,1H),7.49(t,J＝7.5Hz,1H),7.03(d,J＝8.5Hz,1H),6.97-6.93(m,3H),4.20(t,J＝6.0Hz,2H),3.78(t,J＝6.5Hz,2H),2.30-2.25(m,2H)；ESI-MS:m/z＝317[M+H]+。
step three: 2- (4- (3-Chloropropoxy) phenyl) -3-hydroxy-4H-chromen-4-one (intermediate 13).
Intermediate 12(1.05g,3mmol) was dissolved in 10mL of C2H5To OH, 10mL of 0.5N KOH solution was added and 0.6mL of H was added in portions2O2After stirring the aqueous solution (30%) at room temperature for 1h, the reaction solution was poured into ice water to precipitate a large amount of solid, which was then filtered, and the filter cake was washed with water and dried to obtain 930mg of a yellow solid. The yield is 94%;1H NMR(500MHz,CDCl3):8.61(d,J＝7.5Hz,1H),8.04(d,J＝9.0Hz,2H),7.61-7.58(m,2H),7.28(t,J＝7.0Hz,1H),7.01(d,J＝9.0Hz,2H),4.15(t,J＝6.0Hz,2H),3.83(t,J＝6.5Hz,2H),2.23-2.17(m,2H)；ESI-MS:m/z＝331[M+H]+。
step four: 2- (4- (3- (pyrrolidin-1-yl) propoxy) phenyl) -3-hydroxy-4H-chromen-4-one (II-1).
The preparation method is the same as the compound I-1, and the intermediate 13 is used for replacing the intermediate 4 to obtain yellow solid. The yield is 68 percent;1H NMR(500MHz,CDCl3):8.25-8.21(m,3H),7.71(t,J＝7.5Hz,1H),7.59(d,J＝8.5Hz,1H),7.42(t,J＝7.5Hz,1H),7.06(d,J＝9.0Hz,2H),4.14(t,J＝6.0Hz,2H),2.74-2.67(m,2H),2.64-2.58(m,4H),2.11-2.06(m,2H),1.86-1.80(m,4H)；13C NMR(125MHz,DMSO-d6):173.10,160.32,154.88,146.04,138.65,133.96,129.87,125.20,124.95,123.92,121.81,118.80,114.94,66.52,54.10,52.64,28.56,23.56；ESI-MS:m/z＝366[M+H]+。
2- (4- (3- (piperidin-1-yl) propoxy) phenyl) -3-hydroxy-4H-chromen-4-one (II-2).
The preparation method is the same as the compound I-1, the intermediate 13 is used for replacing the intermediate 4, and piperidine is used for replacing pyrrolidine, so that yellow solid is obtained. The yield is 61%;1H NMR(500MHz,CDCl3):8.25-8.21(m,3H),7.71(t,J＝7.5Hz,1H),7.59(d,J＝8.5Hz,1H),7.42(t,J＝7.5Hz,1H),7.06(d,J＝9.0Hz,2H),4.12(t,J＝6.5Hz,2H),2.56(t,J＝7.0Hz,2H),2.46-2.42(m,4H),1.95-1.89(m,2H),1.70-1.67(m,4H),1.52-1.48(m,2H)；13C NMR(125MHz,DMSO-d6):173.47,160.24,154.85,145.98,138.02,133.85,129.77,125.19,124.87,124.09,121.78,118.78,114.93,66.61,55.56,54.59,26.69,26.07,24.61；ESI-MS:m/z＝380[M+H]+。
example 6: synthesis of II-3 and II-4 in II compounds (flavonoids).
The method comprises the following steps: 2- (4- (3-Chloropropoxy) phenyl) -3-methoxy-4H-chromen-4-one (intermediate 14).
Intermediate 13(660mg,2.0mmol), methyl iodide (8.0mmol) and K2CO3(1.1g, 8.0mmol) was dissolved in 10mL of acetone and heated to reflux for 4 h. After the reaction, the reaction mixture was cooled and filtered, and the filtrate was purified by column chromatography (petroleum ether: EtOAc 1:2) after recovering the solvent under reduced pressure to obtain 558mg of a yellow solid. The yield is 78 percent;1H NMR(500MHz,CDCl3):8.59(dd,J＝8.0,1.0Hz,1H),7.71(t,J＝7.5Hz,1H),7.53(d,J＝8.5Hz,1H),7.42(t,J＝7.5Hz,1H),7.31(d,J＝8.5Hz,2H),7.07(d,J＝8.5Hz,2H),4.22(t,J＝6.0Hz,2H),3.81(t,J＝6.0Hz,2H),3.65(s,3H),3.54(s,3H),2.36-2.24(m,2H)；ESI-MS:m/z＝358[M+H]+。
step two, 2- (4- (3- (pyrrolidine-1-yl) propoxy) phenyl) -3-methoxy-4H-benzopyran-4-ketone (II-3).
