CN115475161B - Application of pyran compounds in preparation of medicines for preventing and/or treating parkinsonism - Google Patents
Application of pyran compounds in preparation of medicines for preventing and/or treating parkinsonism Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
Abstract
The invention discloses application of a pyran compound in preparation of a medicament for preventing and/or treating parkinsonism, wherein the structural formula of the pyran compound is shown as a formula I:wherein n is 0 or 1; r is R 1 Selected from H, C 1～6 Alkyl, halogen, C 1～6 Alkoxy, C 1～6 A haloalkyl group of (2); r is R 2 Selected from H, C 1～6 Alkyl, phenyl; r is R 3 Selected from H, halogen, C 1～6 Alkoxy groups of (a). The invention discovers that the pyran compound has antioxidant activity, can effectively reduce the ROS level of transgenic nematode NL5901, can effectively reduce the accumulation of alpha-synuclein and save the degeneration of dopamine neurons induced by 6-OHDA, has a therapeutic effect on nematodes in a Parkinson disease model, has a protective effect on neurons, and can be used for preventing and/or treating Parkinson disease.
Description
Technical Field
The invention relates to the technical field of anti-parkinsonism medicaments, in particular to application of a pyran compound in preparation of a medicament for preventing and/or treating parkinsonism.
Background
Parkinson's Disease (PD) is a kind of neurodegenerative disease, and its typical clinical pathological features are a central substantia nigra dense dopamine (dopamine) capable of neurodegenerative deficiency and a lewis body formed by abnormal accumulation of α -synuclein in neurons, which usually results in involuntary manifestations of motor symptoms such as bradykinesia, myotonia, resting tremor and abnormal posture gait of patients, and also accompanies some non-motor symptoms such as gastrointestinal dysfunction, hypoolfaction, depression symptoms, rapid eye sleep stage behavioral disorder, etc. At present, the pathogenesis of PD is not clear, and no medicine which can finally reverse, prevent or slow down the degeneration process of nigra dopaminergic neurons of PD patients exists clinically. Traditional PD treatment drugs mainly include: levodopa and its compound dopa preparation, dopamine receptor agonist, anticholinergic medicine, monoamine oxidase inhibitor, etc. The medicines play roles in inhibiting parkinsonism symptoms through different ways, can obviously improve parkinsonism symptoms, but cannot delay the progress of the diseases, cannot prevent degeneration of dopaminergic neurons, and have serious toxic and side effects even cause disease deterioration after long-term application.
According to the analysis of the current application situation of the medicine, whether the symptom is improved or the disease development is inhibited, the prevention of the occurrence of the disease or the treatment of the parkinsonism are all the requirements of clinical treatment.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art. Therefore, the invention provides application of a pyran compound in preparing a medicament for preventing and/or treating parkinsonism.
The invention also provides application of the pyran compound in preparing a medicament for preventing and/or treating dopaminergic neuron injury.
The invention also provides application of the pyran compound in preparing a medicament for preventing and/or treating related diseases induced by alpha-synuclein.
The invention also provides a pharmaceutical composition for preventing and/or treating parkinsonism.
The pyran compound according to the first aspect of the present invention is used for preparing a medicament for preventing and/or treating parkinson's disease, and the pyran compound has a structural formula shown in formula i:
wherein n is 0 or 1;
R 1 selected from H, C 1～6 Alkyl, halogen, C 1～6 Alkoxy, C 1～6 A haloalkyl group of (2);
R 2 selected from H, C 1～6 Alkyl, phenyl;
R 3 selected from H, halogen, C 1～6 Alkoxy groups of (a).
The application according to the embodiment of the invention has at least the following beneficial effects:
the invention discovers that the pyran compound has antioxidant activity, can effectively reduce the ROS level of transgenic nematode NL5901, can effectively reduce the accumulation of alpha-synuclein and save the degeneration of dopamine neurons induced by 6-OHDA, has a therapeutic effect on nematodes in a Parkinson disease model, has a protective effect on neurons, and can be used for preventing and/or treating Parkinson disease.
