CN104744433A - ALD and application thereof as EV71 virus and CAV16 virus inhibitor - Google Patents
ALD and application thereof as EV71 virus and CAV16 virus inhibitor Download PDFInfo
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- CN104744433A CN104744433A CN201310746917.1A CN201310746917A CN104744433A CN 104744433 A CN104744433 A CN 104744433A CN 201310746917 A CN201310746917 A CN 201310746917A CN 104744433 A CN104744433 A CN 104744433A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a kind of ALD derivative or its pharmaceutically acceptable salts. Purposes and its application in the drug of preparation treatment hand-foot-and-mouth disease invention also provides the ALD derivative or its pharmaceutical acceptable salts class as EV71 and CAV16 inhibitor. The structural formula of ALD derivative is as shown in the formula (I):
The present invention provides above-mentioned ALD derivative or the preparation methods of its pharmaceutical acceptable salts class.
Description
Technical field
To the present invention relates on ALD derivative and pharmacology thereof acceptable salt and they are preparing the application in medicine, particularly relate to acceptable salt on ALD derivative and pharmacology thereof and suppressing the application in EV71 virus and CAV16 virus.
Background technology
People's hand foot mouth disease (Hand-foot-mouth disease, HFMD) be that global common transmittable is sick, China is all the hotspot of people's hand foot mouth disease all the time, the new cases quantity of China's hand foot mouth disease occupies first of China's Notifiable disease for continuous 3 years 2010,2011,2012, and has obvious ascendant trend.Also do not go on the market for the special efficacy antiviral of hand foot mouth disease at present.
Human enterovirus 71 (EV71 virus) and COxsackie A16 C-type virus C (CAV16 virus) are the main pathogens causing hand foot mouth disease in recent years in China.EV71 and CAV16 belongs to Picornaviridae, enterovirus genus.EV71 and CAV16 virion is icosahedron structure, and whole viral shell is made up of 60 substances (protomer), and each substance is made up of these four protein protomers of VP1, VP2, VP3 and VP4.Clinically, the symptom that CAV16 causes is usually comparatively slight, and in the hand foot mouth disease case caused at EV71, has minority case that serious central nervous system disease can occur, cause higher mortality ratio.
EV71 and CAV16, when infecting host cell, first combines with the specific receptors on host cell membrane, then by the endosome that host cell endocytosis is formed, enters into host cell inside.In endosome, there is a series of structural changes in the virion of EV71 and CAV16, and form a hole at the secondary shaft position of the positive icosahedro structure of virion, be released in cell cytosol by the RNA that viral capsid wraps up from this hole, this process is called the shell process of undressing of virus.
In the VP1 of EV71 and CAV16, there is a conservative hydrophobic pocket.This hydrophobic pocket is often occupied by the lipid molecule that a class comes from host cell in intact virus.By designing specific inhibitor, being combined in the conserved hydrophobic pocket of VP1, the shell process of undressing of enterovirus can be suppressed.Therefore infer, undressing in shell process in virus, will there is obvious conformational change in this hydrophobic pocket, and design suppresses the micromolecular inhibitor of this conformational change, can be undressed shell and suppress it to infect the process of host cell by suppression enterovirus.
Contriver have also discovered the existence of this conservative hydrophobic pocket in the VP1 of its EV71 and CAV16 whole virus particles of resolving, and finds that this pocket is occupied by the lipid molecule of a sphingosinols.According to the three-D space structure information of this hydrophobic pocket, can screen further or design micromolecular inhibitor, be combined in this hydrophobic pocket specifically, to suppress the shell process of undressing of EV71 and CAV16 virus.
Summary of the invention
The invention provides acceptable salt on a kind of ALD derivative or its pharmacology.
The structural formula of above-mentioned ALD derivative is as shown in the formula (I):
Wherein: R is selected from H; C1-6 alkyl; C1-6 alkylamino, as methylamino-, ethylamino.
The invention provides the preparation method of above-mentioned ALD derivative or its pharmaceutical acceptable salts class.
