CN103923077B - Two kinds of acetaldehyde dehydrogenase agonists, Preparation Method And The Uses - Google Patents
Two kinds of acetaldehyde dehydrogenase agonists, Preparation Method And The Uses Download PDFInfo
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- CN103923077B CN103923077B CN201310283295.3A CN201310283295A CN103923077B CN 103923077 B CN103923077 B CN 103923077B CN 201310283295 A CN201310283295 A CN 201310283295A CN 103923077 B CN103923077 B CN 103923077B
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- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
The present invention relates to medical art, particularly two kinds of acetaldehyde dehydrogenase agonists, Its Preparation Method And Uses.Concrete, the present invention relates to two such as formula compound, its preparation method shown in I and formula II, and above-mentioned two kinds of compounds or its pharmaceutically acceptable inorganic or organic salt are in preparation ALDH2 agonist, the preparation crapulent medicine for the treatment of and the application prepared in antialcoholic drugs.
Description
Technical field
The present invention relates to medical art, particularly two kinds of acetaldehyde dehydrogenase agonists, Its Preparation Method And Uses.
Background technology
Existing research is thought, normal adult crowd is a small amount of, responsible drinking can accelerate blood circulation, and have promoting blood circulation and removing obstruction in channels loose cold, Ginseng Extract, promotes the effect of sleep etc.Along with people are to the increase of wine demand, the impact of alcohol on HUMAN HEALTH starts to cause to be paid attention to widely, excessive drinking can make people produce the malaise symptoms such as Nausea and vomiting, and long-term excessive consumption of alcohol then can damage the internal organs such as liver, stomach, spleen, causes the diseases such as liver cirrhosis.The number of alcoholism especially acute alcoholism grows with each passing day, and can cause a series of social concern.The World Health Organization (WHO) points out: alcoholism is the first public hazards within the scope of the world today.In western countries, many people indulge in excessive drinking seriously, and its alcoholic liver disease sickness rate is high, and alcoholic cirrhosis accounts for the 54%-84% of the various liver cirrhosis cause of disease.Domestic alcohol user's radix is huge, and alcoholism is customary, and how not to seek medical advice.
When drinking, alcohol absorbs mainly through stomach (20%) and duodenum (80%).When people at short notice heavy drinking time, just have in blood after 5 minutes ethanol occur; When 30 minutes, the alcohol concn in blood increases sharply; At 1 ~ 1.5 hour, ethanol in blood concentration peaking; After 2h, alcohol concn starts to decline; Ethanol analytic metabolism after 16h in blood is complete.Enter ethanol more than 90% in body at liver metabolism.Under physiological condition, alcohol is acetaldehyde through L-AD (ADH) metabolism in vivo, then is converted into acetic acid through the effect of acetaldehyde dehydrogenase (ALDH).In short period of time during a large amount of absorption ethanol, the metabolism that microsomal ethanol oxidase system (microsomalethanoloxidizingsystem, MEOS) participates in ethanol can be activated.Ethanol all generates acetaldehyde through above-mentioned two kinds of pathways metabolisms oxidation, and the latter is oxidized under the catalysis of ALDH.(at all times, Ma Yaoyao.China's medicinal application and monitoring, 2010; 7 (6): 371).
Acetaldehyde dehydrogenase (aldehydedehydrogenases, ALDH) be one group of NAD (P)+dependent enzyme, 19 kinds of ALDH are had in human body, common are ALDH1-ALDH4 tetra-kinds, ALDH1, ALDH3, ALDH4 are positioned at enchylema, and aldehyde dehydrogenase 2 (ALDH2) is positioned at plastosome.According to enzymic activity height, ALDH2 is divided into two classes, activated ALDH2 is denoted as ALDH2*1, and activity is very low or do not have activated ALDH2 to be denoted as ALDH2*2, has the gook of 40% to carry the gene of saltant type ALDH2*2 through investigation.The gene of ALDH2*2 is dominant inheritance, and namely no matter the genotype of the ALDH2*2 carrier of non-activity is heterozygote or homozygote, ALDH2 all do not have activity or activity lower, the sudden change of ALDH2 gene can cause the serious loss of ALDH2 vigor.ALDH2 gene is positioned on karyomit(e) 12q24, comprises 13 exons and 12 introns, is made up of 43437 base pairs, 517 amino acid of can encoding.12nd exon base A of ALDH2*1 gene is replaced by G and becomes ALDH2*2 gene, this replacement causes the glutaminic acid residue of the 504th to sport Methionin (E504K), this sudden change, we call that E487K suddenlys change, this sudden change makes the activity decrease of ALDH2 enzyme even completely lose.According to this sudden change, ALDH2 gene can be divided into ALDH2*1/*1 (wild-type homozygote, enzymic activity is normal), ALDH2*1/*2 (heterozygote genotype, enzymic activity decline 30%-50%) and ALDH2*2/*2 (anomaly homozygote, enzymic activity is lost substantially) 3 kinds of genotype.
