CN115784983A - 6-amine alkoxy-3,4-dihydroquinolinone derivative, preparation method and application thereof - Google Patents

6-amine alkoxy-3,4-dihydroquinolinone derivative, preparation method and application thereof Download PDF

Info

Publication number
CN115784983A
CN115784983A CN202211577214.6A CN202211577214A CN115784983A CN 115784983 A CN115784983 A CN 115784983A CN 202211577214 A CN202211577214 A CN 202211577214A CN 115784983 A CN115784983 A CN 115784983A
Authority
CN
China
Prior art keywords
dihydroquinolinone
aminoalkoxy
acid
solvent
derivatives
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202211577214.6A
Other languages
Chinese (zh)
Inventor
邓先清
宋明霞
华伊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jinggangshan University
Original Assignee
Jinggangshan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jinggangshan University filed Critical Jinggangshan University
Priority to CN202211577214.6A priority Critical patent/CN115784983A/en
Publication of CN115784983A publication Critical patent/CN115784983A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides a 6-amine alkoxy-3,4-dihydroquinolinone derivative, a preparation method and application thereof, wherein the general structural formula of the derivative is shown as the following formula (I):
Figure DDA0003980046160000011
wherein R is selected from straight chain C 3 ‑C 6 Any one of alkyl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl and 4-bromobenzyl. The compound has significant histamine H 3 Receptor antagonistic activity and exhibit anticonvulsant properties, thereby making them useful as anti-epileptic compounds.