The preparation method is the same as the compound I-1, and the intermediate 14 is used for replacing the intermediate 4 to obtain red solid. The yield is 54 percent;1H NMR(500MHz,CDCl3):8.26(d,J＝8.0Hz,1H),8.12(d,J＝8.5Hz,2H),7.68-7.64(m,1H),7.53-7.50(m,1H),7.40-7.37(m,1H),7.00(d,J＝8.5Hz,2H),4.12(t,J＝6.0Hz,2H),3.90(s,3H),2.74-2.67(m,2H),2.64-2.58(m,4H),2.11-2.06(m,2H),1.86-1.80(m,4H)；13C NMR(125MHz,CDCl3):175.01,161.01,155.72,155.15,140.80,133.28,130.24,125.77,124.58,124.20,123.07,117.90,114.50,66.52,59.92,54.29,53.07,28.68,23.46；ESI-MS:m/z＝380[M+H]+。
2- (4- (3- (piperidin-1-yl) propoxy) phenyl) -3-methoxy-4H-chromen-4-one (II-4).
The preparation method is the same as the compound I-1, the intermediate 14 is used for replacing the intermediate 4, and the piperidine is used for replacing the pyrrolidine, so that yellow is obtainedAnd (3) a solid. The yield is 57 percent;1H NMR(500MHz,CDCl3):8.26(d,J＝8.0Hz,1H),8.12(d,J＝8.5Hz,2H),7.68-7.64(m,1H),7.53-7.50(m,1H),7.40-7.37(m,1H),7.00(d,J＝8.5Hz,2H),4.12(t,J＝6.5Hz,2H),3.89(s,3H),2.56(t,J＝7.0Hz,2H),2.46-2.42(m,4H),1.95-1.89(m,2H),1.70-1.67(m,4H),1.52-1.48(m,2H)；13C NMR(125MHz,CDCl3):175.00,161.03,155.71,155.16,140.82,133.27,130.24,125.80,124.57,124.22,123.09,117.90,114.51,66.65,59.93,55.89,54.67,26.68,25.90,24.38；ESI-MS:m/z＝394[M+H]+。
example 7: synthesis of II-5 and II-6 in II compounds (flavonoids).
The method comprises the following steps: 1- (2, 6-dihydroxyphenyl) -3- (4- (3-chloropropoxy) phenyl) prop-2-en-1-one (intermediate 15).
The preparation method is the same as the intermediate 12, and 2, 6-dihydroxy acetophenone is used for replacing o-hydroxyacetophenone to obtain yellow solid. The yield is 85 percent; ESI-MS: 333[ M + H ] M/z]+。
Step two: 2- (4- (3-Chloropropoxy) phenyl) -5-hydroxy-4H-benzopyran-4-one (intermediate 16)
Intermediate 15(1.00g,3.2mmol) was dissolved in 15mL DMSO and I was added2(128mg, 0.5mmol) and 0.5mL of concentrated sulfuric acid, stirred at 85 ℃ for 24 h. The reaction solution was poured into 200mL of H2In O, extracting with EtOAc three times, combining organic layers, washing with water, washing with saturated NaCl, and washing with anhydrous Na2SO4Dried and separated by column chromatography (petroleum ether: EtOAc ═ 4:1) to give 565mg of white solid. The yield is 45 percent;1H NMR(500MHz,CDCl3):7.88(d,J＝9.0Hz,2H),7.55(t,J＝8.5Hz,1H),7.05(d,J＝9.0Hz,2H),7.00(d,J＝8.0Hz,1H),6.82(d,J＝8.0Hz,1H),6.66(s,1H),4.23(t,J＝6.0Hz,2H),3.79(t,J＝6.0Hz,2H),2.32-2.27(m,2H)；ESI-MS:m/z＝331[M+H]+。
step three: 2- (4- (3- (pyrrolidin-1-yl) propoxy) phenyl) -5-hydroxy-4H-chromen-4-one (II-5).