According to some embodiments of the invention, R 1 Selected from H, methyl, F, methoxy; r is R 3 Selected from H and halogen.
According to some embodiments of the invention, the pyran compound is selected from one of the following structural formulas:
according to some embodiments of the invention, the pyran compound may be obtained commercially or may be prepared with reference to patent CN113150006 a.
According to some embodiments of the invention, the parkinson's disease drug is for the treatment of α -synuclein-induced parkinson's disease.
According to some embodiments of the invention, the parkinson's disease drug is used to treat parkinson's disease caused by dopaminergic neuronal damage.
In a second aspect, the present invention provides a use of a pyran compound in the manufacture of a medicament for the prevention and/or treatment of dopaminergic neuronal damage.
In a third aspect, embodiments of the present invention provide for the use of a pyran compound in the manufacture of a medicament for the prevention and/or treatment of a disorder associated with the induction of alpha-synuclein.
In a fourth aspect, the present invention provides a pharmaceutical composition for preventing and/or treating parkinson's disease, comprising a prophylactically or therapeutically effective amount of a pyranoid compound, and a pharmaceutically acceptable adjuvant.
According to some embodiments of the invention, the adjuvant comprises at least one of a slow release agent, a filler, a binder, a wetting agent, a disintegrant, an adsorption carrier, an absorbent, a surfactant, or a lubricant.
According to some embodiments of the invention, the pharmaceutical composition is in a dosage form selected from at least one of a solution, suspension, emulsion, pill, tablet, capsule, powder or sustained release formulation.
Definitions and general terms
“C 1-6 Alkyl "of (C) represents an alkyl group having 1 to 6 total carbon atoms including C 1-6 Straight chain alkyl, C 1-6 Branched alkyl and C of (2) 3-6 For example, a straight-chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, a branched-chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, or a cycloalkyl group having 3, 4, 5 or 6 carbon atoms, and for example, a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, cyclopropyl group, methylcyclopropyl group, ethylcyclopropyl group, cyclopentyl group, methylcyclopentyl group, cyclohexyl group, or the like may be mentioned.
“C 1-6 Alkoxy "of (C) represents an alkoxy group having 1 to 6 total carbon atoms, including C 1-6 Straight-chain alkoxy, C 1-6 Branched alkoxy and C 2-6 For example, a linear alkoxy group having a total of 1, 2, 3, 4, 5 or 6 carbon atoms, a branched alkoxy group having a total of 1, 2, 3, 4, 5 or 6 carbon atoms, or a cyclic alkoxy group having a total of 2, 3, 4, 5 or 6 carbon atoms, for exampleCan be methoxy, ethoxy, n-propoxy, isopropoxy and the like.
"halogen" includes any one or more of fluorine, chlorine, bromine, iodine.
“C 1～6 "haloalkyl" of (C) represents a haloalkyl group having a total of 1 to 6 carbon atoms which is substituted with one or more halogen atoms which may be the same or different, e.g. -CH 2 Cl、-CF 3 、-CCl 3 、-CH 2 CF 3 、-CH 2 CCl 3 Etc.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
The foregoing and/or additional aspects and advantages of the invention will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:
FIG. 1 is a graph showing the antioxidant activity of the compounds prepared in examples 1 to 6;
FIG. 2 is a graph showing the concentration of antioxidant activity of the compound prepared in example 1;
FIG. 3 is a graph showing the effect of different concentrations of compound on ROS accumulation in example 1;
FIG. 4 is a graph showing the effect of the compound prepared in example 1 on α -synuclein;
FIG. 5 is a graph showing the effect of the compound prepared in example 1 on dopamine neurons.
Detailed Description
The following are specific embodiments of the present invention, and the technical solutions of the present invention will be further described with reference to the embodiments, but the present invention is not limited to these embodiments.
The reagents, methods and apparatus employed in the present invention, unless otherwise specified, are all conventional in the art.
Example 1
Example 1 provides a pyran compound (I-1) of the formula:
the preparation method is prepared according to the method for preparing the compound 7r disclosed in CN 113150006A.
