CN104829568A - Medical application of 2-phenyl-benzo-five-membered heterocycle compound and derivative of 2-phenyl-benzo-five-membered heterocycle compound - Google Patents
Medical application of 2-phenyl-benzo-five-membered heterocycle compound and derivative of 2-phenyl-benzo-five-membered heterocycle compound Download PDFInfo
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Abstract
The invention discloses a 2-phenyl-benzo-five-membered heterocycle compound, pharmaceutically acceptable salt or ester of the 2-phenyl-benzo-five-membered heterocycle compound and an application of the 2-phenyl-benzo-five-membered heterocycle compound as an acetylcholin esterase inhibitor. A structural formula of the 2-phenyl-benzo-five-membered heterocycle compound is shown in a formula (I) described in the specification, wherein R1 is oxygen, nitrogen or sulphur; R2 is hydrogen, alkyl, carbonyl, an ester group or bromine; R3 is hydrogen, a nitrite group, phenyl, a substituted amino group or hydroxyl; R4 is hydrogen, hydroxyl, alkyl, chlorine, bromine, a nitrite group or an ester group; R5 is hydrogen, hydroxyl, alkoxy, a nitrite group, bromine or a substituted amino group; R6 is hydrogen, a nitrite group or bromine; R7 is hydrogen; R8 is hydrogen, bromine or an ether group; R9 is hydrogen, a methoxy group, fluorine or a substituted amino group; R10 is hydrogen, alkoxy or bromine; and R11 is hydrogen or alkoxy. The 2-phenyl-benzo-five-membered heterocycle compound shows high acetylcholin esterase inhibitory activity and provides a direction for development of a new medicine used for preventing or treating related diseases such as myasthenia gravis and senile dementia.
Description
Technical field
The invention belongs to medical art.More specifically, the medical applications of a kind of 2-phenyl-benzene a pair of horses going side by side five-membered heterocycles and derivative thereof is related to.
Background technology
Acetylcholinesterase (acetylcholine esterase, AChE) is the enzyme that a kind of degraded (by its hydrolytic activity) neurotransmitter acetylcholine becomes choline and acetic acid.This enzyme is mainly present in neuromuscular junction and cholinergic nerve system, is exactly to stop cynapse transmission in the activity of these these enzymes local.AChE has high hydrolytic activity, and p.s., the acetylcholinesterase of a part can be hydrolyzed the vagusstoff of 25000 molecules.The choline produced through AChE effect is transported into nerve ending by reuptake, is re-used there to synthesize new acetylcholine molecules.
Research display, the disease relevant to acetylcholinesterase has a lot, as myasthenia gravis disease, AChE inhibitor is exactly the important drugs of this disease for the treatment of, it can the activity of acetylcholine esterase inhibition, slows down the hydrolysis of vagusstoff, thus defect vagusstoff and acceptor being fully combined make up acceptor and destroyed, from the threshold value reaching nerve impulse, improve disease condition.In addition, AChE inhibitor is also a class medicine for the treatment of senile dementia.Therefore, the research of acetylcholinesterase depressant (AChE inhibitor) has great significance.
Known at present, acetylcholinesterase depressant has huperzine compounds, Galanthamine, Physostigmine, tacrine class, piperidines etc.
Summary of the invention
The technical problem to be solved in the present invention is the deficiency overcoming existing acetylcholinesterase depressant, a kind of new AChE inhibitor is provided, for AChE inhibitor new drug development provider to, be used for the treatment of relevant disease (as: myasthenia gravis, glaucoma, senile dementia etc.).
