CN104382890A - Application of N-acetanilide cationic compound in preparation of local nerve blocking drug - Google Patents
Application of N-acetanilide cationic compound in preparation of local nerve blocking drug Download PDFInfo
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- 229960001413 acetanilide Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 239000000203 mixture Substances 0.000 claims abstract description 7
- -1 quaternary ammonium salt compound Chemical class 0.000 claims abstract description 3
- 239000003589 local anesthetic agent Substances 0.000 claims description 18
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- 229960003150 bupivacaine Drugs 0.000 claims description 13
- GPRYKVSEZCQIHD-UHFFFAOYSA-N 1-(4-aminophenyl)ethanone Chemical compound CC(=O)C1=CC=C(N)C=C1 GPRYKVSEZCQIHD-UHFFFAOYSA-N 0.000 claims description 9
- 230000000202 analgesic effect Effects 0.000 claims description 9
- 229960004194 lidocaine Drugs 0.000 claims description 9
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 8
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- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
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- QTGIAADRBBLJGA-UHFFFAOYSA-N Articaine Chemical compound CCCNC(C)C(=O)NC=1C(C)=CSC=1C(=O)OC QTGIAADRBBLJGA-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
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- 229960002725 isoflurane Drugs 0.000 description 1
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- LEBVLXFERQHONN-INIZCTEOSA-N levobupivacaine Chemical compound CCCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-INIZCTEOSA-N 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
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- 229960004919 procaine Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
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- 230000001953 sensory effect Effects 0.000 description 1
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- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of an N-acetanilide cationic compound in preparation of a local nerve blocking drug. The cationic compound is a quaternary ammonium salt compound and has a structure as shown in a formula (I), wherein X is a halogen atom. When used alone, the compound has the characteristics of good safety performance, strong nerve blocking effect and the like, can take a reversible and durable local anaesthesia effect in vivo and can be used as a local anaesthesia drug or an analgesic drug which is long-acting and/or capable of realizing selective blocking. Particularly, a composition composed of the compound and other local anaesthesia drugs has the remarkable characteristics of high effect taking speed, strong effect, long acting time, little nerve injury and the like when used for nerve blocking.
Description
Technical field
The present invention relates to a kind of monoacetylaniline cationoid compound and prepare the application in local nerve blocking medicine.This compound at least can be used as the local anesthetic or analgesic that are used alone, and safety is good, time particularly with other local anesthetic conbined usage used clinically, can have more lasting local nerve blocking synergy.
Background technology
Local anesthetic (Local anesthetics, local anaesthetics) is a class when keeping sick human or animal to regain consciousness, and can block sensory nerve impulsion and occurs and transmit at medication local reversible, cause the medicine of local organization analgesis.The effect of local anaesthetics and neurocyte or the diameter of nerve fiber and the anatomical features of nervous tissue relevant.Universal law be nerve fiber tip, neuroganglion and central nervous system synapses the most responsive to local anaesthetics, thin nerve fiber is more easily blocked than thick nerve fiber.Can be effective when low concentration to fiber after unmyelinated sympathetic, parasympathetic ganglion.High concentration ability generation effect is then needed to medullated sensation and Motor nerve fibre.During to mixed nerve generation effect, what first disappear is persistence dull pain (as tenderness), is secondly transience sharp pain, is then followed successively by the sense of cold, the sense of heat, sense of touch, pressure sensation disappearance, finally moves paralysis.The mechanism of action of local anesthetic, is recognized that the voltage-gated Na on block nerves cell membrane at present
+passage, makes conduction block, produces local anesthetic action.
At present, local anesthetics all is clinically the molecule without electric charge, and they have certain penetrating power for tissue and cell, and its effect can rapidly disappear from medicine-feeding part diffusion along with medicine.If desired obtain long-acting local anesthesia effect, need the dosage improving medication; And increasing dose also can only proper extension action time, still can not obtain desirable long-lasting local anesthesia effect.Long-lasting local anesthesia drug treating time conventional clinically at present is generally no more than 8 hours.
Generally the tertiary atom N of at least one non-amide-type is all contained, if carry out an alkylidene replacement to it again can obtain corresponding quaternary ammonium salt in local anesthetic.Alkylation makes whole molecule have electric charge, thus not easily through cell membrane.As once ethylized again to the tertiary atom N of lignocaine, by obtaining the quaternary ammonium salt (formula II) being called as QX-314, similar to QX-314, QX-222(formula III) be also a kind of quaternary ammonium salt that reporting is crossed.Under given conditions, QX-314 and QX-222 can produce local anaesthetic effect, but the activity of QX-314 is significantly higher than QX-222.Therefore about the bibliographical information of QX-314 far more than QX-222.