The preparation method is the same as the compound I-1, and the intermediate 16 is used for replacing the intermediate 4 to obtain yellow solid. The yield is 58 percent;1H NMR(500MHz,CDCl3):7.88(d,J＝9.0Hz,2H),7.55(t,J＝8.5Hz,1H),7.05(d,J＝9.0Hz,2H),7.00(d,J＝8.0Hz,1H),6.82(d,J＝8.0Hz,1H),6.66(s,1H),4.12(t,J＝6.0Hz,2H),2.78(t,J＝6.0Hz,2H),2.65-2.61(m,4H),2.11-2.06(m,2H),1.89-1.86(m,4H)；ESI-MS:m/z＝366[M+H]+。
2- (4- (3- (piperidin-1-yl) propoxy) phenyl) -5-hydroxy-4H-chromen-4-one (II-6).
The preparation method is the same as the compound I-1, the intermediate 16 is used for replacing the intermediate 4, and piperidine is used for replacing pyrrolidine, so that yellow solid is obtained. The yield is 64 percent;1H NMR(500MHz,CDCl3):7.87(d,J＝9.0Hz,2H),7.56(t,J＝8.5Hz,1H),7.04(d,J＝9.0Hz,2H),6.99(d,J＝8.0Hz,1H),6.81(d,J＝8.0Hz,1H),6.65(s,1H),4.13(t,J＝6.0Hz,2H),2.59-2.53(m,2H),2.50-2.44(m,4H),2.10-2.04(m,2H),1.70-1.62(m,4H),1.48-1.45(m,2H)；ESI-MS:m/z＝380[M+H]+。
example 8: synthesis of II-7 and II-8 in II compounds (flavonoids).
The method comprises the following steps: 2- (4- (3-Chloropropoxy) phenyl) -5-methoxy-4H-chromen-4-one (intermediate 17).
The preparation method is the same as the intermediate 14, and the intermediate 16 is used for replacing the intermediate 13, so that the off-white solid is obtained. The yield is 75 percent;1HNMR(500MHz,CDCl3):7.88(d,J＝9.0Hz,2H),7.55(t,J＝8.5Hz,1H),7.05(d,J＝9.0Hz,2H),6.99(d,J＝8.0Hz,1H),6.82(d,J＝8.0Hz,1H),6.68(s,1H),4.21(t,J＝6.0Hz,2H),3.90(s,3H),3.78(t,J＝6.0Hz,2H),2.32-2.27(m,2H)；ESI-MS:m/z＝345[M+H]+。
step two: 2- (4- (3- (pyrrolidin-1-yl) propoxy) phenyl) -5-methoxy-4H-chromen-4-one (II-7).
The preparation method is the same as the compound I-1, and the intermediate 17 is used for replacing the intermediate 4 to obtain yellow solid. The yield is 61%;1H NMR(500MHz,CDCl3):7.87(d,J＝9.0Hz,2H),7.55(t,J＝8.5Hz,1H),7.05(d,J＝9.0Hz,2H),6.99(d,J＝8.0Hz,1H),6.82(d,J＝8.0Hz,1H),6.68(s,1H),4.13(t,J＝6.0Hz,2H),3.91(s,3H),2.76(t,J＝6.0Hz,2H),2.65-2.60(m,4H),2.10-2.05(m,2H),1.89-1.85(m,4H)；ESI-MS:m/z＝380[M+H]+。
2- (4- (3- (piperidin-1-yl) propoxy) phenyl) -5-methoxy-4H-chromen-4-one (II-8).
The preparation method is the same as the compound I-1, the intermediate 17 is used for replacing the intermediate 4, and piperidine is used for replacing pyrrolidine, so that yellow solid is obtained. The yield is 67 percent;1H NMR(500MHz,CDCl3):7.88(d,J＝9.0Hz,2H),7.56(t,J＝8.5Hz,1H),7.05(d,J＝9.0Hz,2H),7.00(d,J＝8.0Hz,1H),6.83(d,J＝8.0Hz,1H),6.66(s,1H),4.12(t,J＝6.0Hz,2H),3.89(s,3H),2.54-2.49(m,2H),2.48-2.41(m,4H),2.06-2.00(m,2H),1.65-1.59(m,4H),1.47-1.43(m,2H)；ESI-MS:m/z＝394[M+H]+。
example 9: histamine H of phenylquinolinone and flavonoid derivatives3Receptor antagonistic activity.