Description

6-amine alkoxy-3,4-dihydroquinolinone derivative, preparation method and application thereof
Technical Field
The invention relates to the field of antiepileptic drugs, and in particular relates to a 6-amine alkoxy-3,4-dihydroquinolinone derivative, and a preparation method and application thereof.
Background
Epilepsy is the second most common disease of the nervous system after cerebrovascular disease. World health organization survey data has shown that the population of epileptic patients worldwide is up to 5000 million, with nearly 80% of epileptic patients in developing countries. Currently, the treatment of epilepsy is still the main drug therapy, and the existing therapeutic drugs mainly surround the sodium ion channel and the relevant action mechanism of gamma-aminobutyric acid/glutamic acid system. Although these drugs are capable of protecting patients from various epileptic convulsions to varying degrees, the seizures in 30% of epileptic patients remain uncontrollable. And the side effect and drug resistance brought by long-term taking of the antiepileptic drug further obstruct the clinical application of the existing drugs. In order to improve the therapeutic effect and eliminate or reduce adverse reactions, it is necessary to study novel antiepileptic drugs having a novel structure and a novel mechanism.
Histamine H 3 Receptors are distributed primarily in the central nervous system. It acts as a presynaptic autoreceptor, mediating the release and synthesis of histamine in different tissues. Histamine H 3 After receptor activation, inhibition of adenylate cyclase by Gi protein, reduction of c-AMP production or inhibition of N-type Ca by Gi protein 2+ Channels, decrease of nerve cell Ca 2+ Internal flow, thereby reducing histamine release. In addition, it is a heteroreceptor that regulates the release of other neurotransmitters, such as acetylcholine acetate, dopamine, norepinephrine, 5-hydroxytryptamine, GABA, etc., and inhibits both N-type and P-type calcium ion channels. Due to H 3 The relative expression of receptors in the central nervous system is very high and is involved in the mediation of functions such as wakefulness, learning and memory, nerve repair and food intake through the functions of autoreceptors and heteroreceptors, which has become a potential target of many central nervous system diseases such as alzheimer's disease, neuropathic pain, depression and epilepsy (Sadek et al, behav brain res.2016,312: 415-430).
Pitolisant is H developed by Bioprojet company 3 Receptor antagonists, approved for marketing in europe for the treatment of narcolepsy at 3 months of 2016. In addition, the drug has completed phase II clinical trials for a number of other indications, including photosensitive Epilepsy, and the results of the trials show that Pitolisant can provide dose-dependent (20-60 mg/kg) relief of photosensitive Epilepsy (Kasteleijn-Nolst Trenit et al, epilepsy Behav.2013,28 (1): 66-70). Pitolisant also showed significant antiepileptic activity in the rat epileptic seizure model (Beheshti et al, neurosporatt.2022, 782: 136685). Histamine H 3 The receptor becomes a new target for researching antiepileptic drugs.
Is currently about histamine H 3 Receptor antagonismThe study of anti-agents in epilepsy is still in its infancy. Development of novel Histamine H 3 The anti-epileptic drugs of the receptor antagonist class have very important significance and value.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a 6-amine alkoxy-3,4-dihydroquinolinone derivative, and a preparation method and application thereof.
In order to achieve the above object, the technical solution of the present invention is as follows.
The 6-amine alkoxy-3,4-dihydroquinolinone derivative has a structural general formula shown as the following formula (I):
Figure BDA0003980046140000021
wherein R is selected from straight chain C 3 -C 6 Any one of alkyl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl and 4-bromobenzyl.
Further, the compound is an addition salt consisting of the compound shown in the general formula (I) and a medicinal acid; the pharmaceutically acceptable acid is any one of hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, methanesulfonic acid and maleic acid.
Further, specific compounds are as follows:
Figure BDA0003980046140000031
the invention also provides a preparation method of the 6-amine alkoxy-3,4-dihydroquinolinone derivative, which comprises the following steps:
Figure BDA0003980046140000032
s1, adding 6-hydroxy-3,4-dihydroquinolinone (a compound shown in formula II), 1-bromo-3-chloropropane and potassium carbonate into a solvent, carrying out reflux reaction under stirring, concentrating to remove the solvent after the reaction is finished, and carrying out purification treatment to obtain an intermediate 1;
s2, mixing the intermediate 1, piperidine and potassium carbonate (K) 2 CO 3 ) Adding potassium iodide (KI) into a solvent, carrying out reflux reaction under stirring, cooling to room temperature after the reaction is finished, filtering, and purifying a filter cake to obtain an intermediate 2;
and S3, adding the intermediate 2, sodium hydroxide and organic halide into a solvent, carrying out reflux reaction under stirring, concentrating to remove the solvent after the reaction is finished, and carrying out extraction and purification treatment to obtain the 6-amine alkoxy-3,4-dihydroquinolinone derivative.
Further, in S1, the molar ratio of 6-hydroxy-3,4-dihydroquinolinone, 1-bromo-3-chloropropane and potassium carbonate is 1:1 to 2:2.