The object of this invention is to provide the medical applications of a kind of 2-phenyl-benzene a pair of horses going side by side five-membered heterocycles and derivative thereof.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
A kind of 2-phenyl-benzene a pair of horses going side by side five-membered heterocycles, its pharmacy acceptable salt or ester and derivative thereof are as the application of acetylcholinesterase depressant.The structural formula of described 2-phenyl-benzene a pair of horses going side by side five-membered heterocycles is as shown in the formula (I):
Wherein, R
1for oxygen, nitrogen or sulphur; R
2for hydrogen, alkyl, carbonyl, ester group or bromine; R
3for hydrogen, oxynitroso, phenyl, substituted-amino or hydroxyl; R
4for hydrogen, hydroxyl, alkyl, chlorine, bromine, oxynitroso or ester group; R
5for hydrogen, hydroxyl, alkoxyl group, oxynitroso, bromine or substituted-amino; R
6for hydrogen, oxynitroso or bromine; R
7for hydrogen; R
8for hydrogen, bromine or ether; R
9for hydrogen, methoxyl group, fluorine or substituted-amino; R
10for hydrogen, alkoxyl group or bromine; R
11for hydrogen or alkoxyl group.
Preferably, R1 is oxygen or nitrogen; R2 is hydrogen; R3 is hydrogen or oxynitroso; R4 is hydrogen; R5 is hydrogen or oxynitroso; R6 is hydrogen; R7 is hydrogen; R8 is alkane ether; R9 is substituted-amino or phenyl; R10 is hydrogen; R11 is hydrogen.
Described pharmacy acceptable salt is the pharmacy acceptable salt that shown in formula (I), compound is formed with acid or alkali.
More preferably, the structural formula of described 2-phenyl-benzene a pair of horses going side by side five-membered heterocycles is as shown in X4, X10 or X11:
。
Above-claimed cpd can be used for preparing acetylcholine esterase inhibitor medication.
Compound shown in the formula (I) including effective amount can the medicine of acetylcholine esterase inhibition or pharmaceutical composition also within protection scope of the present invention.
In addition, the application of compound shown in formula (I) in the medicine of preparation treatment acetylcholinesterase relative disease.Described acetylcholinesterase relative disease is can carry out the disease for the treatment of by acetylcholine esterase inhibition.
Preferably, described acetylcholinesterase relative disease is myasthenia gravis, glaucoma or senile dementia.
The object of the invention is the method for combined with virtual screening from traditional prescriptions of traditional Chinese medicine, find the acetylcholinesterase depressant that a class is novel.Buzhong Yiqi Decoction improvement side comes from Buzhong Yiqi Decoction, and in view of above basis, we take acetylcholinesterase as target, and combined with virtual screening and experimental technique, find the active substance of acetylcholine esterase inhibition from Buzhong Yiqi Decoction improvement side.We press method establishment four molecular databases of monarch to this prescription 9 kinds of herbal medicine, with collect the calculating that AChE inhibitor (IC50<=10000nM) carries out two and three dimensions similarity from Binging Database, binding molecule docking research, result shows that 2-phenyl-benzene a pair of horses going side by side five-membered ring class suppresses the crucial skeleton structure of a class of AChE onset.
Then, we carry out database search based on 2-phenyl-benzene a pair of horses going side by side five-membered ring class, find out the compound containing this parent nucleus, finally choose 24 compounds.Then acetylcholine esterase active experiment (Ellman assay) is carried out to 24 compounds chosen.Enzymic activity experiment shows that the overwhelming majority all has inhibit activities to acetylcholinesterase, and wherein 5 compounds demonstrate very high activity (the single-point inhibiting rate of 10 μMs is greater than 50%, is up to 84%).
Meanwhile, the present invention has also inspired us from Chinese Traditional Medicine prescription, can to combine the method calculated find active compound, developing new drug with data mining.
The present invention has following beneficial effect:
The present invention is from traditional Chinese medicine prescription angle, find the new skeleton of new drug development, provide the inhibitor of the new acetylcholinesterase of a class, i.e. 2-phenyl-benzene a pair of horses going side by side five-membered heterocycles, they are as the compound suppressing AChE, compared with marketed drug E2020 (Donepezil), show higher AChE inhibit activities.
This compounds can be the new AChE inhibitor new drug provider of research and development to, for the treatment of the relative disease such as myasthenia gravis or senile dementia or the exploitation provider of prevention new drug to.