Be-CH with R
3for example, the synthetic method of the compounds of this invention is as follows:
(1) 4-bromopyridine-2-amine (4-bromopyridin-2-amine, dimethyl dicarbonate butyl ester ((Boc)
2o), DMAP (4-dimethylaminopyridine) and the trimethyl carbinol (tert-Butanol) at room temperature stir reaction overnight and obtain the bromo-pyridine of N-tertbutyloxycarbonyl-4--2-amine (tert-butylN-(4-bromopyridin-2-yl) carbamate);
(2) under a nitrogen, the bromo-pyridine of the N-tertbutyloxycarbonyl-4--2-amine that obtains of step (1) and 1-(5-[4-[(oxyethyl group imines) methyl] phenoxy group]-3-methyl amyl)-tetrahydroglyoxaline-2-ketone (1-(5-[4-[(ethoxyimino) methyl] phenoxy]-3-methylpentyl) imidazolidin-2-one) are at Johnphos(2-(di-t-butyl phosphine) biphenyl), Pd (dba)
2with potassiumphosphate (K
3pO
4) there is the lower reaction acquisition tertiary butyl-N-[4-[3-(5-[-4-[(oxyethyl group imines) methyl] phenoxy group]-3-methyl amyl)-2-Sinerol-1-base]-pyridine-2-base] carbonic ether (tert-butylN-[4-[3-(5-[4-[(ethoxyimino) methyl] phenoxy]-3-methylpentyl)-2-oxoimidazolidin-1-yl] pyridin-2-yl] carbamate);
(3) trifluoroacetic acid/dichloromethane (TFA/CH is added in the tertiary butyl-N-[4-[3-(5-[-4-[(oxyethyl group imines) methyl] phenoxy group]-3-the methyl amyl)-2-Sinerol-1-base]-pyridine-2-base] carbonic ether that step (2) obtains
2cl
2volume ratio=1:1) stirring at room temperature reaction, obtain 1-(PA-4-base)-3-(5-[4-[(oxyethyl group imines) methyl] phenoxy group]-3-methyl amyl)-tetrahydroglyoxaline-2-ketone
（1-(2-aminopyridin-4-yl)-3-(5-[4-[(ethoxyimino)methyl]phenoxy]-3-methylpentyl)imidazolidin-2-one）。
As follows with the said synthesis route that reaction formula represents:
These are only and exemplify, those skilled in the art can select other corresponding initial substance according to above-mentioned reaction scheme, prepare other compound in the present invention with identical reaction principle and route.Equally, those skilled in the art can obtain the pharmacy acceptable salt class of the compounds of this invention according to this area ordinary method.
ALD analog derivative provided by the invention be a class novel EV71 and CAV16 virus micromolecular inhibitor, in the pharmacodynamics test of cell levels, EV71 and the CAV16 virus strain of this type small molecular inhibitor to five kinds of different sourcess all presents good restraining effect.Thus the present invention also provides above-mentioned ALD derivative or its pharmaceutical acceptable salts class as the purposes of EV71 and CAV16 inhibitor and the application in the medicine of preparation treatment hand foot mouth disease thereof.
The present invention also provides acceptable salt on above-mentioned ALD analog derivative and pharmacology thereof separately or in conjunction with the application of other medicines, infects and the medicine of caused hand foot mouth disease and related complication for the preparation for the treatment of EV71 and CAV16.
Compound of the present invention can add pharmaceutically acceptable carrier and be prepared into pharmaceutical composition, and the dosage form of pharmaceutical composition and preparation method are this area routine techniques, as tablet, and capsule, pulvis, syrup, solution, suspension, injection, topical applications etc.
Accompanying drawing explanation
Fig. 1: utilize the collection of illustrative plates that nucleus magnetic resonance is confirmed the ALD compound that embodiment 1 is synthesized
Fig. 2: the mass spectrometric detection collection of illustrative plates of the compound that embodiment 1 is synthesized
Embodiment
Below with reference to preparation embodiment and effect example the present invention is described in further detail, but the scope of protection of present invention is not limited to the scope that following embodiment represents.
