Use of phenylquinolinone and flavonoid derivatives in the preparation of drugs for treating neuropathic pain

Abstract

The present invention provides the use of phenylquinolinone and flavonoid derivatives for neuropathic pain, and the phenylquinolinone and flavonoid derivatives include pharmaceutically acceptable salts thereof. The compound of the present invention is a histamine H3 receptor antagonist, which has a different mechanism of action from existing drugs and can be used in the preparation of drugs for treating neuropathic pain diseases. The effect of the compound of the present invention in treating neuropathic pain is better than amitriptyline, gabapentin, pregabalin and carbamazepine, indicating that the compound of the present invention has a better therapeutic effect, has the characteristics of small dosage, good efficacy, high bioavailability and safety, and compared with opioid drugs, the compound of the present invention is not addictive and is a very effective drug for treating neuropathic pain diseases. Therefore, the clinical application prospects are huge. The general structural formula is as follows:

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and relates to the use of phenylquinolone and flavonoid derivatives in treating neuropathic pain diseases, and specifically to the use of phenylquinolone and flavonoid derivatives or pharmaceutically acceptable salts thereof in preparing drugs for treating neuropathic pain. The drugs have the characteristics of small dosage, good therapeutic effect, high safety, and good clinical application prospects. Background Art

[0002] The World Health Organization (WHO) defines pain as the "fifth vital sign" after blood pressure, respiration, pulse and body temperature. Neuropathic pain, also known as neurogenic pain, neuropathic pain, is a type of pain caused by peripheral and / or central nervous system, primary and / or secondary damage, dysfunction or transient disorder (transitory perturbation). It is a type of chronic pain, with hyperalgesia, abnormal pain, paresthesia and spontaneous pain as the main manifestations.

[0003] The causes and clinical manifestations of neuropathic pain include autoimmune diseases (such as multiple sclerosis), metabolic diseases (such as diabetic neuropathy), infections (such as postherpetic neuralgia), vascular diseases (such as stroke), nerve compression, nerve trauma and cancer, all of which can lead to neuropathic pain, which is mainly manifested as spontaneous pain, hyperalgesia and allodynia. Spontaneous pain is often described as a continuous burning sensation, but it can also be divided into intermittent tingling, tearing pain, electric shock-like pain, or manifested as dullness and paresthesia. Hyperalgesia is manifested as varying degrees of high sensitivity to mild external noxious stimuli. Allodynia is manifested as a noxious response caused by non-noxious stimuli (physiological stimuli).

[0004] At present, the main methods for treating neuropathic pain include: drug therapy, neuromodulation (spinal cord stimulation, transcutaneous electrical stimulation, acupoint electrical stimulation, etc.), nerve block, nerve pulse radiofrequency, nerve destruction (thermocoagulation radiofrequency, chemical drug destruction, gamma knife, etc.). For the vast majority of patients, drug therapy is still the most basic and most commonly used method. Commonly used drugs include tricyclic antidepressants such as amitriptyline, anticonvulsants such as gabapentin, pregabalin and carbamazepine, opioids such as morphine and oxycodone, nonsteroidal anti-inflammatory analgesics and NMDA receptor antagonists such as ketamine and dextromethorphan, etc. These drugs are either inaccurate or have large adverse reactions. So far, there is no drug that can effectively reverse the symptoms and functions of neuropathic pain. Therefore, it is hoped that there will be reasonable drug therapy that can effectively control pain symptoms, relieve patients' suffering and improve their quality of life. Research on drug treatment of neuropathic pain has become a frontier topic in the medical community and has important medical and social value.

[0005] Invention patent application No. 201710488414.7 and PCT / CN2018 / 089970 provide "Preparation and Application of Phenylquinolinone and Flavonoid Derivatives", which are used in the treatment of neurodegenerative diseases, ischemic encephalopathy, Parkinson's syndrome, narcolepsy, epilepsy and amyotrophic lateral sclerosis. Summary of the invention

[0006] The present invention discloses the use of phenylquinolinone and flavonoid derivatives for treating neuropathic pain diseases. The phenylquinolinone and flavonoid derivatives include pharmaceutically acceptable salts thereof. The use refers to the use of phenylquinolinone and flavonoid derivatives in the preparation of drugs for treating neuropathic pain diseases. The general structure of the derivatives is as follows:

[0007]

[0008] Where:

[0009] X is or 1 of the group consisting of: 1-3 Alkyl or C 1-3 Alkoxy;

[0010] R2 is selected from H, hydroxyl or C 1-3 Alkoxy;

[0011] R3 is selected from H, hydroxyl, C 1-3 Alkyl or C 1-3 Alkoxy;

[0012] NR'R" is selected from cyclic amines and open-chain alkylamines having a total of 3 to 6 carbon atoms, including but not limited to the following fragments:

[0013]

[0014] Furthermore, the phenylquinolinone and flavonoid derivatives, when X is When , the general structural formula is (A1).

[0015]

[0016] wherein R2, R3, NR'R" are as described above.

[0017] When X is When the general structural formula is (A2)

[0018]

[0019] wherein R1, R2, R3, NR'R" are as described above.

[0020] Preferred phenylquinolinone and flavonoid derivatives, R1 is preferably hydrogen, methyl, ethyl and isopropyl; R2 is preferably hydrogen, hydroxyl and methoxy; R3 is preferably hydrogen, hydroxyl and methoxy.

[0021] Specifically, preferred compounds of phenylquinolinone and flavonoid derivatives (or pharmaceutically acceptable salts of the compounds) are selected from but not limited to the compounds shown in Table 1.

[0022] Table 1. Preferred compounds of phenylquinolinone and flavonoid derivatives

[0023]

[0024] The pharmaceutically acceptable salt of the compound is one of hydrochloride, sulfate, phosphate, hydrobromide, hydroiodide, carbonate, citrate, malate, tartrate, oxalate, lactate, malonate, succinate, glutarate, ketoglutarate, ascorbate, fumarate, maleate, methanesulfonate, p-toluenesulfonate or benzenesulfonate;

[0025] The "alkyl" described herein includes but is not limited to methyl, ethyl, n-propyl, isopropyl; "alkoxy" includes but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy. "Alkoxy" also includes substituted alkoxy, which may be optionally substituted one or more times by halogen.

[0026] The neuropathic pain disease is one of peripheral neuropathic pain or central neuropathic pain.

[0027] The peripheral neuropathic pain is one of trigeminal neuralgia, glossopharyngeal neuralgia, acute or chronic inflammatory demyelinating polyradiculoneuritis, alcoholic polyneuropathy, chemotherapy-induced polyneuropathy, complex regional pain syndrome, entrapment neuralgia (such as carpal tunnel syndrome), HIV sensory neuralgia, iatrogenic neuralgia (such as pain after mastectomy), tumor compression or infiltration neuralgia, nutritional deficiency-related neuralgia, diabetic neuralgia, phantom limb pain, post-herpetic neuralgia, post-radiotherapy plexus pain, radiculopathy (cervical, thoracic or lumbar sacral), toxic contact-related neuralgia, and post-traumatic neuralgia.