In this section, 18 synthesized target compounds of histamine H were screened by the Lance Ultra TR-FRET method and ThT fluorimetric method using Clobenpropit as a positive control3Receptor antagonistic activity, the other compounds of the present invention have similar beneficial effects to those of the compounds listed below, but this should not be understood as the only beneficial effects of the compounds of the present invention. The results are shown in Table 3.
TABLE 3 Histamine H of phenylquinolinone and flavone derivatives3Receptor antagonistic Activity
Figure GDA0002385267420000151
Figure GDA0002385267420000161
As is clear from the receptor antagonistic activities in Table 3, the selected phenylquinolinone compounds exhibited strong histamine H3Receptor inhibitory activity, most of which were comparable to clobenprot, with six molecules being more active than clobenprot.
Example 10: measurement of anti-amyloid peptide aggregation activity.
A ThT fluorescence assay.
(1) Preparing a solution and a sample: PBS buffer formulation (10mM, pH 7.4): 57.996g of Na were weighed2HPO4·12H2O，5.928g NaH2PO4·2H2Dissolving O in 1000mL of water to obtain 0.2M PBS, diluting 50mL of PBS with water to 1000mL, filtering with 0.22 μ M microporous membrane, preparing Gly-NaOH buffer solution (50mM, pH 8.5), dissolving 3.7535g of glycine in 800mL of water, slowly adding 0.1M NaOH solution to adjust pH to 8.5, adding water to desired volume to 1000mL, preparing A β monomer, and mixing 1mg of A β1-42Dissolving in 1mL HFIP, oscillating with ultrasound for 10min, subpackaging, standing at room temperature for 12h, drying in vacuum, storing in a refrigerator at-20 ℃, redissolving A β monomer in DMSO to 2mM, vortexing briefly, and preparing into 50 mu M stock solution with 10mM PBS buffer solution, preparing into 10mM stock solution with compound, diluting with PBS to corresponding concentration, preparing ThT solution (5 mu M), weighing 1.59g of ThT, dissolving in 100mL Gly-NaOH buffer solution, preparing into 50mM stock solution, storing in dark place, diluting 10 mu L of stock solution with Gly-NaOH buffer solution to 100mL, and obtaining 5 mu M ThT solution.
(2) Addition of A β to an EP tube1-42And the compound (positive control or PBS buffer) to a final concentration of 25. mu.M and 20. mu.M, respectively, were incubated at 37 ℃ for 24 hours with shaking (150 rpm). And adding 20 mu L of incubation liquid into a 96-well plate, adding 180 mu L of 5 mu M ThT solution, incubating for 5min in a dark place, and detecting the 485nm fluorescence intensity of the sample under the excitation of 450nm by using a multifunctional microplate reader.
With A β1-42Fluorescence values after incubation alone served as controls, and to avoid interference of the results with the fluorescence possessed by the compound itself, the fluorescence values measured by ThT were subtracted from the compound as background.
TABLE 4 Ass aggregation inhibitory Activity of phenylquinolinone and flavone derivatives
Figure GDA0002385267420000162
Figure GDA0002385267420000171
As can be seen from the above experimental results, most of the designed and synthesized target molecules are shownShows good A β1-42Self-aggregation activity, whereas the positive control clobenprot has no such activity.
Further selecting compounds I-6, II-1, observing their inhibition A β by transmission electron microscope1-42Self-aggregation and promotion of aggregated A β1-42Activity of sample depolymerization.
The test was performed by Transmission Electron Microscopy (TEM).
(1) Preparing a solution and a sample: preparing a HEPES buffer solution: (20 μ M HEPES, pH 6.6,150 μ M NaCl) 47.77mg HEPES and 87.66mg NaCl were weighed out and dissolved in 100mL water to prepare a mother liquor. Diluting 5mL of mother liquor to 400mL, slowly dropwise adding 1mM NaOH solution to adjust the pH to 6.6, and diluting to 500 mL.
Self-aggregating sample A β was added to an EP tube1-42And the compound (positive control, Curcumin or PBS buffer) at final concentrations of 25. mu.M and 20. mu.M, respectively, were incubated at 37 ℃ for 24 hours with shaking at a constant temperature (150 rpm).
Depolymerizing the samples after self-aggregation by adding A β to the EP tube1-42(final concentration 50. mu.M), incubated at 37 ℃ for 24h, and then mixed with A β by adding a compound (positive control Curcumin or PBS buffer)1-42Were incubated at 20. mu.M and 25. mu.M, respectively, for 24 h.