Because QX-314 molecule is with electric charge, can not cell membrane be passed, thus cannot produce local anesthesia effect rapidly.But it once through cell membrane, just can carry out strong suppression to sodium-ion channel, thus produce lasting anesthetic action in film.At present existing many research discoveries, QX-314 can share with capsaicin (transient receptor potential channel vanillic acid hypotype 1 agonist, i.e. TRPV1 Agonist), produces long-actingly to be separated retardance with sensation of movement.But the intense stimulus of capsaicin makes this compositions be difficult to have application prospect.Although there are some researches show, QX314 with to use clinically can produce rapidly lasting anesthetic action as the local anesthetic such as bupivacaine, lignocaine share, the zest of capsaicin can be avoided, but the safety issue of QX314 itself still cannot be avoided, namely current research finds, the safety of QX314 itself is unsatisfactory, and main manifestations is nerve injury, and laboratory animal can be caused during intrathecal injection dead.Therefore QX314 no matter be used alone or with other active medicine conbined usage, all there is the problem of safety aspect.
Summary of the invention
Given this, the present invention provide firstly a kind of new cationic compound and is preparing the application in local nerve blocking medicine, and further provides a kind of compositions with local nerve blocking effect and analgesic activity being raw material with this cationic compound.
This cationic compound of the present invention is the monoacetylaniline cationoid compound of structure shown in formula I.
Wherein, the anion X of formula I compound
-in fact only exist as charge-balancing moiety, not there is drug activity effect, unimportant to its selection, also can not to actual effect and effect after replacement, the bromine therefore can preferably commonly used the most in medicine or chlorine.
The monoacetylaniline cationoid compound of formula I structure is the compound having report at present.Deep research and experiment show, because itself can have desirable local nerve blocking and analgesic activity, the anesthetic potency more lasting than the QX-314 of existing further investigation at present not only can be had under same dose/concentration, particularly and its safety is significantly better than QX-314, nerve injury is little, intrathecal injection has no experimental animal death, thus can directly as the drug use with local nerve blocking and analgesic activity.
Further research and experimentation also finds, by formula I compound and other conventional clinically local anesthetic, such as bupivacaine, lignocaine, ropivacaine, tetracaine etc., can consist of the compositions having and more preferably have local nerve blocking effect and analgesic activity.The preferred proportion of its combination is: the concentration of formula I compound is 0.5 ~ 55.7 mM/l, and the concentration of other local anesthetic is 0.66 ~ 74 mM/l.Said composition can play reversible and more lasting local anesthesia effect (12 ~ 24 hours) in vivo.
Therefore, the monoacetylaniline cationoid compound of formula I structure, as the medicinal compound of the local nerve blocking and analgesic activity with ideal effect, has good DEVELOPMENT PROSPECT.
Detailed description of the invention is by the following examples described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example.Without departing from the idea case in the present invention described above, the various replacement made according to ordinary skill knowledge and customary means or change, all should comprise within the scope of the invention.
Detailed description of the invention
embodiment 1
Be respectively the Compound I-Br of bromine and chlorine and I-Cl with the X in formula I compound and carry out rat sciatic nerve retardance, compared with the local anaesthetics of QX-314 and clinical typical concentrations, residence time all has obvious prolongation.
experimental technique
Choose SD rat, male and female half and half, the last week is carried out behavioristics's adaptation in experiment, and chooses the qualified rat of baseline 156.Be divided into 13 groups at random, often organize 12, accept left sciatic retardance as shown in table 1 respectively, every 10 min, 30 min, 60 min after injection, 120 min, every 2 h to 12 h later, and every 12 h measure injection and survey the sensation of limbs and motor function later, until sensation, motion recover completely.First sensation, the time point blocking onset that moves are anesthesia onset time; The time point of first sensation, motor function recovery is the anesthesia out-of-service time; Both are spaced apart the anesthesia maintenance time
(8,9).
experimental result
The residence time of I-Br, I-Cl is longer than QX-314; Also obviously extend than clinical conventional local anaesthetics (bupivacaine, lignocaine, ropivacaine and tetracaine); And there is obvious dose-effect relationship action time.The results are shown in Table 1.
embodiment 2
Above-claimed cpd I-Br, I-Cl are to the toxicity test of rat sciatic nerve.