Example 2
Example 2 provides a pyran compound (I-2) of the formula:
the preparation method is prepared according to the method for preparing the compound 7c disclosed in CN 113150006A.
Example 3
Example 3 provides a pyran compound (I-3) of the formula:
the preparation method is prepared according to the method for preparing the compound 7e disclosed in CN 113150006A.
Example 4
Example 4 provides a pyran compound (I-4) of the formula:
the preparation method is prepared according to the method for preparing 7g of compound disclosed in CN 113150006A.
Example 5
Example 5 provides a pyran compound (I-5) of the formula:
the preparation method is prepared according to the method for preparing the compound 7m disclosed in CN 113150006A.
Example 6
Example 6 provides a pyran compound (I-6) of the formula:
the preparation method is prepared according to the method for preparing the compound 7n disclosed in CN 113150006A.
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the pyran compounds (I-1) to (I-6) in examples 1 to 6 are as follows:
product (I-1): 1 H NMR(500MHz,CDCl 3 ):δ7.59-7.21(m,11H),7.15(d,J＝8.7Hz,2H),6.71(d,J＝8.7Hz,2H),5.73(s,1H),2.67(s,2H),2.57-2.39ppm(m,2H). 13 C{ 1 H}NMR(126MHz,CDCl 3 ):δ200.2,156.7,143.6,135.7,134.4,128.8,128.3,128.2,128.1,128.1,127.7,126.8,121.8,115.3,34.0ppm.IR:2883,1752,1669,1575,1512,1406,1259,1080,935,691,599cm -1 .HRMS(ESI)m/z:[M+H] + calcd for C 26 H 21 O 3 381.1485; found,381.1484. Yield 58%.
Product (I-2): 1 H NMR(500MHz,CDCl 3 ):δ7.44-7.23(m,6H),7.23-7.14(m,4H),7.08(d,J＝7.9Hz,2H),6.58(d,J＝8.6Hz,2H),5.64(s,1H),2.58(d,J＝18.3Hz,1H),2.52-2.40(m,1H),2.38-2.15(m,5H),2.06-1.87ppm(m,2H). 13 C{ 1 H}NMR(126MHz,CDCl 3 ):δ194.9,174.1,156.3,144.1,137.0,136.2,134.3,133.9,128.6,128.4,128.1,127.7,126.9,126.6,122.6,115.0,114.0,85.6,37.1,29.4,21.2,19.8ppm.IR:2881,1760,1646,1568,1075,1293,939,795,729,673,543cm -1 .HRMS(ESI)m/z:[M+H] + calcd for C 28 H 25 O 3 ,409.1798；faround 409.1791, 99% yield.
Product (I-3): 1 H NMR(500MHz,CDCl 3 ):δ7.36(d,J＝7.2Hz,2H),7.31(t,J＝7.4Hz,2H),7.27(d,J＝7.0Hz,1H),7.23-7.15(m,4H),6.95(s,1H),6.82(d,J＝8.7Hz,2H),6.61(d,J＝8.5Hz,2H),5.62(s,1H),3.72(s,3H),2.53(dd,J＝66.3,18.1Hz,2H),2.39-2.17(m,2H),1.99ppm(dd,J＝11.1,5.6Hz,2H). 13 C{ 1 H}NMR(126MHz,CDCl 3 ):δ194.6,173.8,158.9,156.0,144.1,134.8,133.8,131.5,128.7,128.2,128.1,127.7,126.7,122.0,115.0,114.1,113.2,85.5,55.2,37.3,29.4,19.9ppm.IR:υ＝3117,2941,1712,1653,1569,1304,1075,1021,943,883,794,670,540cm -1 .HRMS(ESI)m/z:[M+H] + calcd for C 28 H 25 O 4 425.1747; found,425.1739. Yield 94%.