[0028] The central neuropathic pain is one of post-stroke pain, multiple sclerosis-related pain, Parkinson's disease-related pain, post-traumatic spinal cord injury pain, syringomyelia, post-ischemic myelopathy, compressive myelopathy, HIV myelopathy, and post-radiation myelopathy.

[0029] The drug preparations prepared from the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable carriers, diluents or excipients can be administered orally, rectally, nasally, topically (including buccal, sublingual or transdermal) or parenterally (including subcutaneous, intramuscular, intravenous or intradermal injections).

[0030] The preparation method of the above-mentioned compound is provided by the following steps, but is not limited to the following method:

[0031] 1. The general quinolinone derivatives can be synthesized by the following steps:

[0032] (1) Synthesis of I-1 and I-2 in the Compound I (Quinolinone Derivatives) Series (This method is suitable when X=N):

[0033]

[0034] The specific reaction process is:

[0035] The raw material 1, 1,3-bromochloropropane and potassium carbonate are dissolved in acetonitrile and heated to reflux, then reacted in a NaOH / CH3OH system to obtain intermediate 1, then refluxed in a dichlorothionyl solution to obtain intermediate 2, subsequently reacted with o-aminoacetophenone at room temperature to obtain intermediate 3, reacted with potassium tert-butoxide in a microwave to obtain intermediate 4, and finally refluxed with a secondary amine to obtain the target compounds I-1, I-2.

[0036] Wherein NR'R" is as described above.

[0037] (2) Synthesis of I-3 to I-6 in the series of compounds I (quinolinone derivatives) (this method is suitable when X = -NR1-):

[0038]

[0039] The specific reaction process is:

[0040] The intermediate 4 in Example 1 was dissolved in DMF, and sodium hydride and halogenated hydrocarbon were added to react to obtain intermediate 5, which was then refluxed with secondary amine and triethylamine to obtain target compounds I-3 to I-6.

[0041] Wherein NR'R" is as described above.

[0042] (3) Synthesis of I-7 and I-8 in the Compound I (quinolinone derivatives) series (this method is suitable when X = -NR1-):

[0043]

[0044] The specific reaction process is:

[0045] Dissolve p-hydroxyacetophenone (raw material 4) in acetonitrile, add 1,3-bromochloropropane and potassium carbonate for reflux reaction to obtain intermediate 6, which is then reacted with bromine in an ice bath to obtain bromoketone intermediate 7; the latter is heated with o-aminobenzoic acid and potassium carbonate in DMF to obtain ester intermediate 8, which is refluxed with ammonium acetate / acetic acid to obtain intermediate 9, and finally refluxed with secondary amine and triethylamine to obtain target compounds I-7, I-8.

[0046] Wherein NR'R" is as described above.

[0047] (4) Synthesis of I-9 and I-10 in the Compound I (quinolinone derivatives) series (this method is suitable when X = -NR1-):

[0048]

[0049] The specific reaction process is:

[0050] The intermediate 9 in Example 3, dimethyl sulfate and potassium carbonate were dissolved in acetone and refluxed to obtain intermediate 10, which was then refluxed with secondary amine NHR'R" and triethylamine to obtain target compounds I-9, I-10.

[0051] (5) Synthesis method of II-1 and II-2 in the compound II (flavonoid derivative) series (this method is suitable when X=O):

[0052]

[0053] The specific reaction process is:

[0054] The raw material 6 is dissolved in acetonitrile, and 1,3-bromochloropropane and potassium carbonate are added, followed by reflux reaction to obtain intermediate 11. The latter is condensed with p-hydroxyacetophenone in potassium hydroxide to obtain intermediate 12, which is then cyclized through a hydrogen peroxide / KOH system to obtain intermediate 13. Finally, the target compounds II-1 and II-2 are obtained by reflux reaction with secondary amines and triethylamine.

[0055] Wherein NR'R" is as described above.

[0056] (6) Synthesis of II-3 and II-4 in the Compound II (Flavone Derivatives) Series (This method is suitable when X=O)

[0057]

[0058] The specific reaction process is as follows:

[0059] The intermediate 13 in Example 5, iodomethane and potassium carbonate are dissolved in acetone and refluxed to obtain the intermediate 14, which is then refluxed with a secondary amine and triethylamine to obtain the target compounds II-3 and II-4.

[0060] Wherein NR'R" is as described above.

[0061] (7) Synthesis of II-5 and II-6 in the Compound II (Flavone Derivatives) Series (This method is suitable when X=O)

[0062]

[0063] The specific reaction process is as follows:

[0064] Intermediate 11 and 2,6-dihydroxyacetophenone are dissolved in ethanol, potassium hydroxide is added and refluxed to obtain intermediate 15, and then cyclized under the action of iodine and concentrated sulfuric acid to obtain intermediate 16, and finally refluxed with secondary amine and triethylamine to obtain target compounds II-5, II-6.

[0065] Wherein NR'R" is as described above.

[0066] (8) Synthesis of II-7 and II-8 in the Compound II (Flavone Derivatives) Series (This method is suitable when X=O)

[0067]

[0068] The specific reaction process is as follows:

[0069] Example 7: Intermediate 16, potassium iodide and potassium carbonate are dissolved in acetone and refluxed to obtain intermediate 17, which is then refluxed with secondary amine and triethylamine to obtain target compounds II-7 and II-8.

[0070] Wherein NR'R" is as described above.

[0071] Phenylquinolinone and flavonoid derivatives (A) or pharmaceutically acceptable salts thereof can be used to treat neuropathic pain diseases, wherein the neuropathic pain includes peripheral neuropathic pain and central neuropathic pain, wherein peripheral neuropathic pain includes trigeminal neuralgia, glossopharyngeal neuralgia, acute or chronic inflammatory demyelinating polyradiculoneuropathy, alcoholic polyneuropathy, chemotherapy-induced polyneuropathy, complex regional pain syndrome, entrapment neuralgia (such as carpal tunnel syndrome), HIV sensory neuralgia, iatrogenic Neuralgia (such as pain after mastectomy), neuralgia caused by tumor compression or infiltration, neuralgia related to nutritional deficiency, diabetic neuropathy, phantom limb pain, post-herpetic neuralgia, plexus pain after radiotherapy, radiculopathy (cervical, thoracic or lumbar sacral), neuralgia related to toxic exposure, post-traumatic neuralgia; central neuropathic pain includes post-stroke pain, pain related to multiple sclerosis, pain related to Parkinson's disease, post-traumatic spinal cord injury pain, syringomyelia, post-ischemic myelopathy, compressive myelopathy, HIV myelopathy, and post-radiation myelopathy.