Embodiment 1:R is-CH
3the synthesis of the compounds of this invention:
(1) in 250 milliliters of round-bottomed bottles, 4-bromopyridine-2-amine (4-bromopyridin-2-amine) (5g, 28.90mmol) is added, dimethyl dicarbonate butyl ester ((Boc)
2o) (6.8g, 31.16mmol), DMAP (4-dimethylaminopyridine) (0.32g), the trimethyl carbinol (tert-Butanol) (70mL).Stirred overnight at room temperature, vacuum concentration, gained mixture volume ratio is that normal hexane/ether (hexane/ether) 30ml of 5:1 washs, obtain the bromo-pyridine of N-tertbutyloxycarbonyl-4--2-amine (tert-butylN-(4-bromopyridin-2-yl) carbamate) (4.5g, 57%), be white solid.
(2) under a nitrogen, the tertiary butyl-N-(4-bromopyridine-2-base is added in 50 milliliters of round-bottomed bottles) carbonic ether (i.e. step (1) prepare the bromo-pyridine of N-tertbutyloxycarbonyl-4--2-amine) (820mg, 3.00mmol), 1-(5-[4-[(oxyethyl group imines) methyl] phenoxy group]-3-methyl amyl)-tetrahydroglyoxaline-2-ketone (1-(5-[4-[(ethoxyimino) methyl] phenoxy]-3-methylpentyl) imidazolidin-2-one) (500mg, 1.50mmol), Johnphos(2-(di-t-butyl phosphine) biphenyl) (45mg), Pd (dba)
2(38.9mg), potassiumphosphate K
3pO
4(637mg, 3.0mmol), and Isosorbide-5-Nitrae-dioxane 25ml.Gained solution spends the night 60 DEG C of stirrings, cooling final vacuum concentrates, with 15 ml water washings, gained solution with ethyl acetate (each 15ml) extracts three times, organic layer merges, after vacuum concentration drying, on gained resistates, silica gel column chromatography is separated, obtain 200 milligrams of white solids, for product: the tertiary butyl-N-[4-[3-(5-[-4-[(oxyethyl group imines) methyl] phenoxy group]-3-methyl amyl)-2-Sinerol-1-base]-pyridine-2-base] carbonic ether (tert-butyl N-[4-[3-(5-[4-[(ethoxyimino) methyl] phenoxy]-3-methylpentyl)-2-oxoimidazolidin-1-yl] pyridin-2-yl] carbamate).
(3) in 50 milliliters of round-bottomed bottles, add the tertiary butyl-N-[4-[3-(5-[-4-[(oxyethyl group imines) methyl] phenoxy group]-3-the methyl amyl)-2-Sinerol-1-base]-pyridine-2-base] carbonic ether (200mg that step (2) obtains, 0.38mmol), trifluoroacetic acid/dichloromethane (TFA/CH
2cl
2volume ratio=1:1) 20ml.Gained solution stirring at room temperature 6 hours, after vacuum concentration, be separated with flash-preparative high-performance liquid chromatographic, obtaining 30mg (19%) faint yellow solid, is product: 1-(PA-4-base)-3-(5-[4-[(oxyethyl group imines) methyl] phenoxy group]-3-methyl amyl)-tetrahydroglyoxaline-2-ketone
（1-(2-aminopyridin-4-yl)-3-(5-[4-[(ethoxyimino)methyl]phenoxy]-3-methylpentyl)imidazolidin-2-one）；
1H-NMR(CDCl
3，ppm):7.866-7.837(m,3H),7.200(s,1H),6.896-6.777(m,4H),4.708(s,2H),4.278-4.209(m,2H),4.043(s,2H),3.744-3.693(m,2H),3.488-3.409(m,4H),1.901-1.821(m,4H),1.786-1.677(m,4H),1.464-1.383(m,3H).LC-MS(ES,m/z):426[M+H]
+(100%)。
The various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.Shortenings used herein is generally well-known to those skilled in the art, or can be understandable according to rudimentary knowledge.Shortenings used and implication as follows:
ALD compounds as hand foot mouth disease Causative virus inhibitor dissolves in dimethyl sulfoxide (DMSO) (DMSO) solvent, and the concrete compound used is prepared by embodiment 1, and other compounds adopted in the embodiment of the present application are all bought in Sigma.