further, in S2, the molar ratio of intermediate 1, piperidine, potassium carbonate and potassium iodide is 1:2:2:1 to 2.
Further, in S3, the molar ratio of the intermediate 2, sodium hydroxide and organic halide is 2:2 to 3:2 to 3.
Further, in S3, the organic halide is R' Br or ArCH 2 Cl and R' are selected from straight chain C 3 -C 6 Ar is any one selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl and 4-bromophenyl.
Further, the solvent in S1-S3 is acetonitrile; the purification treatment in S1 to S3 is carried out by purifying with a silica gel column chromatography using methylene chloride containing 1% to 1.5% of methanol.
Further, in the extraction in S3, water was added to the concentrated substrate, and extracted three times with dichloromethane, and the dichloromethane layers were combined.
The invention also provides application of the 6-amine alkoxy-3,4-dihydroquinolinone derivative in preparing antiepileptic drugs.
The invention has the beneficial effects that:
1. the invention provides a 6-amine alkoxy-3,4-dihydroquinolinone derivative with antiepileptic activity, which has remarkable histamine H 3 Receptor antagonistic activity and exhibitAnticonvulsant properties, which in turn make them useful as anti-epileptic compounds.
2. Histamine H of the compound (Compound 1) is preferred in the present invention 3 Receptor antagonistic Activity IC 50 0.37. Mu.M; histamine H of Pitolisant under the same conditions 3 Receptor antagonistic Activity IC 50 It was 0.69. Mu.M. In the maximal electroshock seizure model, the anticonvulsant activity (i.e., antiepileptic effect) of compound 1 was similar to that of the control drug sodium valproate and better than that of the control drug Pitolisant. And the anticonvulsant activity of compound 1 is dose-dependent. In the pre-administration of histamine H 3 After the receptor agonist RAMH, the anticonvulsant effect of compound 1 disappeared, indicating that its anticonvulsant activity originated from histamine H 3 Antagonism of the receptor.
Drawings
Figure 1 is the experimental results of compound 1 in a mouse model of onset of maximal electrical shock. Average Duration of hind limb rigidity(s) of mice; sodium valproate, sodium valproate; tillow Li Sheng.
Figure 2 is the results of anticonvulsant experiments with compound 1 at various doses. Average Duration of hind limb rigidity(s) of mice; saline, normal Saline; tillow Li Sheng.
Figure 3 is the results of anticonvulsant experiments with compound 1 under RAMH intervention. Average Duration of hind limb rigidity(s) of mice; saline, normal Saline; RAMH: r-alpha-methyl histamine.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
The invention provides a 6-amine alkoxy-3,4-dihydroquinolinone derivative, which has a structural general formula shown in the following formula (I):
Figure BDA0003980046140000061
wherein R is selected from straight chain C 3 -C 6 Any one of alkyl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl and 4-bromobenzyl. Also comprises an addition salt formed by the compound shown in the general formula (I) and a medicinal acid; the pharmaceutically acceptable acid is any one of hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, methanesulfonic acid and maleic acid.
The synthesis of the compound of formula (I) is as follows:
Figure BDA0003980046140000062
the preparation method of the 6-amine alkoxy-3,4-dihydroquinolinone derivative (the compound shown in the formula I) in the invention is as follows:
6-hydroxy-3,4-dihydroquinolinone (compound shown in formula II) and 1-bromo-3-chloropropane take acetonitrile as solvent K 2 CO 3 Heating and reacting to obtain an intermediate 1 as an acid-binding agent; the resulting intermediate 1 is reacted with piperidine at K 2 CO 3 Heating and reacting with KI by using acetonitrile as a solvent to obtain an intermediate 2; the resulting intermediate 2 is reacted with bromoalkane (R' Br) or chloromethyl arene (ArCH) 2 Cl) under the action of NaOH and acetonitrile as a solvent, heating and reacting to obtain the 6-amine alkoxy-3,4-dihydroquinolinone derivative (the compound shown in the formula I), wherein R' is selected from straight chain C 3 -C 6 Ar is any one selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl and 4-bromophenyl.
The following examples of compound 1 and compound 5 are provided to illustrate the preparation of the compound represented by formula (I), and other compounds can be prepared by the same method.
Example 1
The synthesis method of the intermediate 1 comprises the following steps:
6-hydroxy-3,4-dihydroquinolinone, 1-bromo-3-chloropropane and potassium carbonate were added at a molar ratio of 1.2. The melting point is 99-102 ℃, and the yield is 79%.
1 H-NMR(CDCl 3 ,300MHz):δ2.19-2.27(m,2H,OCH 2 CH 2 ),2.63(t,2H,J＝8.5Hz,CH 2 ),2.95(t,2H,J＝8.5Hz,CH 2 ),3.75(t,2H,J＝6.3Hz,ClCH 2 ),4.09(t,2H,J＝6.3Hz,OCH 2 ),6.71-6.81(m,3H,Ph-H),9.32(s,1H,NH).
13 C-NMR(DMSO-d 6 ,75MHz):δ171.9,154.7,131.1,125.0,116.4,114.5,113.2,64.7,41.5,32.3,30.6,25.7.ESI-HRMS calcd for C 12 H 15 ClNO 2 + ([M+H] + ):240.0786；found:240.0791.
Example 2
A method for synthesizing intermediate 2, comprising the steps of:
intermediate 1, piperidine, potassium carbonate and potassium iodide were added to a round bottom flask containing 20mL of acetonitrile at a molar ratio of 1. The melting point is 138-140 ℃, and the yield is 78%.
1 H-NMR(DMSO-d 6 ,300MHz):δ1.79-1.88(t,2H,CH 2 ),2.38(t,2H,J＝7.4Hz,CH 2 ),2.47-2.60(m,6H,CH 2 ),2.60(s,4H,CH 2 ),2.82(t,2H,J＝7.4Hz,CH 2 ),3.09(s,4H,N-CH 2 ),3.24(s,2H,N-CH 2 ),3.93(t,2H,J＝6.2Hz,O-CH 2 ),6.69-6.77(m,3H,Ph-H),9.89(s,1H,N-H).