[0072] The present invention provides the use of phenylquinolinone and flavonoid derivatives for neuropathic pain, and the phenylquinolinone and flavonoid derivatives include pharmaceutically acceptable salts thereof. The compound of the present invention is a histamine H3 receptor antagonist, which has a different mechanism of action from existing drugs and can be used in the preparation of drugs for treating neuropathic pain diseases. The effect of the compound of the present invention in treating neuropathic pain is better than amitriptyline, gabapentin, pregabalin and carbamazepine, indicating that the compound of the present invention has a better therapeutic effect, has the characteristics of small dosage, good efficacy, high bioavailability and safety, and compared with opioids, the compound of the present invention is not addictive and is a very effective drug for treating neuropathic pain diseases. Therefore, the clinical application prospect is huge. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1 The effect of single administration of I-6 compound (0.3, 1, 3 mg / kg, PO) and pregabalin (30 mg / kg, PO) on thermal threshold of PSL rats (Mean±SEM, N=4).

[0074] One-way ANOVA was used to compare the model group with the sham group: △, P<0.05, △△, P<0.01; each drug-treated group was compared with the model group: *, P<0.05, **, P<0.01; I-6 was compared with the Pre group: #, P<0.05, ##, P<0.01.

[0075] Figure 2 The effect of single administration of I-4 (1 mg / kg, PO), I-6 (1 mg / kg, PO), II-4 (1 mg / kg, PO) and gabapentin (50 mg / kg, PO), carbamazepine (100 mg / kg, PO), and amitriptyline (10 mg / kg, PO) on the thermal pain threshold of PSL rats (Mean±SEM, N=4).

[0076] One-way analysis of variance was used. The model group was compared with the sham group (△, P<0.05, △△, P<0.01); the drug-treated groups were compared with the model group (*, P<0.05, **, P<0.01).

[0077] Figure 3 The effect of a single administration of I-4 compound (1, 3, 9 mg / kg, PO) and gabapentin (Gab, 50 mg / kg, PO) on the mechanical pain threshold of CCI rats (Mean±SEM, N=4).

[0078] One-way ANOVA was used to compare the model group with the sham group: △, P<0.05, △△, P<0.01; each drug-treated group was compared with the model group: *, P<0.05, **, P<0.01; I-4 was compared with the Gab group: #, P<0.05, ##, P<0.01.

[0079] Figure 4 The effect of a single administration of I-6 compound (1 mg / kg, PO) and gabapentin (50 mg / kg, PO) on the thermal pain threshold of rats with STZ-induced diabetic neuropathic pain (Mean±SEM, N=4).

[0080] One-way analysis of variance was used. The model group was compared with the Normal group, △, P<0.05, △△, P<0.01; each drug-treated group was compared with the model group, *, P<0.05, **, P<0.01; the I-6 compound was compared with the gabapentin group, #, P<0.05, ##, P<0.01.

[0081] Figure 5 The effect of single administration of II-4 compound (1, 3, 9 mg / kg, PO) and Pre (30 mg / kg, PO) on the mechanical pain threshold of rats with OXA-induced neuropathic pain (Mean±SEM, N=4).

[0082] One-way analysis of variance was used. The model group was compared with the Normal group, △, P<0.05, △△, P<0.01; each drug-treated group was compared with the model group, *, P<0.05, **, P<0.01; the II-4 compound was compared with the Pre group, #, P<0.05, ##, P<0.01.

[0083] Figure 6 The effect of I-10 compound (0.3, 1, 3 mg / kg, PO) and gabapentin (Gab, 50 mg / kg, PO) on the mechanical pain threshold of CCI rats (Mean±SEM, N=4) was measured after continuous administration for 5 days.

[0084] One-way analysis of variance was used. The model group was compared with the sham group, △, P<0.05, △△, P<0.01; each drug-treated group was compared with the model group, *, P<0.05, **, P<0.01; I-10 was compared with the Gab group, #, P<0.05, ##, P<0.01. DETAILED DESCRIPTION

[0085] The following is further described in conjunction with the accompanying drawings and Examples. The specific embodiments included below are for illustration and should not be construed as limiting the scope of the invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope limited by the appended claims of the application.

[0086] Example 1. Synthesis of I-1 and I-2 in Class I Compounds (Quinolinones)

[0087] Step 1: 4-(3-chloropropoxy)benzoic acid (Intermediate 1)

[0088] Dissolve ethyl p-hydroxybenzoate II-1 (12g, 72mmol), 1,3-bromochloropropane (14.2mL, 144mmol) and K2CO3 (20g, 144mmol) in 100mL acetonitrile and heat to reflux for 12h. Remove excess K2CO3 by suction filtration, and evaporate the solvent under reduced pressure to obtain a colorless oily liquid. Directly add 15mL 6N NaOH solution and 30mL CH3OH, and reflux for 1h. When the reaction liquid becomes clear, cool it, acidify it with 2N hydrochloric acid to pH=2, and a large amount of white solid precipitates. Filter it, wash it with water, and dry it to obtain 14.5g of white solid powder. The yield is 94%;

[0089] 1 H NMR (500MHz, CDCl3): δ8.08(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] + .

[0090] Step 2: N-(2-acetylphenyl)-4-(3-chloropropoxy)benzamide (Intermediate 3)

[0091] Intermediate 1 (5.0 g, 23 mmol) was refluxed in 10 mL SOCl2 for 1 h, and 1-2 drops of DMF were added to the reaction system. After the reaction was completed, the excess SOCl2 was removed under reduced pressure to obtain a colorless liquid intermediate 2. o-Aminoacetophenone (2.83 g, 21 mmol) was dissolved in 15 mL anhydrous CH2Cl2 and 6.5 mL anhydrous TEA, and intermediate 2 was slowly added dropwise at 0°C. After the addition was completed, the reaction was continued at room temperature for 2 h, filtered, and the filtrate was dried by spin drying. The residue was separated by column chromatography (petroleum ether: EtOAc = 10:1) to obtain 5.0 g of a white solid. The yield was 72%;

[0092] 1H NMR (500MHz, CDCl3): δ12.65(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] + .

[0093] Step 3: 2-(4-(3-chloropropoxy)phenyl)quinolin-4(1H)-one (Intermediate 4)

[0094] Dissolve intermediate 3 (995 mg, 3.0 mmol) and potassium tert-butoxide (1.68 g, 15 mmol) in 15 mL THF and react in a sealed container at 110 ° C for 20 min. After the reaction is completed, cool to room temperature, pour into 100 mL ice water, add 2N HCl to adjust the pH to 5-6, and a large amount of yellow solid precipitates. Wash with water, a small amount of ice acetone and CH2Cl2 (1:1) to obtain intermediate 4, 750 mg. Yield 80%;

[0095] 1 H NMR (500MHz, CDCl3): δ11.63(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] + .