In recent years, more and more deep to the research of ALDH2, its using value at medical field is more and more subject to the close attention of investigator.The raising of ALDH2 activity has great importance clinically: alcoholism symptom be alleviated and be treated to the enhancing of ALDH2 activity can, has abated effect to the degree of Ethanol hepatic injury; The enhancing of the activity of ALDH can weaken the response to oxidative stress in body, slows down atherosclerotic development, and therefore, the activity improving ALDH2 is expected to the breakthrough point becoming treating cardiovascular disease; The raising of ALDH2 activity can reduce digestive tract cancer, the sickness rate of cancer of the stomach and the rectum cancer; The enhancing of ALDH2 activity can be treated by aldehydes toxicity, cataract, mouth cancer, esophagus cancer, upper digestive tract cancer, lung cancer, atopic dermatitis, radioepidermitis, ischemic stress or oxidative stress disease, physical function that nitroglycerin tolerance and neural variability disease cause is disorderly.
Summary of the invention
The object of this invention is to provide two kinds of acetaldehyde dehydrogenase agonists, Its Preparation Method And Uses.
In a first aspect of the present invention, contriver, in the process of drug research, finds a kind of such as formula the compound shown in I or formula II, or its pharmaceutically acceptable organic or inorganic salt:
Provide the preparation method of compound of the present invention in a second aspect of the present invention, comprise the steps:
(1) 3,4-(methylene-dioxy) cyanobenzene is under the effect of alkali metal reduction agent, and reduction obtains 3,4-(methylene-dioxy) benzylamine;
(2) 3,4-(methylene-dioxy) benzylamine is obtained by reacting product S L-D021 and SL-D022 with 2 furoyl chloride or 3-fluorobenzoyl chloride under the catalysis of alkali.
Detailed reaction condition in step (1) is as follows: by 3,4-(methylene-dioxy) cyanobenzene is dissolved in suitable solvent, under alkali metal reduction agent effect, react 0.5 ~ 15 hour at 0 DEG C ~ 200 DEG C, preferred 1-5 hour, 3,4-shown in II (methylene-dioxy) benzylamine is collected from reaction product.
Wherein, described suitable solvent can be ether, toluene, tetrahydrofuran (THF) or isopropyl ether, preferred isopropyl ether or tetrahydrofuran (THF).
Described alkali metal reduction agent can be tetrahydrochysene lithium aluminium, metallic nickel, sodium borohydride, POTASSIUM BOROHYDRIDE, preferred tetrahydrochysene lithium aluminium.
Preferably, the mol ratio of 3,4-(methylene-dioxy) cyanobenzene and alkali metal reduction agent is 1: 1 ~ 1: 1.5.
Detailed reaction condition in step (2) is as follows:
3,4-(methylene-dioxy) benzylamine is under alkali effect, and at-10 DEG C ~ 100 DEG C, react 1-20 hour with 2 furoyl chloride or 3-fluorobenzoyl chloride, preferably 0 DEG C-5 DEG C, 1-3 hour, collects SL-D021 or SL-D022 from reaction product; Conventional post-treating method is adopted to obtain SL-D021 and SL-D022 sterling.
The solvent used in step (2) can be water, methylene dichloride, ethyl acetate, acetone or toluene, is preferably water.
Alkali described in step (2) can be conventional mineral alkali, as sodium hydroxide, potassium hydroxide or sodium carbonate etc., is preferably sodium hydroxide.
In the present invention, term " collection ", refers to and adopts in this area ordinary method, be separated by target compound or extract crude product from reactant.Conventional post-treating method, refers generally to concentrated solvent, extraction, drying, recrystallization etc. in this area.