Product (I-4): 1 HNMR(500MHz,DMSO-d 6 ):δ9.57(s,1H),7.55-7.02(m,11H),6.73(d,J＝8.5Hz,2H),5.98(s,1H),2.71-2.54(m,2H),2.26-2.07(m,2H),2.04-1.84ppm(m,2H). 13 C{ 1 H}NMR(126MHz,DMSO-d 6 ):δ192.6,173.1,161.7(1JC-F＝241.9Hz),157.1,144.1,141.71,141.65,133.8,132.3,129.3,129.2,128.3,127.8,127.7,126.0,124.1,123.4,115.0,114.1,114.0,113.7,113.5,112.9,84.2,37.0,28.6,19.4ppm. 19 F NMR(471MHz,DMSO-d 6 ):δ-114.8ppm.IR:2882,1753,1649,1570,1388,1272,938,791,732,661cm -1 .HRMS(ESI)m/z:[M+H] + calcd for C 27 H 22 FO 3 413.1547; found,413.1540. Yield 84%.
Product (I-5): 1 H NMR(500MHz,CDCl3):δ7.42-7.20(m,9H),7.15(d,J＝8.6Hz,2H),7.00(t,J＝8.6Hz,2H),6.58(d,J＝8.6Hz,2H),5.61(s,1H),2.66-2.40(m,2H),2.31(qd,J＝16.6,10.3Hz,2H),2.03-1.91ppm(m,2H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )195.0,174.2,162.1(1JC-F＝247.2Hz),156.5,139.8,138.9,134.2,133.8,128.64,128.57,128.4,127.8,127.4,127.0,122.8,115.1,115.0,114.9,114.0,85.3,37.0,29.3,19.7ppm.19F NMR(471MHz,CDCl 3 ):δ-114.5ppm.IR:2884,1758,1651,1570,1309,1073,934,794,726,675cm -1 .HRMS(ESI)m/z:[M+H] + calcd for C 27 H 22 FO 3 413.1547; found,413.1539. Yield 88%.
Product (I-6): 1 H NMR(500MHz,CDCl 3 ):δ7.33-7.21(m,10H),7.15(d,J＝8.6Hz,2H),7.13(s,1H),6.59(d,J＝8.6Hz,2H),5.60(s,1H),2.51(ddd,J＝25.0,18.8,12.8Hz,2H),2.39-2.20(m,2H),2.08-1.90ppm(m,2H). 13 C{ 1 H}NMR(126MHz,CDCl 3 ):δ194.9,174.0,156.5,142.6,138.9,134.5,133.7,128.5,128.3,128.1,127.8,127.4,127.0,122.5,115.2,114.1,85.1,37.1,29.3,19.8ppm.IR:2882,1757,1649,1570,1241,1073,946,723,674,541cm -1 .HRMS(ESI)m/z:[M+H] + calcd for C 27 H 22 ClO 3 429.1252; found,429.1246. Yield 77%.
Performance detection
1. Antioxidant Activity assay
The pyran compounds prepared in examples 1-6 were used for the detection of antioxidant activity by first preparing a reagent solution, dissolving a sample in DMSO and diluting with ultrapure water to obtain 50. Mu.M of the sample to be tested, simultaneously preparing 50. Mu.M of a positive control VC solution and 75mM PBS buffer solution of pH7.4 with ultrapure water, then preparing 1M of a standard solution VE with PBS and diluting to obtain VE solutions of 0.1, 0.08, 0.06, 0.04 and 0.02mM, and FLA solution, FL solution B and 153mM AAPH solution, wherein PBS, A and B solutions are stored in a refrigerator at 4 ℃ in the dark, finally accurately sucking 500. Mu.L of FL solution B, fixing volume to 25mL with 75mM PBS, shaking and keeping away from light to obtain FL working solution in the dark. And finally, sample adding detection: adding 50 mu L of samples to be tested, positive control VC and standard sample VE with different concentrations into a 96-well plate, adding 100 mu L of FL working solution in a dark place, placing into an enzyme-labeled instrument, measuring with excitation wavelength of 485nm and absorption wavelength of 535nm as an initial fluorescence value (marked as F0), then oscillating an incubator at 37 ℃ for 3min, incubating for 10min, finally rapidly adding 50 mu L of AAPH solution to start reaction, rapidly placing into the enzyme-labeled instrument, starting hole dynamics with excitation wavelength of 485nm and absorption wavelength of 535nm, and measuring the fluorescence value (marked as Fn) every 2min for 30s in the detection process until the fluorescence value decays to a straight line. Simultaneously, 50. Mu.L of 75mM PBS solution was added in place of the sample as a blank. The standard curve and the total antioxidant capacity index were calculated according to the following formulas:
AUC＝2×(F1+F2+F3+…+Fn)-F1-Fn
NetAUCSample＝AUCSample-AUCblank
wherein the Trolox standard curve is plotted with the concentration of the standard sample VE as X-axis and NetAUCVE as Y-axis. The same experiment needs to be repeated 3 times, the result is expressed by equivalent mu M of water-soluble vitamin E Trolox, netAUCSample is substituted into a linear equation of Trolox for calculation, and the ORAC value of the sample is obtained, namely the oxidative free radical absorption capacity of the sample is recorded as mu M TE/g DW.