[0096] Step 4: 2-(4-(3-(Pyrrolidin-1-yl)propoxy)phenyl)quinolin-4(1H)-one (I-1)

[0097] Dissolve intermediate 4 (60 mg, 0.19 mmol) in 3 mL of acetonitrile, dropwise add 41 mg (0.57 mmol) of pyrrolidine and 96 mg (0.96 mmol) of TEA, and heat to reflux for overnight reaction. After the reaction is completed, cool, evaporate the solvent under reduced pressure, and separate by column chromatography (petroleum ether: EtOAc: TEA = 1:5:0.1) to obtain 40 mg of a yellow solid. Yield 60%;

[0098] 1 H NMR (500MHz, CDCl3): δ8.33(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); 13 CNMR (125MHz, CDCl3): δ174.19,155.44,146.00,136.03,127.08,124.08,122.23,120.66,120. 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] + .

[0099] 2-(4-(3-(Piperidin-1-yl)propoxy)phenyl)quinolin-4(1H)-one (I-2)

[0100] The preparation method is the same as compound I-1, except that piperidine is used instead of pyrrolidine to obtain a yellow solid. Yield: 75%;

[0101] 1 H NMR (500MHz, CDCl3): δ8.33(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): δ174.16,155.86,145.64,135.72,127.17,123.84,121.89,120.82,120.43, 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] + .

[0102] Example 2: Synthesis of I-3 to I-6 in Class I Compounds (Quinolinones)

[0103] Step 1: 2-(4-(3-chloropropoxy)phenyl)-1-methylquinolin-4(1H)-one (Intermediate 5a)

[0104] Dissolve intermediate 4 (276 mg, 0.88 mmol) in 5 mL DMF, add 42 mg NaH (60%, 1.05 mmol), stir at room temperature for 30 min, then add iodomethane (138 mg, 0.97 mmol), heat to 35 ° C, and react for 30 min. Pour the reaction solution into 50 mL H2O, extract with EtOAc, wash with water, wash with saturated NaCl, and dry with anhydrous Na2SO4. After recovering the solvent, separate by column chromatography (petroleum ether: EtOAc = 10:1) to obtain 250 mg of white solid. Yield 87%;

[0105] 1 H NMR (500MHz, CDCl3): δ8.17(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] + .

[0106] 2-(4-(3-Chloropropoxy)phenyl)-1-ethylquinolin-4(1H)-one (Intermediate 5b)

[0107] The preparation method is the same as that of compound intermediate 5a, but ethyl bromide is used instead of methyl iodide to obtain a yellow solid. Yield: 67%;

[0108] 1H NMR (500MHz, CDCl3): δ8.21(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] + .

[0109] Step 2, 2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-1-methylquinolin-4(1H)-one (I-3)

[0110] The preparation method is the same as compound I-1, intermediate 5a is used instead of intermediate 4, and the secondary amine is pyrrolidine to obtain white solid I-3 with a yield of 74%;

[0111] 1 H NMR (500MHz, CDCl3): δ8.17(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); 13 C NMR (100MHz, CDCl3): δ162.70,160.18,158.36,149.15,132.72,129.87,128.95,128.79,125.01, 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] + .

[0112] 2-(4-(3-(Piperidin-1-yl)propoxy)phenyl)-1-methylquinolin-4(1H)-one (I-4)

[0113] The preparation method is the same as compound I-1, intermediate 5a is used instead of intermediate 4, and piperidine is used instead of pyrrolidine as the secondary amine to obtain white solid I-4 with a yield of 71%;

[0114] 1 H NMR (500MHz, CDCl3): δ8.17(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); 13 C NMR (100MHz, CDCl3): δ162.70,160.22,158.41,149.18,132.75,129.92,128.99,128.83,125.06,121 .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] + .

[0115] 2-(4-(3-(Pyrrolidin-1-yl)propoxy)phenyl)-1-ethylquinolin-4(1H)-one (I-5)

[0116] The preparation method is the same as compound I-1, intermediate 5b is used instead of intermediate 4, and the secondary amine is pyrrolidine to obtain a light yellow solid I-5. The yield is 74%;

[0117] 1 H NMR (500MHz, CDCl3): δ8.21(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): δ161.98,160.17,158.35,149.25,132.85,129.77,128.96,128.78,124.86,121 .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] + .

[0118] 2-(4-(3-(Piperidin-1-yl)propoxy)phenyl)-1-ethylquinolin-4(1H)-one (I-6)

[0119] The preparation method is the same as compound I-1, intermediate 5b is used instead of intermediate 4, and the secondary amine is piperidine to obtain a light yellow solid I-6. The yield is 85%;

[0120] 1 H NMR (500MHz, CDCl3): δ8.21 (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); 13 C NMR (100MHz, CDCl3): δ162.00,160.18,158.40,149.25,132.85,129.83,128.96,128.81,124.91,121.73 ,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] + .

[0121] Example 3. Synthesis of I-7 and I-8 in Class I Compounds (Quinolinones)

[0122] Step 1: 4-(3-chloropropoxy)acetophenone (Intermediate 6)

[0123] Dissolve p-hydroxyacetophenone (5.0 g, 36.7 mmol), 1,3-bromochloropropane (7.3 mL, 73.5 mmol) and K2CO3 (10 g, 73.5 mmol) in 30 mL of acetonitrile and heat under reflux for 10 h. Remove the excess K2CO3 by suction filtration, evaporate the solvent under reduced pressure, and separate by column chromatography (petroleum ether: EtOAc = 10:1) to obtain 7.6 g of colorless liquid. Yield 98%;

[0124] 1 H NMR (500MHz, CDCl3): δ7.95(d,J=9.0Hz,2H),6.95(d,J=9.0Hz,2H),4.20(t,J=6.0H z,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] + .

[0125] Step 2, 2-bromo-1-(4-(3-chloropropoxy)phenyl)ethanone (Intermediate 7)

[0126] Dissolve intermediate 6 (2.12 g, 10 mmol) in 20 mL of ether, slowly add Br2 (0.51 mL, 10 mmol) at 0°C, and stir at room temperature for 16 h. Pour the reaction solution into saturated NaHCO3 solution, extract with ether, dry the organic layer over anhydrous Na2SO4, and separate by column chromatography (petroleum ether: CH2Cl2 = 3:1) to obtain 2.45 g of light yellow solid. Intermediate 84%;

[0127] 1 H NMR (500MHz, CDCl3): δ7.97 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 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] + .