The present invention adopts novelty, the method for science has prepared SL-D021, SL-D022, and this preparation method is simple, and raw material is cheap and easy to get, and yield high (total recovery 64.0-80.5%), has larger actual application value.
In a third aspect of the present invention, provide a kind of pharmaceutical composition, it contains pharmacologically acceptable vehicle or carrier, and such as formula the compound described in I or formula II or its pharmaceutically acceptable inorganic or organic salt.
The pharmaceutically acceptable inorganic or organic salt of the compounds of this invention, the acid of the inorganic salt such as the concrete above-claimed cpd enumerated and hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid phosphoric acid, the salt formed with the acid of the organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, p-methyl benzenesulfonic acid and the acidic amino acid such as ASP, L-glutamic acid.
In a fourth aspect of the present invention, provide the purposes of compound of the present invention or pharmaceutically acceptable inorganic or organic salt, it is used to preparation ALDH2 agonist.
In a fifth aspect of the present invention, provide the purposes of compound of the present invention or pharmaceutically acceptable inorganic or organic salt, it is used to the crapulent medicine of preparation treatment.
In a sixth aspect of the present invention, provide the purposes of compound of the present invention or pharmaceutically acceptable inorganic or organic salt, it is used to prepare antialcoholic drugs.
Accompanying drawing explanation
Fig. 1 is the histogram that Alda1, SL-D021 and SL-D021 activate ALDH2 activity.Embodiment
Contriver, through studying widely, synthesizes and has screened a large amount of compounds, and the compound that Late Cambrian represents such as formula I or formula II has very strong agonism to acetaldehyde dehydrogenase.
Embodiment 1
The preparation of 3,4-methylene-dioxy benzylamine:
Dry diisopropyl ether 300ml is added in 250ml three-necked bottle, be chilled to-5 DEG C ~ 0 DEG C, add aluminum chloride 12g(90mmol) and tetrahydrochysene lithium aluminium 5.2g(136mmol), magnetic agitation 5 minutes, control temperature is between-5 DEG C ~ 0 DEG C, drip 3,4-(methylene-dioxy) cyanobenzene 10g(68mmol) with the mixing solutions of isopropyl ether 300ml.Reaction mixture stirs 10 hours, quenches at 0 DEG C with methyl alcohol.Reaction mixture 1MNaOH aqueous solution alkalization, extraction into ethyl acetate.Merge organic layer, with water and saturated sodium bicarbonate solution washing, organic layer anhydrous magnesium sulfate drying, normal pressure boils off ethyl acetate, and vacuum pump pressure distills, and collects 136-138 DEG C of 10mmHg cut 9.1g, productive rate 88.5%.1HNMR(300MHz,DMSO)1.73(brs,2H),3.62(s,2H),5.95(s,2H),6.74-6.81(m,2H),6.91(s,1H)。
Embodiment 2
The preparation of SL-D021:
In 100ml three-necked bottle, water 20ml is added under stirring, 3,4-methylene-dioxy benzylamine 2g (0.0132mol), in question response bottle, temperature is down to 5-10 degree, and ice bath lower magnetic force stirs 2 minutes, drips furoyl chloride 1.93g (0.0148mol), drip acyl chlorides and caustic lye of soda (sodium hydroxide 0.6 gram of 0.015mol adds water 2.5 milliliters) simultaneously, finish, continue stirring 30 minutes, the monitoring of TLC thin layer is to reaction end.Stopped reaction, filters, and filter cake is successively with 3ml × 2 water washing, and 3ml saturated sodium bicarbonate washs, 3ml × 2 water washing, and 5%HCl5ml washs, and 3ml × 2 water washing, obtains crude product.Crude product obtains sterling 2.9g with recrystallizing methanol.Productive rate 91%, mp:114-116 DEG C.