As a result, as shown in FIG. 1, 50. Mu.M of compound (I-1) (P < 0.01), (I-2) (P < 0.01), (I-3) (P < 0.001), (I-4) (P < 0.01), (I-5) (P < 0.001), (I-6) (P < 0.001) was statistically stronger in the antioxidant capacity against the free radical than the positive control VC (52.19.+ -. 1.90. Mu.M TE/g DW) of the same concentration, wherein compound (I-1) (80.16.+ -. 2.73. Mu.M TE/g DW) was the most potent.
Further, the concentration of the antioxidant activity of the compound (I-1) was studied, and as a result, as shown in FIG. 2, in the in vitro antioxidant activity test, the scavenging ability of 20. Mu.M of the compound (I-1) (262.81.+ -. 2.55. Mu.M TE/g DW) to oxygen radicals was strongest compared to 20. Mu.M of VC (24.42.+ -. 2.78. Mu.M TE/g DW), and thus the concentration range in the in vivo experiment was between 5. Mu.M and 40. Mu.M.
2. Compound (I-1) reduces ROS accumulation in transgenic nematode NL5901 nematodes
Verification of Compound (I-1) for antioxidant Activity in vivo and therapeutic action on Parkinson's disease Using nematodes, the effect of Compound (I-1) on ROS levels in vivo in nematodes was examined using four concentration gradients of 5. Mu.M, 10. Mu.M, 20. Mu.M, 40. Mu.M designed by double dilutionAnd (5) simultaneously screening the optimal concentration of the in-vivo experiment. Immersing the synchronized eggs of nematodes in sample solution of each concentration, incubating at 20deg.C for 48h, inoculating the incubated L1 stage nematodes on 9cm NGM medium, culturing at 20deg.C until 3-4d to L4 stage, collecting nematode sample, staining, washing with M9 buffer for three times, absorbing supernatant, and washing with M9 to obtain 1mM Mitosox TM Diluting Red stock solution at 1:1000, transferring the washed nematodes into a staining solution, centrifuging at 1000rpm for 3min after 20min, discarding supernatant, repeatedly washing with M9 buffer solution for 3 times, sucking supernatant, and adding appropriate amount of NaN 3 The nematodes were paralyzed, blocked with agarose, observed under a BX63 bioluminescence microscope (normal) in RFP mode, whole insects were photographed at 10X, and pictures were taken and analyzed for fluorescence quantification using imageJ software.
As a result, as shown in FIG. 3, compound (I-1) was able to regulate the ROS level in NL5901 nematodes, had antioxidant activity, and compared to the control group (100% + -2.79), 5. Mu.M compound (I-1) (95.76% + -7.38) did not statistically differ in the reduction of ROS levels (P > 0.05), whereas the optimal concentration was 10. Mu.M (77.35% + -1.05), and 22.65% (P < 0.005) was reduced in NL5901 ROS levels.