And 2-phenyl provided by the invention-benzene a pair of horses going side by side five-membered heterocycles structure simply, is easily synthesized, and is easy to apply.
Accompanying drawing explanation
Fig. 1 is the chemical structural formula of positive control E2020 (Donepezil).
Fig. 2 is the figure of the amount effect curve of compounds X 4 compound.
Fig. 3 is the figure of the amount effect curve of compounds X 10 compound.
Fig. 4 is the figure of the amount effect curve of compounds X 11 compound.
Fig. 5 is the figure of the amount effect curve of compounds X 19 compound.
Fig. 6 is the figure of the amount effect curve of compounds X 21 compound.
Fig. 7 is the figure of the amount effect curve of Compound D onepezil.
Embodiment
Further illustrate the present invention below in conjunction with Figure of description and specific embodiment, but embodiment does not limit in any form to the present invention.Unless stated otherwise, the present invention adopts reagent, method and apparatus are the art conventional reagent, method and apparatus.
Unless stated otherwise, following examples agents useful for same and material are commercial.
the virtual screening of embodiment 1 2-phenyl-benzene a pair of horses going side by side five-membered heterocycles
1, the foundation of TCM database and AChE inhibitor data
(1) for the Buzhong Yiqi Decoction improvement side that Deng is old, found out the compound of monarch by traditional Chinese medicine system pharmacology database and document, establish 4 TCM databases.
(2) from Binding database, collect acetylcholinesterase depressant (IC50<=10000nM), set up the database of AChE inhibitor.
2, compound TCM database preprocessing
Virtual screening compound library is for providing compound database for oneself.Compound library is handled as follows: remove ion and complexing water molecules, add electric charge, protonated, produce three-dimensional conformation.These flow processs all complete in medicinal design software package MOE 2010.Wherein protonatedly to carry out under the condition of pH6.5 ~ 8.5.
Ready database is used for virtual screening.
3, by the method for " Role of five ", the molecule being not suitable as medicine is removed.The database of TCM database and AChE inhibitor is carried out the calculating of two and three dimensions similarity, binding molecule docking research, finds candidate active compound, carries out skeleton classification, result shows, 2-phenyl-benzene a pair of horses going side by side five-membered ring class formation suppresses the crucial skeleton structure of a class of AChE onset.
4, then, carry out the database search of substructure matching based on 2-phenyl-benzene a pair of horses going side by side five-membered ring class formation, find out the compound containing this parent nucleus.Finally obtain 24 2-phenyl-benzene a pair of horses going side by side five-membered heterocycles, be denoted as X1 ~ X24 respectively.Respective structural formula is as follows:
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embodiment 2 Ellman tests
1,24 compounds obtained embodiment 1 carry out acetylcholine esterase active experiment (Ellman assay)
Compound reaction buffer dilution (phosphate buffered saline buffer, 0.08M Na
2hPO
4with 0.02M NaH
2pO
4pH 8.0), the hAChE of 0.057 U/mL hatches 15 minutes with compound at 37 DEG C, after add nitrite ion DTNB, to final concentration 50 μMs, then after mixing with the substrate acetylthiocholine of final concentration 50 μMs, immediately at 412nm wavelength detecting absorbance, within one minute, five sub-values are got at interval continuously, ask the mean value of per minute changing value.Inhibiting rate is the ratio of dosing group and non-dosing group, and E2020 (Donepezil) is as positive control.
According to formula: inhibiting rate (%)=(1-dosing group per minute absorbancy changing value/without medicine group per minute absorbancy changing value) * 100%.
Get the mean value of the first five minute at every turn, in triplicate, calculate standard deviation, calculate the half-inhibition concentration (IC under each compound different concns
50).
2, result
(1) enzymic activity experimental result is as shown in table 1.
Table 1 screens structure and the activity data of 24 compounds
Table 1 data show, in 24 compounds, the overwhelming majority all has inhibit activities to acetylcholinesterase, and wherein these 5 compounds of X4, X10, X11, X19 and X21 demonstrate very high activity (the single-point inhibiting rate of 10 μMs is greater than 50%, is up to 84%.