(2) And (3) placing 10 mu L of the incubation liquid on a carbon-supported film copper net, standing for 2min, sucking dry from the side by using filter paper, standing for 30s, dropwise adding 5 mu L of 1% uranyl acetate solution to carry out negative dyeing on the sample, standing for 2min, sucking dry from the side by using filter paper, airing, placing under a transmission electron microscope for observation, and taking a photo. The acceleration voltage was 80kV and the magnification was 50,000 times, and the results are shown in FIG. 3.
Compounds I-6 and II-1 were subjected to A β1-42Aggregation inhibition experiments, as shown in fig. 3, a β monomer was able to undergo significant self-aggregation after 24 hours (fig. 3b), whereas both compounds were able to significantly inhibit a β self-aggregation (fig. 3c, 3d), compared to 0 hours (fig. 3 a).
Further depolymerization experiments are shown in fig. 4, the sample added with the compounds I-6 and II-1 has obvious depolymerization effect, can degrade the aggregated fiber filaments into short rods or granules (fig. 4b and 4c), and has better activity than curcumin (fig. 4 d).
Example 11: can be used for treating ischemic brain injury.
Rats were anesthetized with 10% chloral hydrate (3.5ml/kg, i.p.), fixed supine, skin incisions were made along the left carotid, the external carotid and the lateral common carotid were ligated, the distal internal carotid was closed with an artery clamp, incisions were made at the bifurcation of the external carotid and the internal carotid, a plug wire (diameter 0.25mm, length 18mm) was inserted, the incision was ligated, the skin was sutured, and the distal internal carotid artery clamp was released. After 2 hours, gently lifting the remained thread ends to a little resistance, realizing the reperfusion of the middle cerebral artery, and completing the molding. The rats in the sham operation group were anesthetized without middle artery plugging money, and the other operations were consistent. The body temperature is kept at 37 +/-0.5 ℃ by using a constant temperature blanket in the experimental process, and penicillin sodium is dripped into the wound after the operation and is returned to the cage for feeding. Rats that survived for 24 hours were randomly divided into a sham-operated group, a model group, and each test group to which the compound of the present invention was administered, and the test groups were grouped by the number corresponding to the compound.
Each group was administered by intraperitoneal injection, and rats in the model group and the sham operation group were administered with an equal volume of physiological saline, and 16 hours after the 1 st administration, each group was administered by intraperitoneal injection 1 time again.
Scoring method for symptoms of nerve damage, point 0: the behavior is normal, and the two forelimbs symmetrically extend to the ground when lifting the tail; 1 minute: the wrist bending of the contralateral forelimb is injured when the tail is lifted; and 2, dividing: the contralateral forelimb elbow is injured to bend when lifting the tail; and 3, dividing: shoulder inward rotation during tail lifting; when walking, the walking stick inclines to the opposite side of the injury; and 4, dividing: no autonomous activity.
Rats were scored for symptoms of nerve injury at 1 st dose, 4 hours after dose and 20 hours after dose, 24 hours after 1 st dose, the whole brain was taken out quickly after neck amputation and was placed on ice, 3 hippocampus isolates were taken out randomly for histamine determination in each group, the remaining part was frozen at-20 ℃, the brain was cut into 5 slices with a blade with the coronal plane, the slices were stained with 1% TTC in the dark at room temperature for 30 minutes, and fixed with 4% paraformaldehyde for 30 minutes. Sections were analyzed by photography and cerebral infarct volume ratio (infarct volume/whole brain volume 100%) was calculated.
TABLE 5 measurement results of nerve injury symptoms, hippocampal block amine content, and cerebral infarction volume ratio of each group
Figure GDA0002385267420000181
Each test group P <0.05 compared to the model group, respectively; # P < 0.01; Δ P < 0.05; | < P < 0.01.
The behavioral grading method of the rat is graded, the nerve injury symptom after 1 time of administration is 4 hours, the compound has significant difference with a model group, and the compound has significant difference with the model group after 1 time of administration is 20 hours, which shows that the compound has significant improvement effect on the nerve function of the rat with ischemic brain injury; the content of hippocampal area amine is different from that of a model group, which shows that the compound can effectively improve the content of histamine in the brain of a rat with ischemic brain injury; compared with the model group, the compound has significant difference, which shows that the compound can effectively reduce the cerebral infarction volume of the rat with ischemic brain injury.