1HNMR(300MHz,CDCl
3)4.51(d,J=5.7Hz,2H),5.94(s,2H),6.48-6.50(m,1H),6.66(brs,1H),6.75-6.79(m,2H),6.82-6.84(m,1H),7.13(d,J=3.6Hz,1H),7.41(d,J=0.9Hz,1H)。HRMS:m/z246.59(M+H)
＋。
Embodiment 3
The preparation of SL-D022:
In 100ml three-necked bottle, water 20ml is added under stirring, 3,4-methylene-dioxy benzylamine 2g (0.0132mol), in question response bottle, temperature is down to 5-10 degree, and ice bath lower magnetic force stirs 2 minutes, drips 3-fluorobenzoyl chloride 2.35g (0.0148mol), drip acyl chlorides and caustic lye of soda (sodium hydroxide 0.6 gram of 0.015mol adds water 2.5 milliliters) simultaneously, finish, continue stirring 30 minutes, the monitoring of TLC thin layer is to reaction end.Stopped reaction, filters, and filter cake is successively with 3ml × 2 water washing, and 3ml saturated sodium bicarbonate washs, 3ml × 2 water washing, and 5%HCl5ml washs, and 3ml × 2 water washing, obtains crude product drying.Crude product obtains sterling 2.6g with recrystallizing methanol.Productive rate 72%, mp:124-126 DEG C.
1HNMR(300MHz,CDCl
3)4.29(d,J=6.0Hz,2H),5.91(d,J=1.2Hz,2H),6.14(brs,1H),6.64-6.69(m,2H),6.70-6.73(m,2H),6.92-6.93(m,1H),6.96-6.99(m,1H)，7.22-7.27(m,1H).HRMS:m/z274.79(M+H)
＋。
Embodiment 4
The ALDH2 agonist activity research of SL-D021, SL-D022:
(1) experimental program: SD lateral ventricle of rat brain gives solvent (DMSO respectively, 5 μ l), compound S L-D021, SL-D022 or known ALDH2 agonist Alda1(CAS 349438-38-6) (50 μ g/5 μ l), extracting mitochondria in brain tissue albumen after 4h, detects ALDH2 active.Wherein Alda1 is positive control drug.By comparing with solvent and positive control, filter out compound ALDH2 to agonism, and repeat single test again and verify its agonism to ALDH2.
(2) experiment reagent, instrument and animal:
DMSO：SinopharmChemicalReagentCo.Ltd.
SL-D021, SL-D022 compound
Organize plastosome separating kit: BeyotimeInstituteofBiotechnology
BCA determination of protein concentration test kit: BeyotimeInstituteofBiotechnology
ALDH2 detection reagent one: acetaldehyde 10mM, MgCl
210mM, PBS20mM
ALDH2 detection reagent two: NAD2.5mM, PBS20mM
Plastosome cracking C liquid: Tris-HCl20mM, NaCl9%, glycerine 10%, NP-400.5%
Clinical biochemical analyser: ShanghaiXundaMedicalInstrumentCo., Ltd
Supercentrifuge: EppendorfAG
Microplate reader: ThermoFisherScientificInc.
Laboratory animal healthy SD male rat 30, body weight 180-220g, purchased from Shanghai Bi Kai animal scientific & technical corporation, is divided into 4 groups at random, corresponds to Vehicle controls group, SL-D021 group, SL-D022 group and Alda1 positive controls respectively.
(3) detailed step is tested
A. administration
Brain intracerebroventricular injection administration SD rat, body weight is between 180-220g.After 15% chloral hydrate anesthesia (300mg/kg, 2ml/kg, ip) animal, brain top incision of skin, the tissues such as periosteum cut off by blade, with anterior anus Bregma point (coronal suture and sagittal suture point of interface) for locating point (marking herein with marker pen), and (AP) 0.9mm backward, (L) 1.6mm left, after having good positioning, marker pen marks, and electric drill is holed, use microsyringe downward inserting needle (H) 3.7mm, the injection liquid scale of construction 5 μ l.
B. mitochondrial protein extracting is organized
After lateral ventricle of rat brain administration 4h, by sacrifice of animal, get left side cerebral tissue, separate mitochondria albumen.Tissue is placed on one and is placed in centrifuge tube on ice or culture dish, with scissors or blade, tissue shear is cut into very tiny fragment of tissue.Add the plastosome separation agent A (with the addition of PMSF before use) of 2ml precooling, ice bath carries out homogenate, homogenate about 30-50 time.Tissue homogenate at 600g, 4 DEG C of centrifugal 5min.Carefully supernatant is transferred in another centrifuge tube, at 11,000g, 4 DEG C of centrifugal 10min.Careful removal supernatant.Precipitation is the plastosome being separated and obtaining.Add the plastosome lysate that 200 μ l configure voluntarily, mixing, acts on 15min on ice, 12,000g, 4 DEG C of centrifugal 10min.Get supernatant and be mitochondrial protein.