[0128] Step 3, 2-(4-(3-chloropropoxy)phenyl)-2-oxoethyl-2-aminobenzoate (Intermediate 8)

[0129] Dissolve anthranilic acid (720 mg, 5.25 mmol) and K2CO3 (760 mg, 5.5 mmol) in 10 mL DMF, stir at room temperature for 30 min, then add intermediate 7 (1.46 g, 5.0 mmol), heat to 50 ° C, react for 3 h, pour the reaction solution into 100 mL water, extract with EtOAc, wash the organic layer with 1N NaOH solution and saturated NaCl solution, dry, evaporate the solvent under reduced pressure, and purify by column chromatography (petroleum ether: EtOAc = 3:1) to obtain 1.6 g of white solid. Yield 92%;

[0130] 1 H NMR (500MHz, CDCl3): δ8.02(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] + .

[0131] Step 4, 2-(4-(3-chloropropoxy)phenyl)-3-hydroxyquinolin-4(1H)-one (Intermediate 9)

[0132] Dissolve intermediate 8 (1.6 g, 4.6 mmol) and ammonium acetate (5.3 g, 69 mmol) in 30 mL of acetic acid and heat to reflux for 3 h. After the reaction, pour the reaction solution into 250 mL of water to precipitate a large amount of solid, filter it, wash it with water until it is neutral, and dry it to obtain 1.02 g of light yellow solid. Yield 67%;

[0133] 1 H NMR (500MHz, CDCl3): δ8.32(d,J=8.5Hz,1H),7.80-7.76(m,2H),7.61-7.57(m,2H),7.32(t,J=7.5Hz,1H),6.97-6.9 5(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] + .

[0134] Step 5, 2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-3-hydroxyquinolin-4(1H)-one (I-7)

[0135] The preparation method is the same as compound I-1, using intermediate 9 instead of intermediate 4 to obtain a beige solid. Yield 59%;

[0136] 1 H NMR (500MHz, DMSO-d6): δ11.48(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); 13 C NMR (125MHz, DMSO-d6): δ170.22,159.80,138.42,138.01,131.81,131.11,130.85,124.85,124 .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] + .

[0137] 2-(4-(3-(Pyrrolidin-1-yl)propoxy)phenyl)-3-hydroxyquinolin-4(1H)-one (I-8)

[0138] The preparation method is the same as compound I-1, intermediate 9 is used instead of intermediate 4, and piperidine is used instead of pyrrolidine to obtain a yellow solid. Yield 67%;

[0139] 1 H NMR (500MHz, DMSO-d6): δ11.47(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,2 H),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): δ170.25,159.49,138.43,138.03,131.75,131.17,130.84,125.04,124.83 ,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] + .

[0140] Example 4. Synthesis of I-9 and I-10 in Class I Compounds (Quinolinones)

[0141] Step 1, 2-(4-(3-chloropropoxy)phenyl)-3-methoxy-1-methylquinolin-4(1H)-one (Intermediate 10)

[0142] Dissolve intermediate 9 (660 mg, 2.0 mmol), dimethyl sulfate (0.75 mL, 8.0 mmol) and K2CO3 (1.1 g, 8.0 mmol) in 10 mL of acetone and heat to reflux for 4 h. After the reaction is completed, cool and filter, and the filtrate is decompressed to recover the solvent and purified by column chromatography (petroleum ether: EtOAc = 1:2) to obtain 558 mg of a yellow solid. The yield is 78%;

[0143] 1 H NMR (500MHz, CDCl3): δ8.59(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,2 H),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] + .

[0144] Step 2, 2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-3-methoxy-1-methylquinolin-4(1H)-one (I-9)

[0145] The preparation method is the same as compound I-1, using intermediate 10 instead of intermediate 4 to obtain an off-white solid. Yield: 65%;

[0146] 1H NMR (500MHz, CDCl3): δ8.59(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); 13 C NMR (125MHz, CDCl3): δ172.96,159.69,147.31,141.26,140.20,131.85,130.38,127.14,126.79,124 .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] + .

[0147] 2-(4-(3-(Piperidin-1-yl)propoxy)phenyl)-3-methoxy-1-methylquinolin-4(1H)-one (I-10)

[0148] The preparation method is the same as compound I-1, except that intermediate 10 is used instead of intermediate 4, and piperidine is used instead of pyrrolidine to obtain an off-white solid. Yield: 67%;

[0149] 1 H NMR (500MHz, CDCl3): δ8.58(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=8.5H z,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): δ172.95,159.72,147.28,141.27,140.21,131.82,130.38,127.15,126.79,124.36 ,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] + .

[0150] Example 5. Synthesis of Class II compounds (flavonoids) II-1 and II-2

[0151] Step 1: 4-(3-chloropropoxy)benzaldehyde (Intermediate 11)

[0152] The preparation method is the same as that of intermediate 6, except that p-hydroxybenzaldehyde is used instead of p-hydroxyacetophenone to obtain a light yellow solid. Yield: 98%;

[0153] 1 H NMR (500MHz, CDCl3): δ9.89 (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] + .

[0154] Step 2: 1-(2-Hydroxyphenyl)-3-(4-(3-chloropropoxy)phenyl)prop-2-en-1-one (Intermediate 12)

[0155] Dissolve p-hydroxyacetophenone (1.36 g, 10 mmol) and intermediate 11 (1.98 g, 10 mmol) in 15 mL C2H5OH, add 1.68 g KOH (30 mmol), and reflux for 2 h. Cool, remove part of the solvent under reduced pressure, add 200 mL of ice water to the remaining residue, adjust the pH to 4-5 with 2N HCl, precipitate a large amount of solid, filter and dry, and obtain 2.82 g of yellow solid. Yield 89%;

[0156] 1H NMR (500MHz, CDCl3): δ12.92(s,1H),7.94-7.89(m,2H),7.63(d,J=8.5Hz,2H),7.57and 7.54(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] + .

[0157] Step 3: 2-(4-(3-chloropropoxy)phenyl)-3-hydroxy-4H-benzopyran-4-one (Intermediate 13)

[0158] Dissolve the intermediate 12 (1.05 g, 3 mmol) in 10 mL C2H5OH, add 10 mL 0.5 N KOH solution, and then add 0.6 mL H2O2 aqueous solution (30%) in batches. After stirring at room temperature for 1 h, pour the reaction solution into ice water to precipitate a large amount of solid. Filter by suction, wash the filter cake with water and dry it to obtain 930 mg of yellow solid. Yield 94%;

[0159] 1 H NMR (500MHz, CDCl3): δ8.61 (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] + .

[0160] Step 4: 2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-3-hydroxy-4H-benzopyran-4-one (II-1)

[0161] The preparation method is the same as compound I-1, using intermediate 13 instead of intermediate 4 to obtain a yellow solid. Yield: 68%;

[0162] 1H NMR (500MHz, CDCl3): δ8.25-8.21(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); 13 C NMR (125MHz, DMSO-d6): δ173.10,160.32,154.88,146.04,138.65,133.96,129.87,125.20,124 .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] + .

