CN108143727A - The new application of allyl benzene derivatives - Google Patents
The new application of allyl benzene derivatives Download PDFInfo
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- CN108143727A CN108143727A CN201711437060.XA CN201711437060A CN108143727A CN 108143727 A CN108143727 A CN 108143727A CN 201711437060 A CN201711437060 A CN 201711437060A CN 108143727 A CN108143727 A CN 108143727A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
- A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
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Abstract
The present invention provides the new applications with general structure (I) allyl benzene derivatives, this kind of compound has 5 hydroxytryptamine transporter (SERT) of enhancing/inhibition activity, it can be applied in terms of the drug for treating the digestive system functions disorders such as the neuropsychiatric diseases such as depression, anxiety disorder, schizophrenia, obsessive-compulsive disorder, neurodegenerative disease, drug addiction and slow Constipation, irritable bowel syndrome and functional distension is prepared, there is important drug development to be worth.
Description
Technical field
The present invention relates to compound new application fields, the especially new application of allyl benzene derivatives.
Background technology
Serotonin transporter (SERT) is a kind of transmembrane transporter for having high affinity to 5-HT, containing about 630
Amino acid residue, encoding gene (SLC6A4) are located on No. 7 and No. 11 chromosomes respectively, are about outside 14 of 35kb by span
Aobvious son composition.SERT albumen includes 12~13 transmembrane regions, and N-terminal and C-terminal are located in cytoplasm, has cAMP dependences at N-terminal
Protein kinase binding site has one to be located at extracellular annulus between third and the 4th transmembrane region, is the sugar of N- connections
Base site.
SERT belongs to Na+/Cl-Dependent form transport protein is predominantly located at 5-HT serotonergic neurons, SERT in central nervous system
5-HT is reuptaked from nerve synapse gap and enters presynaptic neuron, directly affects synaptic cleft 5-HT concentration, is changed prominent
The amount and acting duration of receptor-mediated signal after touch.Intestinal epithelial cell is predominantly located in digestive system SERT, again
The 5-HT of the chromaffin cell release of intestinal mucosa layer is absorbed to adjust gastrointestinal function.In addition, SERT blood platelet, placenta tissue,
Marrow, kidney, lung, the heart, adrenal gland, liver, parathyroid gland, thyroid gland, pancreas etc. are also distributed, and SERT is prompted to participate in a variety of physiology work(
Energy.
SERT is the important molecule for transporting 5-HT, is permitted in central nervous system and mood, appetite, sleep, memory, study etc.
More Physiological Psychology functions are related, and SERT and 5-HT expression changes can cause anxiety, depression, obsessive-compulsive disorder, neurosis or even spirit point
Disease is split, and closely related with drug addiction；SERT plays key player, 5-HT signals system in gastrointestinal function disease
System is abnormal can to lead to gastrointestinal tract dynamia and pathocrinia, visceral hypersensitivity, with chronic constipation, irritable bowel syndrome, abdomen
It rushes down and the gastrointestinal functions disease such as functional dyspepsia FD is closely related.
SERT is the important target spot of clinical medicine research and development.Classical antidepressants based on SERT target spots belong to selectivity more
SERT inhibitor (SSRI), such as Prozac (Fluoxetine)；Serotonin reuptake transporter accelerating agent (SSRE) then rare report,
So far reported that SSRE has Tianeptine (Tianeptine), alias Tatinol (Stablon), chemical constitution category tricyclic antidepressants resist
Depressant drug, clinic are mainly used for antidepression and antianxiety.Experimental studies have found that Tianeptine can promote 5-HT reuptakes, in nerve
In terms of structure plasticity, Tianeptine to stress/the hippocampal neuron dendron atrophy of cortisone induction has prevention effect, can
Hippocampus precursor proliferation, the decline of hippocampus volume and the N- acetyl aspartates concentration for fighting stress induction decline, and prevent apricot
Benevolence core dendron hyperplasia.In terms of nerve excitability, Tianeptine, which can overcome, stress block hippocampal long-term humidification,
Reverse stress be to inhibiting effect of hippocampus-preceding cortex cynapse etc..In terms of neuroprotection, Tianeptine can reduce hippocampus and temporo
The Apoptosis of leaves layer.In terms of memory function, Tianeptine to stress reduced space memory impairment have blocking effect, increase
Memory is added to retain, attention is contributed to concentrate (the McEwen BS, Olie such as behavior, the illeffects of antagonism alcohol
JP.2005.Neurobiology of mood,anxiety,and emotions as revealed by studies of a
unique antidepressant:tianeptine.Molecular Psychiatry 10,525–537).In addition, how general thiophene is
Spit of fland can increase maincenter 5-HT metabolins 5-hydroxyindoleacetic acid, after deduction may be due to presynaptic membrane reuptake -5-HT increases, god
Accordingly increase through interior 5-HT catabolism related；Tianeptine may act on hypothalamus-pituitary-adrenal axis, make hypothalamus skin
Matter releasing factor and anterior pituitary adrenal cortical hormone concentration decline.