C.BCA method measures protein concentration
Getting 1.2ml protein standard preparation liquid joins in a tubulin standard (30mgBSA), is mixed with the protein standard solution of 25mg/ml after fully dissolving.Can use immediately after preparation, also can-20 DEG C of preservations for a long time.Get appropriate 25mg/ml protein standard, being diluted to final concentration is 0.5mg/ml.Quantity per sample, adds 1 volume BCA reagent B (50:1) by 50 volume BCA reagent A and prepares appropriate BCA working fluid, fully mix.Stable in BCA working fluid room temperature 24h.Standard substance are added in the standard sample wells of 96 orifice plates by 0,1,2,4,8,12,16,20 μ l, add standard dilutions and supply 20 μ l.Add proper volume sample in the sample well of 96 orifice plates, add standard dilutions to 20 μ l.Each hole adds 200 μ lBCA working fluids, places 30min for 37 DEG C.Measure the absorbancy at 570nm place.The protein concentration of sample is calculated according to typical curve.Be as the criterion with the minimum protein concentration in sample, adjust protein concentration with PBS consistent.
D.ALDH2 vitality test
Principle: this reagent take acetaldehyde as substrate, and measuring principle is as follows:
ALDH2
Acetaldehyde+NAD
+→ → → acetic acid+NADH
+h
+
ALDH2 catalysis converting acetaldehyde is acetic acid, reduces NAD simultaneously
+(cozymase) is NADH
+h
+(reduced coenzyme Ⅰ).Reduced coenzyme Ⅰ (NADH
+h
+) generating rate be directly proportional to ALDH2 activity in sample, by wavelength 340nm place monitoring absorbancy climbing speed, the activity of ALDH2 in sample can be recorded.
Step: by used in combination to ALDH2 detection reagent one and ALDH2 detection reagent 25: 1.As: 500 μ l reagent one+100 μ l reagent two+100-200 μ gprotein suspension/samples, rapidly loading after mixing.Each example reaction 2min.Washed with de-ionized water machine is used after measuring 5 samples.Semi-automatic biochemical analyzer detects ALDH2 vigor.It is as follows that semi-automatic biochemical analyzer measures ALDH2 motility parameters: method is rate method, wavelength 340nm, temperature 37 DEG C, reading duration 60sec, time of lag 30sec, soakage 450 μ l, the Direction of Reaction is positive dirction, factor 1746.
(4) experimental result
A. tricorn gives ALDH2 agonist Alda1 (positive drug, 50 μ g/5 μ l), detects ALDH2 vigor in brain after 4h, finds: compared with Vehicle controls, ALDH2 vigor increase about 1 times (Fig. 1).This experimental technique is pointed out to screen ALDH2 agonist feasible.
B. tricorn gives SL-D021, SL-D022 compound (50 μ g/5 μ l), detects ALDH2 vigor in brain after 4h, finds: compared with Vehicle controls, and ALDH2 vigor increase about 0.5-1 doubly (Fig. 1).Illustrate that SL-D021, SL-D022 compound has the effect of exciting ALDH2.
As can be seen from Figure 1, compound S L-D021, SL-D022 all have significant activation (170% ± 36%, 202% ± 54%vs100% ± 18%incontrol) to cerebral tissue ALDH2.
Embodiment 5
SL-D021, SL-D022 compound relieves the effect of alcohol experiment:
The object of this research is to having been found that two compound Ss L-D021, SL-D022 of ALDH2 agonism test again, to finding the compound best to alcoholism result for the treatment of, above-mentioned two compounds are provided with three various dose (12.5mg/kg by this experiment, 25mg/kg, 50mg/kg) repeat three experiments; Having found that SL-D021 is best to mouse alcoholism effect, is below the specific experiment process of embodiment 5.
(1) tested material and laboratory animal:
By test product SL-D021, SL-D022 compound, outward appearance is buff powder; Positive reference substance selects aldehyde dehydrogenase 2 agonist (Alda1), and outward appearance is white powder.Three kinds of compounds are all water insoluble, and first dissolve with methyl-sulphoxide before using, then use normal saline dilution, the ratio of methyl-sulphoxide and physiological saline is 1: 9.