[0163] 2-(4-(3-(Piperidin-1-yl)propoxy)phenyl)-3-hydroxy-4H-benzopyran-4-one (II-2)

[0164] The preparation method is the same as compound I-1, intermediate 13 is used instead of intermediate 4, and piperidine is used instead of pyrrolidine to obtain a yellow solid. Yield: 61%;

[0165] 1 H NMR (500MHz, CDCl3): δ8.25-8.21(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); 13 C NMR (125MHz, DMSO-d6): δ173.47,160.24,154.85,145.98,138.02,133.85,129.77,125.19,124.87 ,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] + .

[0166] Example 6: Synthesis of Class II compounds (flavonoids) II-3 and II-4

[0167] Step 1: 2-(4-(3-chloropropoxy)phenyl)-3-methoxy-4H-benzopyran-4-one (Intermediate 14)

[0168] Intermediate 13 (660 mg, 2.0 mmol), iodomethane (8.0 mmol) and K2CO3 (1.1 g, 8.0 mmol) were dissolved in 10 mL of acetone and heated to reflux for 4 h. After the reaction was completed, the mixture was cooled and filtered, and the filtrate was decompressed to recover the solvent and purified by column chromatography (petroleum ether: EtOAc = 1:2) to obtain 558 mg of a yellow solid. The yield was 78%;

[0169] 1 H NMR (500MHz, CDCl3): δ8.59(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,2 H),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] + .

[0170] Step 2, 2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-3-methoxy-4H-benzopyran-4-one (II-3)

[0171] The preparation method is the same as compound I-1, using intermediate 14 instead of intermediate 4 to obtain a red solid. Yield: 54%;

[0172] 1 H NMR (500MHz, CDCl3): δ8.26(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): δ175.01,161.01,155.72,155.15,140.80,133.28,130.24,125.77,124.58, 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] + .

[0173] 2-(4-(3-(Piperidin-1-yl)propoxy)phenyl)-3-methoxy-4H-benzopyran-4-one (II-4)

[0174] The preparation method is the same as compound I-1, intermediate 14 is used instead of intermediate 4, and piperidine is used instead of pyrrolidine to obtain a yellow solid. Yield: 57%;

[0175] 1 H 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); 13 C NMR (125MHz, CDCl3): δ175.00,161.03,155.71,155.16,140.82,133.27,130.24,125.80,124.57,124 .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] + .

[0176] Example 7: Synthesis of Class II compounds (flavonoids) II-5 and II-6

[0177] Step 1: 1-(2,6-dihydroxyphenyl)-3-(4-(3-chloropropoxy)phenyl)prop-2-en-1-one (Intermediate 15)

[0178] The preparation method is the same as that of intermediate 12, except that 2,6-dihydroxyacetophenone is used instead of o-hydroxyacetophenone to obtain a yellow solid. Yield: 85%; ESI-MS: m / z = 333 [M+H] + .

[0179] Step 2: 2-(4-(3-chloropropoxy)phenyl)-5-hydroxy-4H-benzopyran-4-one (Intermediate 16)

[0180] Intermediate 15 (1.00 g, 3.2 mmol) was dissolved in 15 mL DMSO, and I2 (128 mg, 0.5 mmol) and 0.5 mL concentrated sulfuric acid were added, and stirred at 85 ° C for 24 h. The reaction solution was poured into 200 mL H2O, extracted three times with EtOAc, and the organic layers were combined, washed with water and saturated NaCl, dried over anhydrous Na2SO4, and separated by column chromatography (petroleum ether: EtOAc = 4:1) to obtain 565 mg of white solid. Yield: 45%;

[0181] 1 H NMR (500MHz, CDCl3): δ7.88(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] + .

[0182] Step 3: 2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5-hydroxy-4H-benzopyran-4-one (II-5)

[0183] The preparation method is the same as compound I-1, using intermediate 16 instead of intermediate 4 to obtain a yellow solid. Yield: 58%;

[0184] 1H NMR (500MHz, CDCl3): δ7.88(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] + .

[0185] 2-(4-(3-(Piperidin-1-yl)propoxy)phenyl)-5-hydroxy-4H-benzopyran-4-one (II-6)

[0186] The preparation method is the same as compound I-1, using intermediate 16 instead of intermediate 4 and piperidine instead of pyrrolidine to obtain a yellow solid. Yield: 64%;

[0187] 1 H NMR (500MHz, CDCl3): δ7.87(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] + .

[0188] Example 8: Synthesis of Class II compounds (flavonoids) II-7 and II-8

[0189] Step 1: 2-(4-(3-chloropropoxy)phenyl)-5-methoxy-4H-benzopyran-4-one (Intermediate 17)

[0190] The preparation method is the same as that of intermediate 14, but intermediate 16 is used to replace intermediate 13 to obtain an off-white solid. Yield: 75%;

[0191] 1H NMR (500MHz, CDCl3): δ7.88(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] + .

[0192] Step 2: 2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5-methoxy-4H-benzopyran-4-one (II-7)

[0193] The preparation method is the same as compound I-1, using intermediate 17 instead of intermediate 4 to obtain a yellow solid. Yield: 61%;

[0194] 1 H NMR (500MHz, CDCl3): δ7.87(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] + .

[0195] 2-(4-(3-(Piperidin-1-yl)propoxy)phenyl)-5-methoxy-4H-benzopyran-4-one (II-8)

[0196] The preparation method is the same as compound I-1, using intermediate 17 instead of intermediate 4 and piperidine instead of pyrrolidine to obtain a yellow solid. Yield: 67%;

[0197] 1H NMR (500MHz, CDCl3): δ7.88(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),2.0 6-2.00(m,2H),1.65-1.59(m,4H),1.47-1.43(m,2H); ESI-MS:m / z=394[M+H] + .

[0198] Example 9: Effects of different doses on the thermal pain threshold of PSL model rats

[0199] SD male rats, 200-250g, had 1 / 3-1 / 2 of the sciatic nerve of the right hind leg partially ligated, and the muscles and skin were sutured to establish the PSL model; the sham group model (sham) was not ligated, and the muscles and skin were directly sutured. On the 6th day, the thermal pain threshold was tested with a plantar hot spot analgesia (BME-410). For 2 consecutive days, rats with stable thermal pain thresholds were selected and randomly divided into 5 groups, namely the model group (model), pregabalin group (Pre, 30mg / kg), I-6 compound group (3mg / kg), I-6 compound group (1mg / kg), and I-6 compound group (0.3mg / kg). The drugs were administered by gavage at 1ml / 100g. The basal value was measured before administration. The sham group and the model group (model) were gavaged with the same volume of normal saline. After a single administration, the thermal pain threshold of each group was tested with a plantar hot spot analgesia at 1, 2, 4, and 6h. The results are shown in the figure. Figure 1 .