Tianeptine is effective to major depressive disorder, is better than Prozac, and safe to depression long-term efficacy, bad anti-
Should lack, be suitable for depression in old age, anxiolytic effect better than Prozac (sprout recklessly, Li Zhen .2007. Tianeptines pharmacological researches and
Clinical advances Guangdong medicine 28 (7)：1192-1193.) Tianeptine includes the action character of human body：To mental state disorder
There is certain effect, between sedating antidepressants and excitability antidepressants；To Somatic discomfort, especially for anxiety and
The related upset,gastro-intestinal of mental state disorder has obvious effect；The personality and conduct disorder occur during abstinence from alcohol to alcoholism patient
There is certain effect；Moreover, Tianeptine to following aspect without ill-effect：Sleep and vigilance；Cardiovascular system；Cholinergic system
(nonreactive cholinergic symptoms)；Drug habit.Above research has prompted serotonin reuptake transporter accelerating agent (SSRE) in clinical practice
The characteristics of middle and advantage.
Allyl benzene derivatives have general structure (I)：Structure parent nucleus is allyl benzene or propenylbenzene, in propenylbenzene
Double bond has two kinds of cis and trans, and phenyl ring can be replaced by methoxyl group or hydroxyl, disubstituted or three with 2-, 4- and 5- methoxyl groups
Replace common, such as α-asarone, beta-Asarone, eugenol methyl ether and isoeugenol methyl ether.
Invention content
The technical problems to be solved by the invention are to provide the new application of allyl benzene derivatives.
In order to solve the above technical problems, the technical scheme is that：
Application of the allyl benzene derivatives in terms of the drug for promoting serotonin transporter (SERT) activity is prepared,
The structure parent nucleus of the allyl benzene derivatives is allyl benzene or propenylbenzene, and double bond has cis and trans in propenylbenzene
Two kinds, phenyl ring can be replaced by methoxyl group or hydroxyl, with 2-, 4- and 5- methoxyl groups it is disubstituted or three substitution it is common, such as α-asarum
Ether, beta-Asarone, eugenol methyl ether and isoeugenol methyl ether etc..
Preferably, the application of above-mentioned allyl benzene derivatives, the allyl benzene derivatives have the following structure general formula, according to
Secondary is A. α-asarone, B. beta-Asarones, C. eugenol methyl ethers and D. isoeugenol methyl ethers：
Above-mentioned allyl benzene derivatives are being prepared for treating neuropsychiatric disease, including depression, anxiety disorder, spirit point
Split the application in terms of the drug of disease, obsessive-compulsive disorder, digestive system function disorder, neurodegenerative disease and/or drug addiction.
Preferably, the application of above-mentioned allyl benzene derivatives, the digestive system function disorder include slow Constipation,
Irritable bowel syndrome and/or functional distension.
Realize the pharmaceutical composition of such use, the allyl benzene derivatives comprising therapeutically effective amount and optional pharmacy
Acceptable excipient.
Above-mentioned pharmaceutically acceptable excipient can be any conventional excipient, particular excipient in field of pharmaceutical preparations
Selection by depending on being used to treat the administering mode of particular patient or disease type and state, for the conjunction of specific administration pattern
The preparation method of suitable pharmaceutical composition is completely in the knowledge of drug field technical staff.For example, can as pharmacy
The excipient of receiving includes the diluent of pharmaceutical field routine, carrier, filler, adhesive, wetting agent, disintegrant, absorbs rush
Into agent, surfactant, absorption carrier and lubricant etc., when necessary, flavouring agent, anti-corrosion can also be added in pharmaceutical composition
Agent and sweetener etc..
Tablet, pulvis, granule, capsule, oral liquid, paste, creme, injection breast can be made in aforementioned pharmaceutical compositions
The diversified forms such as agent, aseptic powder needle for injection.The drug of above-mentioned various dosage forms can be according to the conventional method system of pharmaceutical field
It is standby.