Bulk drug is put normal temperature in sealing bag and is preserved, and before experiment, interim physiological saline and methyl-sulphoxide are mixed with the not isocyatic solution of corresponding isometric(al).
56 degree of commercially available edible distillate spirits: Beijing Erguotou wine industry limited-liability company produces, food production licence: QS110015010354.
Physiological saline: pharmaceutical factory, Anhui BBCA Pharmaceuticals Co., Ltd. Tushan produces, authentication code: H34022484, product batch number: 090919-13.
Methyl-sulphoxide: Chemical Reagent Co., Ltd., Sinopharm Group produces, product batch number: T20080902.
Laboratory animal strain: ICR mouse, purchased from Shanghai western pul-Bi Kai laboratory animal company limited, male, body weight 22 ~ 24g.Quantity: 120.Rank: SPF level.Animal productiong credit number: SCXK (Shanghai) 2008-0016.Animal divides cage adaptability to raise three days after buying back after our unit's experimental animal room, and use normal rats forage feed, freely drink water, light 12 hours light and shades are changed automatically, room temp 20-22 DEG C.
(2) dosage is arranged and grouping
Experiment is divided into three times and carries out:
For the first time: SL-D022, SL-D02121, Alda1 are 12.5mg/kg, separately establish solvent control, totally 4 groups, often organize 10 animals.
For the second time: SL-D022, SL-D02121, Alda1 are 25mg/kg, separately establish solvent control, totally 4 groups, often organize 10 animals.
For the third time: SL-D022, SL-D02121, Alda1 are 50mg/kg, separately establish solvent control, totally 4 groups, often organize 10 animals.
Route of administration and administration volume: route of administration adopts intravenous administration, and with clinical plan route of administration is consistent from now on, administration volume is 10ml/kg(90% physiological saline+10% methyl-sulphoxide).Administration number of times is single.Administration time awards 15min before edible distillate spirit gavage.
(3) experimental technique mouse weights pneumoretroperitoneum injection test medicine, by the white wine 5.5g/kg gavage of 56% after 15min, then puts back to Animal House by animal and normally raises, and observes 48h mortality ratio.
Observation index is mortality of animals difference between administration group and control group.
(4) statistical study
Experimental result represents with mortality of animals, adopts chi square test to compare the difference of mortality of animals between administration group and control group, with P<0.05 for having statistical significant difference standard.
(5) experimental result: through finding various dose three experiments of SL-D022 and SL-D021 bis-kinds of compounds, the compound best to the provide protection of alcoholism mouse is SL-D021.
Table 1 three kinds of acetaldehyde dehydrogenase agonist various dose are on the impact (n=10) of alcoholism mouse death rate
* P<0.05, * * P<0.01 compares with solvent control group
(6) experiment conclusion three kinds of compound intravenous injection administrations are to the provide protection of alcoholism mouse, and SL-D021 effect is best, is secondly SL-D022 and Alda1.
Embodiment 6
SL-D021 compound is to mouse alcoholism Antidotal Effect
In embodiment 5, by three experiments, find that SL-D021 rescue alcoholism mouse effect is best, whether this experiment is divided by SL-D021 low middle high three dosage again to test, have amount-result relation to exist to finding.
(1) experiment material
Test medicine: SL-D021 compound, outward appearance is buff powder, not soluble in water, and first dissolve with methyl-sulphoxide before using, then use normal saline dilution, the ratio of methyl-sulphoxide and physiological saline is 1: 9.
Bulk drug is put normal temperature in sealing bag and is preserved, and before experiment, interim physiological saline and methyl-sulphoxide are mixed with the not isocyatic solution of corresponding isometric(al).
56 degree of edible distillate spirits: Beijing Erguotou wine industry limited-liability company produces, food production licence: QS110015010354.
Physiological saline: pharmaceutical factory, Anhui BBCA Pharmaceuticals Co., Ltd. Tushan produces, authentication code: H34022484, product batch number: 090919-13.
Methyl-sulphoxide: Chemical Reagent Co., Ltd., Sinopharm Group produces, product batch number: T20080902.