[0200] The results showed that for the PSL neuropathic pain model of SD rats, single administration of 0.3 mg / kg, 1.0 mg / kg, and 3.0 mg / kg of I-6 compound could increase the thermal pain threshold of PSL model rats in a dose-dependent manner; 2 hours after administration of 0.3 mg / kg of I-6 compound, the thermal pain threshold of PSL model rats was significantly different from that of the model group (P<0.01); 1.0 mg / kg of I-6 compound increased the thermal pain threshold of PSL model rats to the same level as pregabalin (Pre) 30.0 mg / kg; 1 to 2 hours after administration of 3.0 mg / kg of I-6 compound, the thermal pain threshold of PSL model rats could be increased to the level of sham operation group rats, which was better than pregabalin 30.0 mg / kg. This shows that I-6 compound can effectively increase the thermal pain threshold of PSL neuropathic pain model to normal level, and its efficacy is better than pregabalin (Pre).

[0201] Example 10: Comparison of the effects on the thermal pain threshold of PSL model rats

[0202] SD male rats, 200-250g, had 1 / 3-1 / 2 of the sciatic nerve of the right hind leg partially ligated, and the muscles and skin were sutured to establish the PSL model; the sham operation group model (sham) was not ligated, and the muscles and skin were directly sutured. On the 6th day, the thermal pain threshold was tested with a plantar hot spot analgesia (BME-410). Rats with stable thermal pain threshold were selected for 2 consecutive days and randomly divided into 7 groups, namely model group (model), gabapentin group (Gab, 50 mg / kg), carbamazepine group (Car, 100 mg / kg), amitriptyline group (Ami, 10 mg / kg), I-4 compound group (1 mg / kg), I-6 compound group (1 mg / kg), and II-4 compound group (1 mg / kg). The drugs were intragastrically administered at 1 ml / 100 g. The basal value was measured before administration. The sham group (sham) and model group (model) were intragastrically administered with the same volume of normal saline. After a single administration, the thermal pain threshold of each group was tested with a plantar hot spot analgesia at 1, 2, 4, and 6 h. The results are shown in Figure 2 .

[0203] The results showed that in the PSL neuropathic pain model of SD rats, oral administration of 1 mg / kg of I-4, I-6, and II-4 compounds for 1 hour could significantly increase the thermal pain threshold of rats, which was significantly different from the model group; the 1 mg / kg dose of each compound increased the thermal pain threshold of rats, which was equivalent to the effect of gabapentin 50 mg / kg, carbamazepine 100 mg / kg, and amitriptyline 10 mg / kg, indicating that the compounds have significant efficacy.

[0204] Example 11: Effect on the mechanical pain threshold of CCI model rats

[0205] SD male rats, 200-250g, right hind leg, sciatic nerve exposed, sterile chromic gut (No. 4, 0.15mm diameter) was used to loosely ligate 4 loops at the anterior segment of the sciatic nerve before bifurcation, and the muscle and skin were sutured to establish the CCI model. The sham operation group only exposed the sciatic nerve without ligation, and the muscle and skin were sutured. After 3 days of observation, the mechanical pain threshold was tested with an electronic analgesic (IITC-2391) on the 7th day for 2 consecutive days.

[0206] The CCI model rats with stable mechanical pain threshold were randomly divided into 5 groups, namely model group, gabapentin (Gab) group (50 mg / kg), I-4 compound group (9 mg / kg), I-4 compound group (3 mg / kg), and I-4 compound group (1 mg / kg). The rats were intragastrically administered with 1 ml / 100 g of saline. The sham group (sham) and model group (model) were intragastrically administered with the same volume of normal saline. The basal value was measured before administration, and the mechanical pain threshold was measured 1, 2, 4, and 6 h after a single administration. The results are shown in Figure 3 .

[0207] The results showed that in the CCI neuropathic pain model of SD rats, the I-4 compound was administered at three doses of 1 mg / kg, 3 mg / kg, and 9 mg / kg, respectively, and the mechanical pain threshold of the CCI model rats was dose-dependently increased; the I-4 compound was administered at a dose of 3 mg / kg, and the mechanical pain threshold of the CCI model rats was increased 1 hour to 4 hours after administration, which was significantly different from that of the model group (P<0.01); the gabapentin (Gab) was administered at a dose of 50 mg / kg, and the mechanical pain threshold of the CCI model rats was increased only 1 hour to 2 hours after administration, which was significantly different from that of the model group, indicating that the I-4 compound has a longer effective action time and is superior to gabapentin.

[0208] Example 12: Effects on diabetic neuropathic pain model

[0209] SD male rats, 200-250g, were used for modeling. After fasting for 12h but not water, a rat diabetes model was induced by a single intraperitoneal injection of streptozotocin (STZ) 60mg / kg. Blood glucose was measured by taking tail vein blood 2h after meal 1w later. A blood glucose value greater than 16mmol / L indicated that the diabetes model was successful. The normal control group (Normal) was given an equal volume of citric acid-sodium citrate buffer (pH4.2). Two weeks after STZ administration, the plantar heat pain threshold of the normal control group and STZ rats was measured using a plantar hot spot analgesia instrument (BME-410). Diabetic rats with neuropathic pain induced by STZ were randomly divided into a model group (Model), a gabapentin group (50mg / kg), and an I-6 compound group (1mg / kg). The rats were given intragastric administration at 1ml / 100g. The normal control group and the model group were given corresponding volumes of normal saline. The basal value was measured before administration. After a single administration, the heat pain threshold was measured at 1, 2, 4, and 6h. The results are shown in Figure 4 .

[0210] The results showed that both I-6 compound and gabapentin could increase the thermal pain threshold of the diabetic neuropathic pain model in SD rats. Compared with the dose of gabapentin 50 mg / kg, the dose of I-6 compound 1 mg / kg had a stronger effect on increasing the thermal pain threshold (P<0.01) and a longer effective duration.

[0211] Example 13: Effects on chemotherapy-induced neuropathic pain model

[0212] SD male rats, 200-250g, were intraperitoneally injected with oxaliplatin (OXA) 4mg / kg, twice a week, for 4 consecutive weeks (Days 1, 2, 8, 9, 15, 16, 22and 23). The mechanical pain threshold of the normal control group (Normal) and the model control group (Model) rats was tested with an electronic analgesic (IITC-2391) on day 24. The rats with stable mechanical pain threshold were randomly divided into model group (Model), pregabalin (Pre) group (30mg / kg), II-4 compound group (9mg / kg), II-4 compound group (3mg / kg), and II-4 compound group (1mg / kg), and were intragastrically administered at 1ml / 100g. The normal control group and the model group were given the corresponding volume of physiological saline, and the basal value was measured before administration. After a single administration, the mechanical pain threshold was tested at 1, 2, 4, and 6h.