The beneficial effects of the invention are as follows：
Allyl benzene derivatives of the present invention have enhancing serotonin transporter (SERT) activity, can be used as treatment
Depression, anxiety disorder, schizophrenia, obsessive-compulsive disorder, digestive system function disorder, neurodegenerative disease, drug addiction etc.
There is the medicine of the nervous system disease important drug development to be worth.
Description of the drawings
Fig. 1 is humidification of the allyl benzene derivatives to SERT activity, wherein, positive control medicine inhibits including SERT
2.0 μM of Fluoxetine groups of agent and SERT reinforcing agents 1.0 μM of Tianeptine, * p<0.05, * * p<0.01, * * * p<0.001,
In figure, A. α-asarone, B. beta-Asarones, C. eugenol methyl ethers, D. isoeugenol methyl ethers.
Specific embodiment
In order to which those skilled in the art is made to be better understood from technical scheme of the present invention, With reference to embodiment
Technical solution of the present invention is described in further detail.
Embodiment 1
Influence of the compound of the present invention to serotonin transporter (SERT)
Compound includes A. α-asarone, B. beta-Asarones, C. eugenol methyl ethers, D. isoeugenol methyl ethers
Using the hSERT-HEK293 cell strains of stable transfection, with 4- (4- (dimethylamino) phenyl) -1-
Methylpyridinium (APP+) is fluorogenic substrate, and allyl benzene derivatives are detected in high intension system to SERT activity
It influences.
1) laboratory apparatus and reagent
Laboratory apparatus：
High intension Operetta systems and Columbus data managements and analysis system (PerkinElmer), super-clean bench move
Liquid rifle (1000 μ L, 200 μ L, 20 μ L, 10 μ L, 2.5 μ L, Eppendorf companies of the U.S.)
Reagent and material：
Human embryonic kidney cell line HEK293 (the American Type Culture Collection committee of Chinese Academy of Sciences cell bank), hSERT pcDNA3
Plasmid (Addgene, plasmid 15483), MEM culture mediums (Gibco), APP+ (Sigma), 33342 (Cell of Hoechst
Signaling Technology), 96 orifice plates (Costar 3605)；α-asarone (No. CAS：2883-98-9, article No.：
231282-1G), beta-Asarone (No. CAS：5273-86-9, article No.：221074-1G), eugenol methyl ether (No. CAS：93-15-2,
Article No.：284424-5G) and isoeugenol methyl ether (No. CAS：93-16-3, article No.：D136905-5G) it is purchased from U.S. Sigma-
Aldrich.
2) experimental implementation process
It initially sets up and identifies stable expression hSERT-HEK293 cell strains and { pacify the people source 5- such as of heap of stone, Li Jing, golden blast
The foundation of hydroxytryptamine transporter stable expression cell line and its function investigation [J] military medicines 2011,35 (9):681-684}.
Using APP+ as fluorogenic substrate, function { Fowler A, Seifert N, the Acker V.et based on high intension system detectio SERT
al.A nonradioactive high-throughput/high-content assay for measurement of the
human serotonin reuptake transporter function in vitro[J].Journal of
Biomolecular Screening,2006,11(8):1027-1034}
Specific steps：
(1) precision weighs allyl benzene derivatives, and the mother liquor of 20.0mM is configured to DMSO, is trained with without phenol red MEM bases
Base dilutes drug to 10.0 μM, 1.0 μM, 0.1 μM.
(2) by 1.0 × 104In the hSERT-HEK293 cells to 96 orifice plates of the density inoculation stable transfection of cells/well,
37 DEG C, 5%CO2Under the conditions of cultivate for 24 hours.
(3) blank control group is set up in experiment, positive control include 2.0 μM of Prozacs (Fluoxetine) of SERT inhibitor and
1.0 μM of tianeptine (Tianeptine) groups of SERT reinforcing agents, testing drug set up 10.0 μM respectively, 1.0 μM, 0.1 μM of group.Carefully
Born of the same parents discard culture medium, are washed 2 times with PBS buffer solution, and each sample to be tested is added according to 80 μ L/ pore volumes, each 3 multiple holes of concentration,
At 37 DEG C, 5%CO2Under the conditions of be protected from light be incubated 2-3h.
(4) after the completion of being incubated, 20 μ L APP+ (2.0 μM of final concentration) are added in per hole, are incubated 10 minutes.
(5) liquid in hole is discarded, is washed 2 times with PBS buffer solution, 1.0 μ g/mL Hoechst50 μ L are added in per hole, is protected from light and incubates
Educate 20min.