experimental technique
Euthanasia was carried out in 7 days upon administration to rats all in embodiment 1.Get every rat injection site sciatic nerve, be divided into two parts, after a copy of it HE dyes, light Microscopic observation sciatic nerve tissues changes; Portion makes electron microscopic observation in addition.Light microscopic visual score standard: 0 point (epineurium blood vessel is slightly congested, and expansion, without cell infiltration); 1 point (adventitia blood vessel is slightly congested, and expansion, accompanies a small amount of cell infiltration); 2 points (adventitia blood vessel is obviously congested, expansion, companion's cell infiltration); 3 points (spinal cord parenchyma has cell infiltration for the adventitia congestion of blood vessel, expansion).Electronic Speculum visual score: 0 point (nerve fiber ultrastructure is without obvious Pathologic changes); 1 point (part of nerve fibers has slight demyelination); 2 points (part of nerve fibers has demyelination phenomenon, occurs cavity in endochylema); 3 points (nerve fiber demyelination phenomenon is serious, neuromechanism severe atrophy, middle visible large cavity, mitochondrial swelling).
experimental result
As shown in table 2.Show I-Br, the sciatic nerve toxicity of I-Cl is significantly less than QX-314.
embodiment 3
The toxicity test of the independent intrathecal drug delivery of I-Br and I-Cl.
experimental technique
As described in Example 1, choose qualified SD male rat 80, be divided into 8 groups at random, often organize 10, under isoflurane anesthesia, percutaneous intrathecal injection 10 ul medicine as shown in table 2.Observe rat after injection and whether occur irritative symptoms: as writhing, shout, twitch, excited, stupor, even dead etc.
(7).
experimental result
Result is summed up as table 3.Intrathecal drug delivery, I-Br and I-Cl does not all cause death, and irritation incidence rate is low; QX314 can cause death, and irritation incidence rate is high.Show that the toxicity of I-Br and I-Cl is significantly less than QX-314.
embodiment 4
Combine with other conventional local anaesthetics, the anesthesia duration of I-Br and I-Cl is longer than QX-314, and sensation-spor ts choice blockage effect is better.
experimental technique
According to the method for embodiment 1, adopt the model of rat sciatic nerve retardance, investigate the anaesthetic effect (each dosage ratio group n=10) of QX-314 (5.57 ~ 27.86mM)+bupivacaine (1.15 ~ 15.38mM), Compound I (5.57 ~ 27.86mM)+bupivacaine (1.15 ~ 15.38mM), QX-314 (5.57 ~ 27.86mM)+lignocaine (1.15 ~ 15.38mM), bupivacaine, lignocaine, ropivacaine, tetracaine.Wherein, Compound I is respectively I-Br and I-Cl.
experimental result
When Compound I and bupivacaine combine, Compound I is being 26.59 ~ 97.98% with the molar percentage scope in the compound preparation of bupivacaine, and the molar percentage scope of bupivacaine is 73.41 ~ 2.02%; Compound I is being 26.82 ~ 97.34% with the molar percentage scope in the compound preparation of ropivacaine, and the molar percentage scope of ropivacaine is 73.18 ~ 2.66%; Compound I is being 7.02 ~ 88.32% with the molar percentage scope in lignocaine compound preparation, and the molar percentage scope of lignocaine is 92.98% ~ 12.68%; Compound I is being 1.77 ~ 45.62% with the molar percentage scope in the compound preparation of tetracaine, and the molar percentage scope of tetracaine is 98.23 ~ 54.38%.Experimental result is as table 4.
embodiment 5
Compound I and bupivacaine combine, and toxicity when being applied to subarachnoid space is significantly less than QX-314.
experimental technique
According to the method for embodiment 2, adopt the model of rat intrathecal injection, for subarachnoid injection after combining with QX-314, I-Br or I-Cl respectively with bupivacaine, observe anaesthetic effect, zest and mortality rate (n=10).
experimental result
Use after combining with bupivacaine, there is not death in compounds I group, zest also reduces greatly; Toxicity is much smaller than QX-314 group.Result is as shown in table 5.
embodiment 6
After combining with other conventional local anaesthetics, the neurotoxicity of Compound I is much smaller than QX-314.
experimental technique
According to the method for embodiment 2, the histological observation of light microscopic and Electronic Speculum is carried out to the sciatic nerve of injection side in embodiment 4; And calculate in maximum dose level group (most possibly nervous lesion occurring), the incidence rate of serious neurological damage.
experimental result
As shown in table 6, maximum dose level polypharmacy, the neurotoxicity of I-Br and I-Cl is all much smaller than QX-314.
Above-mentioned experimental result shows, the monoacetylaniline cationoid compound that the present invention proposes is except having except definite local anaesthetic effect and analgesic activity when being used alone, be particularly after the compound medicine combined with other local anesthetic used clinically, local anesthesia and the analgesic activity of the safety of use and long-acting and/or selectivity retardance are all even more ideal.Above-mentioned experiment also shows simultaneously, the change of the anion X in monoacetylaniline cationoid compound of the present invention, impact can't be brought to the effect embodied in experiment and/or effect, and have reason to know by inference, this monoacetylaniline cationoid compound is except combining with above-described embodiment used other local anesthetic conventional, with include but not limited to that the local anesthetic of other Clinical practice such as procaine, chloroprocaine, levobupivacaine, articaine combines, also can have similar or same effect or effect.