The compounds of this invention suppresses the detection method of virus activity:
Adopt the cytopathy after observing virus infection cell and fluorometry.Namely first the inhibitor of different concns is added in the virus of certain titre, and hatch 1-1.5 hour in 37 DEG C of CO2gas incubator, and then remove infected cell with inhibitor and the mixed solution of virus, set up without inhibitor simultaneously and do not add viral control group, 5 days are cultivated in 37 DEG C of CO2gas incubator, visual inspection cytopathy situation, and the cell of pathology and the cell of non-pathology are counted, directly to calculate the restraining effect of inhibitor to virus infection.
Fluorometry is the virus of the band eGFP built: build eGFP gene in virus genomic front end, by transcribing the RNA obtaining virus, RNA transfection is entered RD cell, the virus of generating strap eGFP, when just can see green virus when fluorescence microscopy Microscopic observation.Add in 96 orifice plates by the inhibitor of gradient dilution and after virus incubation 1-1.5 hour, without inhibitor is set simultaneously and does not add viral control group.After for some time, virus starts infected cell, when producing fluorescent spot after cell entry cell.The virus quantity entering cell under different inhibitor concentration is different, virus infected cell after 24 hours at fluorescence microscopy Microscopic observation, according to the effective concentration of how many detection inhibitor of hot spot.If no special instructions, the virus that virus stain used is band eGFP is below tested.
Activity test method of the present invention comprises following 6 steps:
The preparation of step 1. viral inhibitors ALD compounds
The HIV suppression immunomodulator compounds of test is prepared by the method for embodiment 1, and purity is greater than 98%.
The process of step 2. compound
By HIV suppression immunomodulator compounds at 95%DMSO+5%ddH
2dissolve in O, be mixed with the solution of 10mM concentration, then the compound solution prepared is placed in 1.5ml ep pipe, saves backup at 4 DEG C.
Step 3.RD, Vero cell recovery and go down to posterity
From liquid nitrogen container, take out a RD cell and a Vero cell, cell cryopreservation tube is put into 37 DEG C of water-baths and thaw rapidly, cell is added in the 50ml centrifuge tube of the substratum filling 20mlDMEM+10%FBS+1%PS after thawing completely, mixing.Then 50ml centrifuge tube is put into whizzer, the centrifugal 3min of 800rpm, outwells supernatant, then uses the above-mentioned substratum re-suspended cell of 25ml, is transferred in T75 culturing bottle, at 37 DEG C, and 5%CO
2incubator in cultivate.Substratum in RD and Vero culturing bottle is sucked, add 10ml PBS respectively to clean, add 5ml 0.25% pancreatin in every bottle of T75 bottle, 37 DEG C of digestion 5min, are transferred in two centrifuge tubes, the centrifugal 3min of 800rpm, outwell supernatant, add 50ml substratum, then cell is respectively transferred in T75 culturing bottle, at 37 DEG C, 5%CO
2incubator in cultivate.
Step 4.EV71, CAV16 virus amplification
Get 5 RD cell T75 cell bottles, cell concn is about 90%, add 5 kinds of hand foot mouth disease Causative virus strains of 50 μ l respectively, be respectively EV71 (A), EV71 (B), EV71 (C), CAV16 (A) and CAV16 (B), at 37 DEG C, 5%CO
2incubator in cultivate.Protovirus titre (TCID50/ml) is respectively:
After step 5.EV71, CAV16 virus amplification, virus titer measures
5 kinds of virus titer measuring methods are identical, for EV71 (A): in one piece of 96 orifice plate, every Kong Jun adds 100 μ l concentration for 2 × 10
5rD or the Vero cell of individual cell/ml, at 37 DEG C, 5%CO
2incubator in cultivate 12h, now cell attachment, be 90% full scale.Every hole adds 100 μ l substratum again, and volume is 200 μ l.From-80 DEG C of refrigerators, take out EV71 (A) virus that a pipe is frozen, thaw rapidly in 37 DEG C of water-baths, get 22 μ l and join in 6 holes of secondary series, inhaling 22 μ l with the volley of rifle fire after mixing joins in next column 6 holes, analogy successively, until be diluted to the 11st row, at 37 DEG C, 5%CO
2incubator in cultivate.