[0213] See also Figure 5 The results showed that, in the neuropathic pain model induced by chemotherapy in SD rats, single administration of Ⅱ-4 compound at three doses of 1mg / kg, 3mg / kg, and 9mg / kg respectively, could increase the mechanical pain threshold of OXA model rats in a dose-dependent manner; 1-2 hours after administration of Ⅱ-4 compound at a dose of 1mg / kg, the mechanical pain threshold of OXA model rats was significantly different from that of the model group (P<0.01); 2-4 hours after administration, 3mg / kg and 9mg / kg of Ⅱ-4 compound increased the mechanical pain threshold of OXA model rats better than pregabalin (Pre) 30.0mg / kg (P<0.05). This shows that Ⅱ-4 compound can more effectively increase the mechanical pain threshold of OXA neuropathic pain model, and the effective time is longer, but pregabalin takes effect faster.

[0214] Example 14 Effect of continuous drug administration for 5 days (d) on the mechanical pain threshold of CCI model rats

[0215] SD male rats, 200-250g, right hind leg, sciatic nerve exposed, sterile chromic gut (No. 4, 0.15mm diameter) was used to loosely ligate 4 loops at the anterior segment of the sciatic nerve before bifurcation, and the muscle and skin were sutured to establish the CCI model. The sham operation group only exposed the sciatic nerve without ligation, and the muscle and skin were sutured. After 3 days of observation, the mechanical pain threshold was tested with an electronic analgesic (IITC-2391) on the 7th day for 2 consecutive days.

[0216] The CCI model rats with stable mechanical pain threshold were randomly divided into 6 groups, namely model group, gabapentin (Gab) group (50 mg / kg), I-10 compound group (3 mg / kg), I-10 compound group (1 mg / kg), and I-10 compound group (0.3 mg / kg). The rats were intragastrically administered with 1 ml / 100 g of normal saline. The sham group (sham) and model group (model) were intragastrically administered with the same volume of normal saline. The basal value was measured before administration. The drug was administered for 5 consecutive days (d). The mechanical pain threshold was measured 2 h after each administration. The results are shown in Figure 6 .

[0217] The results showed that in the CCI neuropathic pain model of SD rats, the I-10 compound was administered at three doses of 0.3 mg / kg, 1 mg / kg, and 3 mg / kg, respectively, which could dose-dependently increase the mechanical pain threshold of the CCI model rats; the I-10 compound was administered at a dose of 1 mg / kg, and the mechanical pain threshold of the CCI model rats was significantly different from that of the model group from 1d to 5d (P<0.01); the gabapentin (Gab) was administered at a dose of 50 mg / kg, and the mechanical pain threshold of the CCI model rats was significantly different from that of the model group from 2d to 5d, indicating that the I-10 compound has good dose dependence and pharmacodynamic stability, and is superior to gabapentin.

[0218] Example 15. Bioavailability

[0219] The results of the pharmacokinetic study of compound I-6 in SD rats (n=3) showed that the half-life T1 / 2 in rats after IV administration (dose of 1.00 mg / kg) was 6.00±1.43 h.

[0220] After PO administration (dose of 10.0 mg / kg), the average peak time of the plasma concentration of I-6 compound in rats was 2.00±1.73h, and the half-life T1 / 2 was 3.79±0.12h.

[0221] The absolute bioavailability of compound I-6 in SD rats was 51.32%.

[0222] Example 16: Safety

[0223] ICR mice (n=4 in each group) were gavaged with I-6 compound. No abnormality was observed in the 64 mg / kg group. One mouse in the 256 mg / kg group had convulsions, which returned to normal on the second day, and no death was observed. One mouse in the 1024 mg / kg group had convulsions and eventually died on the second day, and the median lethal dose was not obtained. This indicates that the LD50 of I-6 compound 50 Greater than 1024 mg / kg, good safety.

Claims

1. Use of phenylquinolinone and flavonoid derivatives in the preparation of drugs for treating peripheral neuropathic pain diseases, characterized in that: The phenylquinolinone and flavonoid derivatives are compounds represented by the following general structural formula (A) or pharmaceutically acceptable salts thereof: Where: X is or One of the following, wherein R1 is selected from H, C 1-3 Alkyl or C 1-3 Alkoxy; R2 is selected from H, hydroxyl or C 1-3 Alkoxy; R3 is selected from H, hydroxyl, C 1-3 Alkyl or C 1-3 Alkoxy; NR'R" is selected from 2. The use according to claim 1, characterized in that: In the general structure (A), when X is NR1, it is a phenylquinolone compound or a pharmaceutically acceptable salt thereof having the following general structure (A1): Where: R1 is selected from H, methyl, ethyl or isopropyl; R2 is selected from H, hydroxyl or methoxy; R3 is selected from H, hydroxyl or methoxy; NR'R" is selected from 3. The use according to claim 1, characterized in that: In the general structure (A), when X is O, it is a flavonoid compound having the following general structure (A2) or a pharmaceutically acceptable salt thereof: Where: R2 is selected from H, hydroxyl or methoxy; R3 is selected from H, hydroxyl or methoxy; NR'R" is selected from 4. The use according to claim 1, characterized in that The phenylquinolone and flavonoid derivatives are compounds having the structural formula described in the following table or pharmaceutically acceptable salts thereof: 。 5. The use according to claim 4, characterized in that The phenylquinolone and flavonoid derivatives are compounds represented by the following structural formula or pharmaceutically acceptable salts thereof:

6. The use according to any one of claims 1 to 5, characterized in that The salt is one of hydrochloride, sulfate, phosphate, hydrobromide, hydroiodide, carbonate, citrate, malate, tartrate, oxalate, lactate, malonate, succinate, glutarate, ketoglutarate, ascorbate, fumarate, maleate, methanesulfonate, p-toluenesulfonate and benzenesulfonate.

7. The use according to claim 1, characterized in that The peripheral neuropathic pain is one of trigeminal neuralgia, glossopharyngeal neuralgia, acute or chronic inflammatory demyelinating polyradiculoneuritis, alcoholic polyneuropathy, chemotherapy-induced polyneuropathy, complex regional pain syndrome, entrapment neuralgia, HIV sensory neuralgia, iatrogenic neuralgia, tumor compression or infiltration neuralgia, nutritional deficiency-related neuralgia, diabetic neuralgia, phantom limb pain, post-herpetic neuralgia, post-radiotherapy plexus pain, radiculopathy, toxic contact-related neuralgia, and post-traumatic neuralgia.

8. The use according to claim 7, characterized in that The peripheral neuropathic pain is selected from chemotherapy-induced polyneuropathy.

9. The use according to claim 7, characterized in that: The peripheral neuropathic pain is selected from diabetic neuropathy.

10. The use according to claim 1, characterized in that The administration route of the drug is selected from oral administration, rectal administration, nasal administration, topical administration or parenteral administration.

11. The use according to claim 10, characterized in that The topical administration is transdermal administration.

12. The use according to claim 10, characterized in that The parenteral administration is carried out by subcutaneous injection, intramuscular injection, intravenous injection or intradermal injection.

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