(2) IC of these 5 active compounds of X4, X10, X11, X19 and X21 in addition, is measured
50(half-inhibition concentration) is as shown in table 2:
Table 2
。
Claims (10)
1. a 2-phenyl-benzene a pair of horses going side by side five-membered heterocycles, its pharmacy acceptable salt or ester and derivative thereof are as the application of acetylcholinesterase depressant, it is characterized in that, the structural formula of described 2-phenyl-benzene a pair of horses going side by side five-membered heterocycles as shown in the formula (I):
Wherein, R
1for oxygen, nitrogen or sulphur; R
2for hydrogen, alkyl, carbonyl, ester group or bromine; R
3for hydrogen, oxynitroso, phenyl, substituted-amino or hydroxyl; R
4for hydrogen, hydroxyl, alkyl, chlorine, bromine, oxynitroso or ester group; R
5for hydrogen, hydroxyl, alkoxyl group, oxynitroso, bromine or substituted-amino; R
6for hydrogen, oxynitroso or bromine; R
7for hydrogen; R
8for hydrogen, bromine or ether; R
9for hydrogen, methoxyl group, fluorine or substituted-amino; R
10for hydrogen, alkoxyl group or bromine; R
11for hydrogen or alkoxyl group.
2. apply according to claim 1, it is characterized in that, in formula (I), R1 is oxygen or nitrogen; R2 is hydrogen; R3 is hydrogen or oxynitroso; R4 is hydrogen; R5 is hydrogen or oxynitroso; R6 is hydrogen; R7 is hydrogen; R8 is alkane ether; R9 is substituted-amino or phenyl; R10 is hydrogen; R11 is hydrogen.
3. apply according to claim 1, it is characterized in that, described pharmacy acceptable salt is the pharmacy acceptable salt that shown in formula (I), compound is formed with acid or alkali.
4. applying according to claim 1, it is characterized in that, is preparing the application in acetylcholine esterase inhibitor medication.
5. apply according to claim 1, it is characterized in that, the structural formula of described 2-phenyl-benzene a pair of horses going side by side five-membered heterocycles is as shown in X4, X10 or X11:
。
6. a medicine for acetylcholine esterase inhibition, is characterized in that, includes the shown compound of claim 1 Chinese style (I) of effective amount.
7. the application of compound shown in claim 1 Chinese style (I) in the medicine of preparation treatment acetylcholinesterase relative disease.
8. the application of medicine described in claim 6 in the medicine of preparation treatment acetylcholinesterase relative disease.
9. apply according to claim 7 or 8, it is characterized in that, described acetylcholinesterase relative disease is can carry out the disease for the treatment of by acetylcholine esterase inhibition.
10. apply according to claim 7 or 8, it is characterized in that, described acetylcholinesterase relative disease is myasthenia gravis, glaucoma or senile dementia.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1260792A (en) * | 1997-04-09 | 2000-07-19 | 伊莱利利公司 | Treatment of central nervous system disorders with selective estrogen receptor modulators |
| WO2004048331A1 (en) * | 2002-11-28 | 2004-06-10 | Suven Life Sciences Limited | N-arylalkyl-3-aminoalkoxyindoles and their use as 5-ht ligands |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1260792A (en) * | 1997-04-09 | 2000-07-19 | 伊莱利利公司 | Treatment of central nervous system disorders with selective estrogen receptor modulators |
| WO2004048331A1 (en) * | 2002-11-28 | 2004-06-10 | Suven Life Sciences Limited | N-arylalkyl-3-aminoalkoxyindoles and their use as 5-ht ligands |
Non-Patent Citations (1)
| Title |
|---|
| D P GUPTA ET.AL: "《Synthesis, antiacetylcholinesterase, and anthelmintic activities of newer indolyl derivatives》", 《INDIA JOURNAL OF CHEMISTRY, SECTION B：ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY》 * |
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