Start observation of cell pathology after adding the virus of gradient dilution, if the complete pathology of cell is denoted as " ++++", 75% cytopathy is denoted as " +++ ", and 50% cytopathy is denoted as " ++ ", and 25% cytopathy is denoted as "+", does not have cytopathy to be denoted as "-".More than 50% cytopathy is designated as the positive, and the cytopathy of less than 50% is denoted as feminine gender, and Continuous Observation 4 ~ 5 days, until cytopathy is fixed.Reed & Muench Calculate method is adopted to calculate TCID
50.
The titre of the rear 5 kinds of viruses that increase on RD and Vero cell is respectively:
RD cell:
Vero cell
Step 6. viral inhibitors ALD compounds measures the inhibit activities of 5 kinds of hand foot mouth disease viruses on RD and Vero cell line
6.1 to inoculate 100 μ l concentration be respectively 2 × 10
5individual cell/ml RD and Vero cell in 96 orifice plates, at 37 DEG C, 5%CO
2incubator in cultivate 12h, now cell attachment, be 90% full scale.
Initial concentration is that the inhibitor compound solution DMEM substratum of the present invention of 400 μMs carries out proportional diluted in the ratio of 1:2 (volume ratio) by 6.2, and dilution is C1-C28 totally 28 concentration gradients altogether, concrete as table 1.
Table 1
| Numbering | Concentration (μM) | Numbering | Concentration (μM) | Numbering | Concentration (μM) | Numbering | Concentration (μM) |
| C1 | 100 | C8 | 0.78 | C15 | 6.1×10 -3 | C22 | 4.8×10 -5 |
| C2 | 50 | C9 | 0.39 | C16 | 3.1×10 -3 | C23 | 2.4×10 -5 |
| C3 | 25 | C10 | 0.20 | C17 | 1.5×10 -3 | C24 | 1.2×10 -5 |
| C4 | 12.5 | C11 | 0.10 | C18 | 7.6×10 -4 | C25 | 6.0×10 -6 |
| C5 | 6.25 | C12 | 4.9×10 -2 | C19 | 3.8×10 -4 | C26 | 3.0×10 -6 |
| C6 | 3.13 | C13 | 2.4×10 -2 | C20 | 1.9×10 -4 | C27 | 1.5×10 -6 |
| C7 | 1.56 | C14 | 1.2×10 -2 | C21 | 9.5×10 -5 | C28 | 7.5×10 -7 |
5 kinds of hand foot mouth disease Causative virus EV71 (A) in 6.3 RD and Vero step 4 increased two kinds clones, EV71 (B), EV71 (C), CAV16 (A), CAV16 (B) are diluted to 2000TCID with DMEM substratum
50.
6.4 are diluted to 2000TCID by the inhibitor compound and 6.3 of kind of the different concns gradient of 28 in 6.2
50rD and Vero two kinds of clones on 5 kinds of hand foot mouth diseases cause a disease malicious equal-volume mixing, now drug effect concentration is 1/2 in 6.2 tables.At 37 DEG C of 5%CO
2incubator in hatch 1-1.5 hour.
6.5 being joined in 6.1 by the mixed solution of the inhibitor of 5 kinds of hand foot mouth disease Causative virus after hatching in 6.4 and different concns gradient (i.e. the mixed solution of virus and medicine) is vaccinated with in 96 orifice plates of cell, at 37 DEG C, 5%CO
2incubator in cultivate 4 ~ 5 days.
6.6 observe and record cytopathy situation according to the method in step 5, and Continuous Observation 4 ~ 5 days, until cytopathy is fixed.Determine that inhibitor is to 5 kinds of hand foot mouth disease Causative virus inhibit activities by microscopic examination and cell counting, the inhibitor concentration that during half cell generation pathology, (++) is corresponding and be inhibitor to this kind of viral IC
50value.
Embodiment 2: inhibitor compound prepared by embodiment 1 suppresses the determination of activity of 5 kinds of hand foot mouth disease Causative virus EV71 (A), EV71 (B), EV71 (C), CAV16 (A) and CAV16 (B) infected cell
Inhibitor compound prepared by embodiment 1 is dissolved in 95%DMSO, is mixed with the solution of 10mM concentration, save backup at 4 DEG C.