Laboratory animal strain: ICR mouse, purchased from Shanghai western pul-Bi Kai laboratory animal company limited, male, body weight 22 ~ 24g.Quantity: 40.Rank: SPF level.Animal productiong credit number: SCXK (Shanghai) 2008-0016.
Animal divides cage adaptability to raise three days after buying back after our unit's experimental animal room, and use normal rats forage feed, freely drink water, light 12 hours light and shades are changed automatically, room temp 20-22 DEG C.
(2) dosage is arranged and grouping: SL-D021 dosage establishes 12.5mg/kg, and 25mg/kg, 50mg/kg tri-dosage groups, separately establish solvent control group, totally four groups.
Route of administration is intravenous administration, and with clinical plan route of administration is consistent from now on, administration volume is 10ml/kg(90% physiological saline+10% methyl-sulphoxide).Administration number of times is single.Administration time is 15min before alcohol gavage.
(3) experimental technique: mouse weights pneumoretroperitoneum injection test medicine, by 56 degree of edible distillate spirit 5.5ml/kg gavages after 15min, puts back to Animal House by animal after white wine gavage and normally raises, observe 48h mortality ratio.
(4) statistical study
Experimental result represents with mortality of animals, adopts chi square test to compare the difference of mortality of animals between administration group and control group, with P<0.05 for having statistical significant difference standard.
(5) experimental result
Table 2SL-D021 affects n=10 to alcoholism mouse death rate
| Group (mg/kg) | Mortality ratio (%) |
| Solvent control group | 70 |
| 12.5mg/kg group | 40 |
| 25mg/kg group | 20* |
| 50mg/kg group | 10** |
**P<0.01*P<0.05
In sum, the compounds of this invention is comparatively strong to ALDH2 agonism, and the exciting experiment effect of ALDH2 and Alda1 are quite in vitro, but in experimentation on animals, in the provide protection of alcoholism mouse significantly better than Alda1.
All documents that the present invention mentions are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.
Claims (1)
1. such as formula the compound shown in I or formula II, or its pharmaceutically acceptable organic or inorganic salt:
In the application that preparation ALDH2 agonist, preparation are treated crapulent medicine or prepared in antialcoholic drugs.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1732919A (en) * | 2004-08-11 | 2006-02-15 | 中国医学科学院药物研究所 | Application of bicyclol in preparation of drugs for preventing and/or treating acute alcoholism and acute and chronic alcoholic liver injury |
| US20090209533A1 (en) * | 2006-07-27 | 2009-08-20 | Jeff Zablocki | Aldh-2 inhibitors in the treatment of addiction |
| CN101669030A (en) * | 2007-03-08 | 2010-03-10 | 利兰·斯坦福青年大学托管委员会 | Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof |
| US20100113423A1 (en) * | 2008-10-28 | 2010-05-06 | Daria Mochly-Rosen | Modulators of Aldehyde Dehydrogenase and Methods of Use Thereof |
-
2013
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1732919A (en) * | 2004-08-11 | 2006-02-15 | 中国医学科学院药物研究所 | Application of bicyclol in preparation of drugs for preventing and/or treating acute alcoholism and acute and chronic alcoholic liver injury |
| US20090209533A1 (en) * | 2006-07-27 | 2009-08-20 | Jeff Zablocki | Aldh-2 inhibitors in the treatment of addiction |
| CN101669030A (en) * | 2007-03-08 | 2010-03-10 | 利兰·斯坦福青年大学托管委员会 | Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof |
| US20100113423A1 (en) * | 2008-10-28 | 2010-05-06 | Daria Mochly-Rosen | Modulators of Aldehyde Dehydrogenase and Methods of Use Thereof |
Non-Patent Citations (3)
| Title |
|---|
| Electron impact induced loss of C-5/C-8 substituents of 1,2,3,4-tetrahydroisoquinolines，V：Synthesis and mass spectrometric fragmentation of dihydroisoindole derivatives;Frank Knefeli，等;《Arch. Pharm.》;19891231;第322卷;第419-426页 * |
| RN：325809-77-6;ACS;《STN Registry数据库》;20010306;CAS RN：325809-77-6 * |
| RN：423729-70-8;ACS;《STN Registry数据库》;20020531;CAS RN：423729-70-8 * |
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