Claims (5)
1. as shown in formula I, the monoacetylaniline cationoid compound of structure is preparing the application in local nerve blocking medicine,
X in formula is halogen element.
2. apply as claimed in claim 1, it is characterized in that the X in formula I structure is bromine or chlorine.
3. apply as claimed in claim 1 or 2, it is characterized in that the compositions with local nerve blocking effect and analgesic activity be jointly made up of other local anesthetic of formula I compound and Clinical practice.
4. apply as claimed in claim 3, it is characterized in that other described local anesthetic is any one in bupivacaine, lignocaine, ropivacaine, tetracaine, or any one in the salt compounds of these compounds.
5. the application as described in claim 3 or 4, it is characterized in that the portfolio ratio of formula I compound and other local anesthetic in described compositions is: the concentration of formula I compound is 0.5 ~ 55.7 mM/l, the concentration of other local anesthetic is 0.66 ~ 74 mM/l.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410688865.1A CN104382890B (en) | 2014-11-26 | 2014-11-26 | The application in local nerve blocking medicine of the monoacetylaniline cationoid compound |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410688865.1A CN104382890B (en) | 2014-11-26 | 2014-11-26 | The application in local nerve blocking medicine of the monoacetylaniline cationoid compound |
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| Publication Number | Publication Date |
|---|---|
| CN104382890A true CN104382890A (en) | 2015-03-04 |
| CN104382890B CN104382890B (en) | 2016-09-07 |
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| CN110092731A (en) * | 2018-01-31 | 2019-08-06 | 四川大学华西医院 | Dimethyl puratized agricultural spray class compound, preparation, self-assembled structures and the purposes that long-chain amine replaces |
| CN110156666A (en) * | 2018-02-11 | 2019-08-23 | 四川大学华西医院 | A kind of cationic compound and preparation method thereof and purposes |
| CN111153851A (en) * | 2019-02-01 | 2020-05-15 | 四川大学华西医院 | Quaternary ammonium salt compound and preparation method and application thereof |
| WO2021142577A1 (en) * | 2020-01-13 | 2021-07-22 | 易天奇 | Arylamide compound based on benzene ring supramolecular interaction, self-assembly morphology, and use |
| CN114075184A (en) * | 2020-08-17 | 2022-02-22 | 四川大学华西医院 | Quaternary ammonium salt compound for anesthesia and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601650A (en) * | 2013-01-16 | 2014-02-26 | 四川大学华西医院 | N-diethylaminoacetyl-2,6-dimethylaniline derivatives, preparation method and applications thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103601650A (en) * | 2013-01-16 | 2014-02-26 | 四川大学华西医院 | N-diethylaminoacetyl-2,6-dimethylaniline derivatives, preparation method and applications thereof |
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| CN110092731A (en) * | 2018-01-31 | 2019-08-06 | 四川大学华西医院 | Dimethyl puratized agricultural spray class compound, preparation, self-assembled structures and the purposes that long-chain amine replaces |
| CN110092731B (en) * | 2018-01-31 | 2022-03-04 | 四川大学华西医院 | Long-chain amine substituted dimethylanilinium compounds, preparation, self-assembly structure and application |
| CN110156666A (en) * | 2018-02-11 | 2019-08-23 | 四川大学华西医院 | A kind of cationic compound and preparation method thereof and purposes |
| CN110156666B (en) * | 2018-02-11 | 2022-04-12 | 四川大学华西医院 | Cation compound and preparation method and application thereof |
| CN111153851A (en) * | 2019-02-01 | 2020-05-15 | 四川大学华西医院 | Quaternary ammonium salt compound and preparation method and application thereof |
| CN111153851B (en) * | 2019-02-01 | 2022-02-08 | 四川大学华西医院 | Quaternary ammonium salt compound and preparation method and application thereof |
| WO2021142577A1 (en) * | 2020-01-13 | 2021-07-22 | 易天奇 | Arylamide compound based on benzene ring supramolecular interaction, self-assembly morphology, and use |
| CN113396139A (en) * | 2020-01-13 | 2021-09-14 | 易天奇 | Aryl amide compound based on benzene ring supermolecule interaction, self-assembly form and application |
| CN114075184A (en) * | 2020-08-17 | 2022-02-22 | 四川大学华西医院 | Quaternary ammonium salt compound for anesthesia and preparation method and application thereof |
| CN114075184B (en) * | 2020-08-17 | 2023-05-05 | 四川大学华西医院 | Quaternary ammonium salt compound for anesthesia and preparation method and application thereof |
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