According to experimental procedure 6, (inhibitor suppresses virus infection IC
50the mensuration of value) described in content operate, respectively test inhibitor compound to two kinds of cells (RD cell, the Vero cell) provide protection under above-mentioned five kinds of virus infections.Inhibitor concentration corresponding when method experimentally in step 5 observes half cell generation pathology, and obtain IC50 value.Shown in the result table 2 finally recorded:
Table 2
As can be seen from above experiment, the compound of the application all has significant restraining effect for 5 kinds of hand foot mouth disease Causative virus EV71 (A) in RD and Vero two kinds of clones, EV71 (B), EV71 (C), CAV16 (A), CAV16 (B), has broad application prospects in control related viral infections and hand foot mouth disease.
Claims (13)
1. suppress compound or its pharmacy acceptable salt of EV71 and/or CAV16 virus, described compound as shown in the formula (I),
Wherein: R is selected from H; C1-6 alkyl; C1-6 alkylamino.
2. compound as claimed in claim 1 or its pharmacy acceptable salt, wherein R is selected from methyl, methylamino-or ethylamino.
3. the compound described in any one of claim 1-2 or its pharmacy acceptable salt suppress the purposes in the medicine of EV71 and/or CAV16 virus in preparation.
4. the compound described in any one of claim 1-2 or its pharmacy acceptable salt prevent in preparation or treat the purposes in the medicine of hand foot mouth disease and related complication.
5. the compound according to any one of claim 1-2 or its pharmacy acceptable salt purposes in the medicine of the hand foot mouth disease caused by preparation treatment EV71 and CAV16 virus infection and related complication.
6. the compound according to any one of claim 1-2 or its pharmacy acceptable salt purposes in the medicine of preparation EV71 (A), EV71 (B), EV71 (C), CAV16 (A), CAV16 (B) virus infection and caused hand foot mouth disease and related complication.
7. a pharmaceutical composition, containing the compound described in any one of claim 1-2 or its pharmacy acceptable salt as activeconstituents.
8. a preparation, containing pharmaceutical composition according to claim 7, dosage form is selected from tablet, capsule, pulvis, syrup, solution, suspension, injection and topical applications.
9. pharmaceutical composition according to claim 7 or preparation according to claim 8 suppress the purposes in the medicine of EV71 and/or CAV16 virus in preparation.
10. pharmaceutical composition according to claim 7 or preparation according to claim 8 prevent in preparation or treat the purposes in the medicine of hand foot mouth disease and related complication.
11. pharmaceutical compositions according to claim 7 or preparation according to claim 8 purposes in the medicine of the hand foot mouth disease caused by preparation treatment EV71 and CAV16 virus infection and related complication.
12. pharmaceutical compositions according to claim 7 or preparation according to claim 8 purposes in the medicine of preparation EV71 (A), EV71 (B), EV71 (C), CAV16 (A), CAV16 (B) virus infection and caused hand foot mouth disease and related complication.
The preparation method of 13. 1 kinds of compounds:
Wherein: R is methyl; Step is as follows:
(1) 4-bromopyridine-2-amine, dimethyl dicarbonate butyl ester, DMAP and the trimethyl carbinol, at room temperature stirs and spends the night, react to obtain the bromo-pyridine of N-tertbutyloxycarbonyl-4--2-amine;
(2) the bromo-pyridine of the N-tertbutyloxycarbonyl-4--2-amine that obtains of step (1) and 1-(5-[4-[(oxyethyl group imines) methyl] phenoxy group]-3-methyl amyl)-tetrahydroglyoxaline-2-ketone are at 2-(di-t-butyl phosphine) biphenyl, Pd (dba)
2there is lower reaction with potassiumphosphate and obtain the tertiary butyl-N-[4-[3-(5-[-4-[(oxyethyl group imines) methyl] phenoxy group]-3-methyl amyl)-2-Sinerol-1-base]-pyridine-2-base] carbonic ether;
(3) trifluoroacetic acid and methylene dichloride is added in the tertiary butyl-N-[4-[3-(5-[-4-[(oxyethyl group imines) methyl] phenoxy group]-3-the methyl amyl)-2-Sinerol-1-base]-pyridine-2-base] carbonic ether that step (2) obtains, stirring at room temperature is reacted, and obtains 1-(PA-4-base)-3-(5-[4-[(oxyethyl group imines) methyl] phenoxy group]-3-methyl amyl)-tetrahydroglyoxaline-2-ketone.
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