(6) liquid in orifice plate is discarded, PBS is washed 2-3 times, using the intracellular fluorescence intensity of high intension system detectio
Hoechst 33342Excitation：360-400nm, Emission：410-480nm
APP+Excitation：460-490nm, Emission：505-550nm
3) data analysis：
Image analysis is carried out using Columbus data managements and analysis system, according to 33342 fluorescence identifyings of Hoechst
Nuclear pattern determines cell, determines SERT transport activities according to intracellular APP+ fluorescence intensities, calculates relative intensity of fluorescence
=(the intracellular APP+ fluorescence intensities of intracellular APP+ fluorescence intensities/control group of medicine group).
For statistical analysis using SSPS16.0 softwares, experimental result uses one-way analysis of variance (ANOA), Post
Hoc Comparison using Dunnett's Multiple Comparison Test each groups compared with the control group, tie by experiment
Fruit is represented using Mean ± S.E.M.
4) experimental result
As shown in Fig. 1-A, one-way analysis of variance result shows that α-asarone does not show SERT in three test concentrations
Activity.As shown if figure 1-b, one-way analysis of variance result show beta-Asarone significantly increase SERT transport activities (F (5,52)=
205.3,p<0.0001), comparison among groups use multiple comparative test (the Dunnett's Multiple of Dunnett
Comparison Test) 10.0 μM of (q=6.462, p are confirmed compared with blank control group<0.001), 1.0 μM of (q=4.926, p
<0.001), 0.1 μM of (q=3.078, p<0.05), 2.0 μM of Prozacs of positive controls significantly inhibit compared with blank control group
SERT activity (q=20.38, p<0.001), positive controls Tianeptine can significantly increase SERT activity (q at 1.0 μM
=4.433, p<0.001)
As shown in Fig. 1-C, one-way analysis of variance result show eugenol methyl ether significantly inhibit SERT transport activities (F (5,
38)=735.9, p<0.0001), comparison among groups use multiple comparative test (the Dunnett's Multiple of Dunnett
Comparison Test) 10.0 μM of (q=2.692, p are confirmed compared with blank control group<0.05), 1.0 μM of (q=3.974, p<
0.01), 0.1 μM of (q=4.214, p<0.001), 2.0 μM of Prozacs of positive controls significantly suppress compared with blank control group
SERT activity (q=47.11, p<0.001), positive controls Tianeptine can significantly increase SERT activity (q=at 1.0 μM
14.30,p<0.001)。
As shown in Fig. 1-D, one-way analysis of variance result shows that isoeugenol methyl ether is not shown in 3 test concentrations
SERT activity.
In summary, the serotonin transporter (SERT) is a kind of Na for having high affinity to 5-HT+/Cl-It relies on
Type turns transmembrane transporter, and 5-HT serotonergic neurons are predominantly located in central nervous system, by from nerve synapse gap again
Intake 5-HT enters presynaptic neuron, directly affects synaptic cleft 5-HT concentration, changes the amount of postsynaptic receptor mediation signal
And acting duration, so as to participate in a variety of Physiological Psychology functions (such as mood, appetite, sleep, memory, study)；It is digesting
System SERT is predominantly located at intestinal epithelial cell, reuptakes the 5-HT of intestinal mucosa layer chromaffin cell release to adjust stomach and intestine
Function, in addition, in devices such as placenta tissue, genital tract, marrow, kidney, lung, the heart, adrenal gland, liver, parathyroid gland, thyroid gland and pancreas
Official is distributed, and SERT is prompted to participate in different physiological roles.
SERT is the important target spot of clinical medicine research and development, and the serotonin reuptake transporter accelerating agent (SSRE) reported so far has thiophene
Nai Puting (Tianeptine), clinic is mainly used for antidepression and antianxiety.Tianeptine includes the action character of human body：It is right
Mental state disorder has certain effect, between sedating antidepressants and excitability antidepressants；It is especially right to Somatic discomfort
There is obvious effect in the anxiety upset,gastro-intestinal related with mental state disorder；The personality that occurs during abstinence from alcohol to alcoholism patient and
Conduct disorder has certain effect；Moreover, Tianeptine to following aspect without ill-effect：Sleep and vigilance；Cardiovascular system；Courage
Alkali energy system (nonreactive cholinergic symptoms)；Drug habit.Tianeptine belongs to a kind of SSRE, and action character has prompted 5- hydroxyl colors
The characteristics of amine reuptake accelerating agent (SSRE) is in clinical practice and advantage.