13 C-NMR(DMSO-d 6 ,75MHz):δ170.20,154.19,132.18,125.29,116.23,114.51,113.49,66.29,54.48,49.76,43.43,41.15,30.83,26.40,25.56.
ESI-HRMS calcd for C 17 H 25 N 2 O 2 + ([M+H] + ) 289.1911; found 289.1912 example 3
A method of synthesizing compound 1, comprising the steps of:
Figure BDA0003980046140000081
sodium hydroxide (3 mmol), intermediate 2 (2 mmol) and bromopropane (3 mmol) were added to a round bottom flask containing 20mL acetonitrile, stirred and refluxed for 24h, after evaporation of the solvent, 50mL water was added to the flask, extracted three times with dichloromethane (30 mL. Times.3), the dichloromethane layers were combined, anhydrous MgSO 4 Drying and evaporation of the solvent gave the crude product which was purified by column chromatography on silica gel (1% methanol in dichloromethane) to give compound 1. Oil, yield 78%.
1 H-NMR(CDCl 3 ,300MHz):δ0.87(t,3H,J＝7.5Hz,CH 3 ),1.51-1.63(m,4H,CH 2 ),1.77-1.85(m,4H,CH 2 ),2.12-2.21(m,2H,CH 2 ),2.52(t,2H,J＝7.4Hz,CH 2 ),2.75-2.85(m,8H,CH 2 ),3.78(t,2H,J＝7.5Hz,N-CH 2 ),3.96(t,2H,J＝6.1Hz,O-CH 2 ),6.65-6.83(m,3H,Ph-H).
13 C-NMR(CDCl 3 ,75MHz):δ169.63,154.01,133.25,128.12,115.77,114.49,112.61,65.92,55.49,53.91,43.56,31.34,25.76,25.14,23.97,22.97,20.34,11,14.ESI-HRMS calcd for C 20 H 31 N 2 O 2 + ([M+H] + ):331.2380；found:331.2381.
Example 4
A method of synthesizing compound 5 comprising the steps of:
Figure BDA0003980046140000091
sodium hydride (6 mmol), intermediate 2 (2 mmol) and benzyl chloride (3 mmol) were added to a round bottom flask containing 20mL of acetonitrile, stirred and refluxed for 24h. After the solvent was distilled off, 50mL of water was added to the flask, and the mixture was extracted three times with methylene chloride (30 mL. Times.3). The dichloromethane layers were combined, anhydrous MgSO 4 Drying and evaporation of the solvent gave the crude product. Purification by silica gel column chromatography (1% methanol in dichloromethane) afforded compound 5. Oil, yield 66%.
1 H-NMR(CDCl 3 ,400MHz):δ1.43-1.50(m,2H,CH 3 ),1.63-1.69(m,4H,CH 2 ),1.97-2.05(m,2H,CH 2 ),2.50-2.57(m,6H,CH 2 ),2.76(t,2H,J＝7.1Hz,CH 2 ),2.93(t,2H,J＝7.4Hz,CH 2 ),3.94(t,2H,J＝6.3Hz,OCH 2 ),5.15(s,2H，NCH 2 Ph),6.60(dd,1H,J1＝2.8Hz,J2＝8.8Hz,Ph-H),6.72(d,1H,J＝2.8Hz,Ph-H),6.76(d,1H,J＝8.8Hz,Ph-H),7.19-7.32(m,5H,Ph-H).
13 C-NMR(101MHz,CDCl 3 )δ170.15,154.58,137.05,133.3,128.69,127.83,127.00,126.35,116.48,114.44,112.51,66.50,55.85,54.44,46.19,31.85,26.31,25.80,25.37,24.02.ESI-HRMS calcd for C 24 H 30 N 2 O 2 Na + ([M+Na] + ):401.2199；found:401.2213.
The properties of the compounds prepared in inventive example 3 and example 4 are essentially identical, so that histamine H was performed only on compound 1 prepared in inventive example 3 3 Receptor antagonistic activity and anticonvulsant activity in mice.
1. Histamine H 3 Determination of receptor antagonistic Activity:
will react with histamine H 3 Stable HEK-293T cells co-transfected with receptor and pCRE-Luc were seeded in 96-well plates overnight and grown to 90-95% confluency. The cells were then treated with varying concentrations of the test compound in serum-free DMEM (serum-free cell freezing medium) and incubated for 20 minutes. Then adding the mixture containing Forskolin (final concentration)Degree 2. Mu.M) and histamine (final concentration 100 nM) in serum-free DMEM and incubated at 37 ℃ for 4 hours. Measuring luciferase activity with firefly luciferase assay kit, and calculating histamine H of the compound 3 Receptor antagonistic Activity IC 50 。
The results show that most compounds exhibit better histamine H 3 Receptor antagonistic Activity, wherein IC of Compound 1 50 IC of Pitolisant at 0.37. Mu.M under the same conditions 50 It was 0.69. Mu.M.
2. Determination of anticonvulsant Activity in mice:
the Maximal Electroshock Seizure (MES) model was used to determine the efficacy of compounds against generalized seizures. The compound is used for inhibiting or delaying epileptic seizure by being administrated to the abdominal cavity of a mouse.
The specific method comprises the following steps: 18-22g Kunming mice were selected and injected intraperitoneally with test compound 1 (10 mg/kg), plus the positive drugs Pitolisant (10 mg/kg) and sodium valproate (300 mg/kg). Half an hour later, the mice were stimulated by alternating current (0.2 sec, 60 hz, 50 ma) through both ears to induce tonic seizures. The test compound at this dose is considered to have a protective effect on MES-induced convulsions in mice that have had a reduced or absent hindlimb hyperextension Time (THLE) after administration. The results are shown in FIGS. 1 to 3.
Figure 1 is the experimental results of compound 1 in a mouse model of onset of maximal electrical shock. Figure 2 is the results of anticonvulsant experiments with compound 1 at various doses. Figure 3 is the results of an anticonvulsant experiment of compound 1 under RAMH (R- α -methyl histamine) intervention.
As shown by the results of fig. 1 to 3, the anticonvulsant activity (i.e., antiepileptic effect) of compound 1 was superior to that of the control drugs Pitolisant and sodium valproate, 10mg/kg of compound 1 gave a protective effect equivalent to that of 300mg/kg of sodium valproate (see fig. 1), and the anticonvulsant activity of compound 1 was dose-dependent (see fig. 2). In addition, histamine H was administered in advance 3 After the receptor agonist RAMH, the anticonvulsant effect of compound 1 disappeared, indicating that its anticonvulsant activity originated from histamine H 3 Antagonism of the receptor (see figure 3).
The present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