Example 12: the effect on mice with acute epilepsy caused by the pentylenetetrazol.
The test drug and the positive drug phenytoin sodium are respectively given to each group of mice, the gavage administration is carried out according to the gavage volume of 0.1ml/10g, the model group is given with physiological saline with the same volume, the positive control group is given with phenytoin sodium dosage of 50mg/kg, each dosage of the test drug group is 50mg/kg, the test drug group is given with the compound provided by the invention, and the test drug group is divided into groups according to the corresponding number of the compound.
After the administration of the medicines for 1h, 70mg/kg of pentylenetetrazol was injected intraperitoneally, and the recording of myoclonus Latency (LTMJ) was started, and if the onset did not occur within 30min, the latency was recorded as 30 min.
The epileptic seizure standard refers to the Racine standard, and timing is finished when complete grand mal seizures of facial muscle or twitching of the corner of the mouth, one side limb twitching, tetany or generalized limb twitching occur.
Table 6 mouse latency to seizure assay (n ═ 6)
Rank of Number of animals Incubation period (min)
Model set 8 3.56±0.88
Control group 8 10.11±6.69
Group I-3 8 13.64±5.76
Group I-6 8 14.49±7.17
Group I-9 8 15.11±8.19
Group II-4 8 17.86±9.53
Group II-7 8 14.39±8.69
The results show that compared with a model group, the compound of the invention can obviously delay the acute epileptic seizure of mice, and the latency period is prolonged by 3 to 5 times; compared with the phenytoin sodium in a control group, the compound provided by the invention has longer latency period, which indicates that the compound provided by the invention has a remarkable anti-epileptic effect.

Claims (9)

1. A phenylquinolinone and flavonoid derivative is a compound with the following general structure (A) or pharmaceutically acceptable salt thereof:
Figure FDA0002385267410000011
in the formula:
x is selected from NR1Or O;
R1selected from H, C1-3Alkyl or C1-3An alkoxy group;
R2selected from H, hydroxy or C1-3An alkoxy group;
R3selected from H, hydroxy, C1-3Alkyl or C1-3An alkoxy group;
NR 'R' is selected from
Figure FDA0002385267410000012
2. Phenyl quinolinone and flavonoid derivatives according to claim 1, characterized in that: in the general structure (A), when X is NR1When the compound is a benzoquinolinone compound with the following general structure (A1) or a pharmaceutically acceptable salt thereof:
Figure FDA0002385267410000013
in the formula:
R1selected from H, C1-3Alkyl or C1-3An alkoxy group;
R2selected from H, hydroxy or C1-3An alkoxy group;
R3selected from H, hydroxy, C1-3Alkyl or C1-3An alkoxy group;
NR 'R' is selected from
Figure FDA0002385267410000014
3. Phenyl quinolinone and flavonoid derivatives according to claim 2, characterized in that: in the general structure (A1), R1Is selected from H or C1-3An alkyl group; r2Selected from H, hydroxy or C1-3An alkoxy group; r3Selected from H, hydroxy or C1-3An alkoxy group;
NR 'R' is selected from
Figure FDA0002385267410000015
4. Phenyl quinolinone and flavonoid derivatives according to claim 1, characterized in that: in the general structure (A), when X is O, the benzoflavonoid compound or the pharmaceutically acceptable salt thereof has the following general structure (A2):
Figure FDA0002385267410000021
in the formula:
R2selected from H, hydroxy or C1-3An alkoxy group;
R3selected from H, hydroxy, C1-3Alkyl or C1-3An alkoxy group;
NR 'R' is selected from
Figure FDA0002385267410000022
5. Phenyl quinolinone and flavonoid derivatives according to claim 4, characterized in that: in the general structure (A2), R2Selected from H, hydroxy or C1-3An alkoxy group; r3Selected from H, hydroxyOr C1-3An alkoxy group; NR 'R' is selected from
Figure FDA0002385267410000023
Figure FDA0002385267410000024
6. Phenyl quinolinone and flavonoid derivative according to any one of claims 1 to 5, characterized in that: is a compound having the structural formula set forth in the following list:
Figure FDA0002385267410000025
Figure FDA0002385267410000031
7. a pharmaceutical composition comprising as an active ingredient at least one compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or excipient.
8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of neurodegenerative diseases and ischemic brain injury diseases.
9. Use according to claim 8, characterized in that: the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, lethargy, epilepsy or gradually freezing disease.
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