The present invention by the way that allyl benzene derivatives are carried out with the external research for influencing serotonin transporter (SERT) activity,
It was found that allyl benzene derivatives significantly increase SERT transport activities, so as to confirm allyl benzene derivatives, to adjust, SERT is unbalance to be drawn
The relevant physiological mental disease and digestive system function disorders active ingredient risen.Therefore, allyl benzene derivatives can be used
To prepare the treatment functional disturbances of gastrointestinal tract disease such as the neuropsychiatric diseases such as depression and anxiety disorder and irritable bowel syndrome
Drug.
Embodiment 2
Preparation method：Allyl benzene derivatives, newborn sugar and starch are uniformly mixed according to the above ratio, 200 mesh sieve is crossed, uses water
Mixture after wetting is dried re-sieving, magnesium stearate is added in, then by mixture tabletting, every weight by uniform wet
250mg, active component content 10mg.
Embodiment 3
Capsule：Allyl benzene derivatives 20mg
Galactolipin 188mg
Magnesium stearate 2mg
Preparation method：Allyl benzene derivatives with galactolipin are uniformly mixed according to the above ratio, 200 mesh sieve are crossed, obtaining
Mixture, add in magnesium stearate, be packed into No. 2 capsules to get.
The above-mentioned detailed description carried out with reference to specific embodiment to the new application of allyl benzene derivatives, is illustrative
Rather than it is limited, several embodiments can be enumerated according to limited range, therefore do not departing from present general inventive concept
Under change and modification, should belong within protection scope of the present invention.
Claims (5)
1. application of the allyl benzene derivatives in terms of the drug for promoting serotonin transporter activity is prepared, the phenylpropyl alcohol
The structure parent nucleus of vinyl derivative is allyl benzene or propenylbenzene, and double bond has two kinds of cis and trans, benzene in propenylbenzene
Ring can be replaced by methoxyl group or hydroxyl, disubstituted or three substitutions are common with 2-, 4- and 5- methoxyl groups, such as α-asarone, β-thin
Octyl ether, eugenol methyl ether and isoeugenol methyl ether.
2. the application of allyl benzene derivatives according to claim 1, it is characterised in that：The allyl benzene derivatives tool
Just like lower structure general formula, it is followed successively by A. α-asarone, B. beta-Asarones, C. eugenol methyl ethers and D. isoeugenol methyl ethers：
3. allyl benzene derivatives described in claims 1 or 2 are being prepared for treating neuropsychiatric disease, including depression, coke
Consider the drug side of disease, schizophrenia, obsessive-compulsive disorder, digestive system function disorder, neurodegenerative disease and/or drug addiction
The application in face.
4. the application of allyl benzene derivatives according to claim 3, it is characterised in that：The digestive system function is disorderly
Including slow Constipation, irritable bowel syndrome and/or functional distension.
5. realize the pharmaceutical composition of one of the claim 1-4 purposes, it is characterised in that：Phenylpropyl alcohol comprising therapeutically effective amount
Vinyl derivative and optional pharmaceutically acceptable excipient.
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|---|---|---|---|---|
| CN1895477A (en) * | 2006-06-14 | 2007-01-17 | 广州汉方现代中药研究开发有限公司 | Antidespressant and its preparation |
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| CN101366708A (en) * | 2008-09-19 | 2009-02-18 | 沈阳药科大学 | Application of alpha-ararin in preparing anxiolytic and antidepressant medicament |
| CN102258577A (en) * | 2010-05-21 | 2011-11-30 | 成都医学院 | Application of caryophyllus oil, eugenol and eugenol derivative in preparation of antagonist or reverse agonist of histamine H3 receptors |
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2017
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| CN1895477A (en) * | 2006-06-14 | 2007-01-17 | 广州汉方现代中药研究开发有限公司 | Antidespressant and its preparation |
| US20070190187A1 (en) * | 2006-09-07 | 2007-08-16 | Kneller Bruce W | Formulation for enhanced delivery of phenethylamine |
| CN101366708A (en) * | 2008-09-19 | 2009-02-18 | 沈阳药科大学 | Application of alpha-ararin in preparing anxiolytic and antidepressant medicament |
| CN102258577A (en) * | 2010-05-21 | 2011-11-30 | 成都医学院 | Application of caryophyllus oil, eugenol and eugenol derivative in preparation of antagonist or reverse agonist of histamine H3 receptors |
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