3. Compound (I-1) reduces aggregation of alpha-Syn in transgenic nematode NL5901
The main pathological features of Parkinson's Disease (PD) are the reduced number of DA-capable neurons of the substantia nigra compacta (substantia nigrapars compacta, SNc), leading to neurological dysfunction, and aggregation of Lewy bodies, consisting mainly of alpha-Synuclein (alpha-Syn). Therefore, the method utilizes transgenic nematode NL5901 of PD model to verify the influence of compound (I-1) on alpha-Syn, the eggs synchronized with the nematodes are soaked in a sample solution with the final concentration of 10 mu M, incubated for 48h at 20 ℃, then the incubated L1-stage nematodes are inoculated on 9cm NGM medium, the culture is continued at 20 ℃ until 3-4d to L4 stage, the nematodes are collected, the nematodes are repeatedly washed for 3 times by M9 buffer, the supernatant is sucked, then a proper amount of NaN3 paralyzed nematodes are added, agarose is used for sealing, GFP mode is selected for observation under BX63 biological fluorescence microscope (positive setting), 20X is adopted for shooting head alpha-Synucelin, pictures are taken, and image J software is used for fluorescence quantitative analysis.
As a result, as shown in FIG. 4, 10. Mu.M of Compound (I-1) (78.70% + -9.74) significantly reduced the accumulation of alpha-Syn in NL5901 nematodes by 21.06% (P < 0.01) compared to the control group (99.76% + -1.84). This demonstrates that compound (I-1) can reduce the aggregation of alpha-Syn in the PD model and can exert a therapeutic effect on one of the pathologies of PD.
4. Compound (I-1) has protective effect on dopamine neuron injury induced by 6-OHDA
It has been demonstrated that 10. Mu.M compound (I-1) significantly reduces the aggregation of alpha-Syn in NL5901, next we verified whether the compound has a protective effect on neuronal damage using the 6-OHDA-induced transgenic nematode BZ555 model, soaked nematode synchronized eggs in a sample solution with a final concentration of 10. Mu.M for 48h at 20℃and then inoculated the incubated L1 phase of small nematodes onto 9cm NGM medium for further incubation at 20℃for 2-3d to L3 phase, collected nematodes, washed repeatedly 3 times with M9 buffer and aspirated supernatant, then exposed to 50mM 6-OHDA1h in a tinfoil seal, and shaken once every 10 min. Finally, after three times of washing with M9 buffer solution, inoculating on a UFDR-NGM plate for 3d culture at 20 ℃, washing with M9 buffer solution, adding a proper amount of NaN3 paralyzed nematodes, sealing with agarose, selecting GFP mode under a BX63 bioluminescence microscope (forward), observing, taking pictures by taking DA neurons at the head and tail with 20X, and performing fluorescent quantitative analysis by using imageJ software.
As a result, as shown in FIG. 5, fluorescence quantification was performed on 8 dopaminergic neurons of BZ555 nematodes, including 4 CEPs, 2 ADE cephala neurons, and 2 caudal PDE neurons, and as shown in FIG. 5, the fluorescence intensity of the dopaminergic neurons (CEP, ADE, PDE) decreased after exposure of BZ555 nematodes to 50mM 6-OHDA, and the fluorescence intensity of nematodes increased after treatment with 10. Mu.M compound (I-1). The total dopaminergic neuron fluorescence intensity after the 6-OHDA induction treatment (60.05% + -5.11) was reduced by 42.61% compared to the control BZ555 (102.65% + -2.87), and the total dopaminergic neuron fluorescence intensity after the 10 μM compound (I-1) treatment was restored to 96.28% + -6.33, and the fluorescence intensity was enhanced by 36.24% compared to the 6-OHDA group. This suggests that compound (I-1) has a protective effect on the 6-OHDA-induced dopaminergic neuron damage.