  1. The 1.6-amine alkoxy-3,4-dihydroquinolinone derivative is characterized in that the general structural formula is shown as the following formula (I):
    Figure FDA0003980046130000011
    wherein R is selected from straight chain C 3 -C 6 Any one of alkyl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl and 4-bromobenzyl.
  2. 2. The 6-aminoalkoxy-3,4-dihydroquinolinone derivative according to claim 1, which is an addition salt of a compound represented by the general formula (I) with a pharmaceutically acceptable acid; the pharmaceutically acceptable acid is any one of hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, methanesulfonic acid and maleic acid.
  3. 3. The process for the preparation of 6-aminoalkoxy-3,4-dihydroquinolinone derivatives as claimed in claim 1, comprising the steps of:
    s1, adding 6-hydroxy-3,4-dihydroquinolinone, 1-bromo-3-chloropropane and potassium carbonate into a solvent, carrying out reflux reaction under stirring, concentrating to remove the solvent after the reaction is finished, and carrying out purification treatment to obtain an intermediate 1;
    s2, adding the intermediate 1, piperidine, potassium carbonate and potassium iodide into a solvent, carrying out reflux reaction under stirring, cooling to room temperature after the reaction is finished, filtering, and purifying a filter cake to obtain an intermediate 2;
    and S3, adding the intermediate 2, sodium hydroxide and organic halide into a solvent, carrying out reflux reaction under stirring, concentrating to remove the solvent after the reaction is finished, and carrying out extraction and purification treatment to obtain the 6-amine alkoxy-3,4-dihydroquinolinone derivative.
  4. 4. The process for preparing 6-aminoalkoxy-3,4-dihydroquinolinone derivatives as claimed in claim 3, wherein the molar ratio of 6-hydroxy-3,4-dihydroquinolinone, 1-bromo-3-chloropropane and potassium carbonate in S1 is 1:1 to 2:2.
  5. 5. the process for preparing 6-aminoalkoxy-3,4-dihydroquinolinone derivatives as claimed in claim 3, wherein in S2, the molar ratio of intermediate 1, piperidine, potassium carbonate and potassium iodide is 1:2:2:1 to 2.
  6. 6. The process for preparing 6-aminoalkoxy-3,4-dihydroquinolinone derivatives as claimed in claim 3, wherein in S3, the molar ratio of intermediate 2, sodium hydroxide and organic halide is 2:2 to 3:2 to 3.
  7. 7. The method for preparing 6-aminoalkoxy-3,4-dihydroquinolinone derivatives as in claim 3, wherein in S3, said organic halide is R' Br or ArCH 2 Cl and R' are selected from straight chain C 3 -C 6 Ar is any one selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl and 4-bromophenyl.
  8. 8. The method for preparing 6-aminoalkoxy-3,4-dihydroquinolinone derivatives as in claim 3, wherein the solvent in S1 to S3 is acetonitrile;
    the purification treatment in S1 to S3 is carried out by purifying with a silica gel column chromatography using methylene chloride containing 1% to 1.5% of methanol.
  9. 9. The method for producing 6-aminoalkoxy-3,4-dihydroquinolinone derivatives as in claim 3, wherein the extraction in S3 is to add water to the concentrated substrate and extract three times with dichloromethane, and the dichloromethane layers are combined.
  10. 10. The use of the 6-aminoalkoxy-3,4-dihydroquinolinone derivative of claims 1 or 2 in the preparation of an antiepileptic drug.
CN202211577214.6A 2022-12-05 2022-12-05 6-amine alkoxy-3,4-dihydroquinolinone derivative, preparation method and application thereof Pending CN115784983A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202211577214.6A CN115784983A (en) 2022-12-05 2022-12-05 6-amine alkoxy-3,4-dihydroquinolinone derivative, preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202211577214.6A CN115784983A (en) 2022-12-05 2022-12-05 6-amine alkoxy-3,4-dihydroquinolinone derivative, preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN115784983A true CN115784983A (en) 2023-03-14