In summary, in vitro antioxidant activity test experiments show that pyran compounds have stronger antioxidant capacity than VC, and researches show that the generation mechanism of PD may have a certain relation with oxidative stress, mitochondrial dysfunction, immune inflammatory reaction and the like, so that the compound (I-1) prepared in example 1 is taken as an example to study whether the compound (I-1) has therapeutic protection effect in PD. First, the effect of compound (I-1) on ROS levels was examined in transgenic nematode NL5901 of PD model, as shown in FIG. 3, 10. Mu.M compound (I-1) was able to significantly reduce ROS levels (P < 0.005), so we next examined two pathological mechanisms of PD (reduction of dopaminergic neurons and aggregation of alpha-Syn), as shown in FIGS. 4 and 5, 10. Mu.M compound (I-1) was able to significantly reduce aggregation of alpha-Syn in NL5901 nematode (P < 0.01), and restore damage to dopaminergic neurons of 6-OHDA induced model BZ555 nematode (P < 0.001). This suggests that compound (I-1) plays a positive role in PD and is promising for the development of drugs for the treatment of PD.
The present invention has been described in detail with reference to the above embodiments, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present invention.
Claims (5)
1. The application of the pyran compound in preparing a medicament for treating parkinsonism is characterized in that the structural formula of the pyran compound is shown as a formula I:
formula I.
2. The use according to claim 1, wherein the parkinson's disease drug is for the treatment of α -synuclein-induced parkinson's disease.
3. The use according to claim 1, wherein the parkinson's disease drug is used for the treatment of parkinson's disease caused by dopaminergic neuronal damage.
4. Use of a pharmaceutical composition for the preparation of a medicament for the treatment of parkinson's disease, characterized in that it is prepared from a therapeutically effective amount of a pyran compound according to claim 1 and a pharmaceutically acceptable adjuvant;
the auxiliary materials comprise at least one of slow release agent, filling agent, disintegrating agent, adsorption carrier, absorbent, surfactant or lubricant.
5. The use according to claim 4, wherein the pharmaceutical composition is in the form of a solution, emulsion, pill, tablet, capsule or powder.
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| WO2000000484A1 (en) * | 1998-06-29 | 2000-01-06 | Smithkline Beecham Plc | Substituted benzopyran derivatives and their use as anticonvulsants |
| US8653023B1 (en) * | 2006-06-30 | 2014-02-18 | Iowa State University Research Foundation, Inc. | Dual beneficial effect of dopamine enhancing and neuroprotective actions of PKC delta inhibitors for treatment of Parkinson's disease |
| CN110437196A (en) * | 2018-05-04 | 2019-11-12 | 五邑大学 | A kind of preparation and its application of 4 hydroxy coumarin class compound |
| CN113150006A (en) * | 2021-02-02 | 2021-07-23 | 五邑大学 | Pyran compound and synthetic method thereof |
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| AU2002249639A1 (en) * | 2002-04-09 | 2003-10-27 | Elcom Biotechnology, Co., Ltd. | Pyranocoumarin derivatives |
| US20110105462A1 (en) * | 2008-04-29 | 2011-05-05 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Modulators of dopamine neurotransmission |
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|---|---|---|---|---|
| WO2000000484A1 (en) * | 1998-06-29 | 2000-01-06 | Smithkline Beecham Plc | Substituted benzopyran derivatives and their use as anticonvulsants |
| US8653023B1 (en) * | 2006-06-30 | 2014-02-18 | Iowa State University Research Foundation, Inc. | Dual beneficial effect of dopamine enhancing and neuroprotective actions of PKC delta inhibitors for treatment of Parkinson's disease |
| CN110437196A (en) * | 2018-05-04 | 2019-11-12 | 五邑大学 | A kind of preparation and its application of 4 hydroxy coumarin class compound |
| CN113150006A (en) * | 2021-02-02 | 2021-07-23 | 五邑大学 | Pyran compound and synthetic method thereof |
Non-Patent Citations (1)
| Title |
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| Brønsted Acid-Catalyzed Formal (3+3)-Annulation of Propargylic (Aza)- para-Quinone Methides with 4-Hydroxycoumarins and 1,3-Dicarbonyl Compounds;Zong-Wang Qiu等;J Org Chem .;第86卷(第9期);第6075-6089页 * |
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