Family

ID=85419083

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202211577214.6A Pending CN115784983A (en) 2022-12-05 2022-12-05 6-amine alkoxy-3,4-dihydroquinolinone derivative, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN115784983A (en)

Similar Documents

Publication Publication Date Title
JP6838773B2 (en) Pyrimidinyl derivative of anti-influenza virus
CN102264707A (en) Novel bicyclic heterocyclic compound
JP2019529386A5 (en)
JP5851053B2 (en) Anti-tumor azabenzo [f] azulene derivatives and method for producing the same
JPH0240069B2 (en)
NO147104B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ACETYLENDER DERIVATIVES OF AMINO ACIDS
CA3213289A1 (en) Phenalkylamines and methods of making and using the same
KR20110139274A (en) Methods for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid and precursors thereof
CZ292947B6 (en) Process for preparing substituted piperidines and novel intermediates of such process
CN103649060A (en) Process
Plazinska et al. Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β2-adrenergic receptor
EP0413667A1 (en) Halogenoalkyl-phenyl-alcohols, -ketones and their hydrates
EP0296321B1 (en) Synthesis of cisplatinum analogs
CN115784983A (en) 6-amine alkoxy-3,4-dihydroquinolinone derivative, preparation method and application thereof
FR2593818A1 (en) ACYLAMINOMETHYL-3 IMIDAZO (1,2-A) PYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
NO152787B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PHENYL-CHINOLIZIDINES
EP0415634A2 (en) Benzazabicyclic carbamates as cholinesterase inhibitors
US4612312A (en) Glutarimide antianxiety and antihypertensive agents
NZ222382A (en) Diazole derivatives and pharmaceutical compositions
US5173502A (en) Substituted trifluoropropan-1-yl-imidazole alpha 2-receptor anagonists
JP2017530958A (en) Aminosulfonyl compounds, methods for their production, and uses
WO2003037904A1 (en) Novel 3beta-amino azabicyclooctane heteroaromatic amide derivatives, preparation method and therapeutic uses thereof
CN106220607B (en) A kind of synthetic method of S-3- (piperidin-2-yl)-aza-cyclobutane -3-alcohol
AU686722B2 (en) Heterocyclic compounds
CA2005547C (en) Derivatives of 1,7' (imidazo-(1,2-a)-pyridine)5'-(6'h)ones

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination