CN104382890B - The application in local nerve blocking medicine of the monoacetylaniline cationoid compound - Google Patents
The application in local nerve blocking medicine of the monoacetylaniline cationoid compound Download PDFInfo
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- CN104382890B CN104382890B CN201410688865.1A CN201410688865A CN104382890B CN 104382890 B CN104382890 B CN 104382890B CN 201410688865 A CN201410688865 A CN 201410688865A CN 104382890 B CN104382890 B CN 104382890B
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- 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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Abstract
The application in preparing local nerve blocking medicine of the N antifebrin cationoid compound.This cationic compound is a kind of quarternary ammonium salt compound, and structure is as shown in (I), and the X in formula is halogen atom.This compound is used alone, the feature such as can have that security is good and nerve block effect is strong, it is possible to plays reversible and lasting local anaesthesia effect in vivo, can use as long-acting and/or that realize selectively blocking local anesthetic or analgesic.The composition being particularly made up of with other local anesthetic this compound, when carrying out nerve block, more can have that rapid-action, effect is strong, long action time, to outstanding features such as neurotrosis are little.
Description
Technical field
The present invention relates to the application in preparing local nerve blocking medicine of a kind of monoacetylaniline cationoid compound.
This compound at least can be as the local anesthetic being used alone or analgesic, and security is good, particularly with clinic
When other local anesthetic of upper use is used in combination, can have more longlasting local nerve blocking synergy.
Background technology
Local anesthetic (Local anesthetics, local anaesthetics) is that a class is in the situation keeping sick human or animal to regain consciousness
Under, sensory nerve impulsion generation and transmission can be blocked at medication local reversible, cause the medicine of local organization analgesis.Office
The effect of anaesthetic is relevant with the anatomical features of nerve cell or the diameter of nerve fibre and nerve fiber.Universal law is god
Most sensitive to local anaesthetics through the synapses of fiber tip, neuromere and central nervous system, thin nerve fibre is more neural than thick
Fiber is more easy to be blocked.Can be effective when low concentration to fiber after unmyelinated sympathetic, parasympathetic ganglion.To medullated sense
Feel and motor fibre then needs high concentration ability generation effect.During to composite nerve generation effect, first disappear is to continue
Property dull pain (such as tenderness), next to that transience sharp pain, be followed by followed successively by the sense of cold, the sense of heat, sense of touch, pressure sensation disappear, finally transport
Dynamic paralysis.The mechanism of action of local anesthetic, the voltage-gated Na being recognized that at present on block nerves cell membrane+Logical
Road, makes block, produces local anesthetic action.
At present, the most all of local anesthetic is the molecule without electric charge, and they are for tissue and cell
Having certain penetrating power, its effect can rapidly disappear from medicine-feeding part diffusion along with medicine.If desired obtain long-acting
Local anaesthesia effect, needs to improve the dosage of medication；And improve dosage also can only proper extension action time, still can not obtain
Preferably long-lasting local anesthesia effect.Long-lasting local anesthesia drug treating time the most conventional is generally little less than 8
Time.
Local anesthetic typically all contains at least one tertiary atom N of non-amide-type, if again it being carried out an alkylidene
Replacement can obtain corresponding quaternary ammonium salt.Alkylation makes whole molecule have electric charge, thus is difficult to through cell membrane.As to benefit card
The tertiary atom N of cause the most once ethylizes, and will obtain being referred to as the quaternary ammonium salt (formula II) of QX-314, similar to QX-314, QX-
222(formula III) also it is a kind of quaternary ammonium salt of crossing of reporting.Under given conditions, QX-314 Yu QX-222 can produce local fiber crops
Liquor-saturated effect, but the activity of QX-314 is significantly higher than QX-222.Therefore the document about QX-314 is reported far more than QX-222.
Owing to QX-314 molecule is with electric charge, it is impossible to through cell membrane, thus local anaesthesia effect cannot be produced rapidly.
But it once through cell membrane, just can carry out strong suppression in film, thus produce lasting anesthesia sodium-ion channel
Effect.At present existing many research finds, QX-314 can with capsicim (transient receptor potential channel vanillic acid hypotype 1 activator,
I.e. TRPV1 Agonist) share, produce and long-acting separate retardance with kinaesthesis.But the intense stimulus of capsicim makes this group
Compound is difficult to have application prospect.Although there are some researches show, QX314 with use clinically such as Bupivacaine, lidocaine etc.
Local anesthetic share and can produce rapidly lasting anesthetic effect, can avoid the excitant of capsicim, but QX314 itself
Safety issue still cannot avoid, research is it has been found that the security of QX314 itself is unsatisfactory i.e. at present, mainly shows
For neurotrosis, and animal used as test during intrathecal injection, can be caused dead.Therefore QX314 is either used alone still and other
Active medicine is used in combination, and all there is the problem in terms of security.
Summary of the invention
In consideration of it, present invention firstly provides a kind of new cationic compound in preparing local nerve blocking medicine
Application, and further provide and a kind of with this cationic compound as raw material, there is local nerve blocking effect and analgesic activity
Composition.
This cationic compound of the present invention, for the monoacetylaniline cationoid compound of structure shown in formula (I).
Wherein, the anion X of formula (I) compound-Actually it is only used as charge-balancing moiety to exist, not there is drug effect and live
Property effect, unimportant to its selection, also will not be to actual effect and effect after replacement, therefore preferably at medicine
In the most commonly used bromine or chlorine.
The monoacetylaniline cationoid compound of formula (I) structure is the compound having had been reported at present.Deep grinds
Study carefully and experiment shows, because itself can have preferable local nerve blocking and analgesic activity, not only under same dose/concentration
Can have ratio more longlasting for a QX-314 anesthetic potency furtherd investigate at present, particularly and its security is more significantly better than
QX-314, neurotrosis is little, and intrathecal injection has no that experimental animal is dead, thus can directly as have local nerve blocking and
The drug use of analgesic activity.
Further research and experimentation also finds, by formula (I) compound and other conventional clinically local anesthetic,
Such as Bupivacaine, lidocaine, Ropivacaine, totokaine etc., can consist of have more preferably have local nerve resistance
Residual effect fruit and the composition of analgesic activity.The preferred proportion of a combination thereof is: the concentration of formula (I) compound is 0.5 ~ 55.7 mmoles
You/liter, the concentration of other local anesthetic is 0.66 ~ 74 mM/l.Said composition can play in vivo reversible and
More longlasting local anaesthesia effect (12 ~ 24 hours).
Therefore, the monoacetylaniline cationoid compound of formula (I) structure hinders as the local nerve with ideal effect
The stagnant medicinal compound with analgesic activity, has good DEVELOPMENT PROSPECT.
The foregoing of the present invention is described in further detail by detailed description of the invention by the following examples again.But
This should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to Examples below.Without departing from the above-mentioned technological thought of the present invention
In the case of, the various replacements made according to ordinary skill knowledge and customary means or change, the present invention all should be included in
In the range of.
Detailed description of the invention
Embodiment 1
Rat sciatic nerve retardance is carried out with compound I-Br and I-Cl of the X respectively bromine in formula (I) compound and chlorine,
Compared with the local anaesthetics of QX-314 and clinical typical concentrations, residence time is all obviously prolonged.
Experimental technique
Choosing SD rat, male and female half and half, experiment carries out behaviouristics adaptation, and choose the qualified rat of baseline 156 the last week
Only.It is randomly divided into 13 groups, often group 12, accepts left sciatic as shown in table 1 respectively and block, every 10 min after injection,
30 min, 60 min, 120 min, later every 2 h to 12 h, and the most every 12 h measure injection and survey sensation and the fortune of limbs
Dynamic function, until feeling, moving and recover completely.First sensation, the time point of motion retardance onset are anesthesia onset time；First
Individual sensation, the time point of motor function recovery are 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 local anaesthetics (Bupivacaine, lidocaine, sieve are commonly used than clinic
Piperazine cacaine and totokaine) it is obviously prolonged；And there is obvious dose-effect relationship in action time.The results are shown in Table 1.
Embodiment 2
Above-claimed cpd I-Br, I-Cl toxicity test to rat sciatic nerve.
Experimental technique
Rats all in embodiment 1 are carried out euthanasia in 7 days upon administration.Take every rat injection site sciatic nerve,
Being divided into two parts, after a copy of it HE dyeing, light Microscopic observation sciatic nerve tissues changes；Additionally portion makees electron microscopic observation.Light
Mirror visual score standard: 0 point (perilemma epineurium blood vessel is the most congested, and expansion, without cell infiltration)；1 point (adventitia blood vessel slightly fills
Blood, expansion, accompany a small amount of cell infiltration)；2 points (adventitia blood vessel is the most congested, expansion, accompanies cell infiltration)；3 points of (adventitia blood
Pipe is congested, expansion, and spinal cord parenchyma has cell infiltration).Electronic Speculum visual score: 0 point (nerve fibre ultra microstructure is without obvious pathology
Learn change)；1 point (part of nerve fibers has slight demyelinate)；2 points (part of nerve fibers has demyelinate phenomenon, occurs in endochylema
Cavity)；3 points (nerve fibre demyelinate phenomenon is serious, neuromechanism severe atrophy, middle visible big cavity, mitochondrial swelling).
Experimental result
As shown in table 2.Show that the sciatic nerve toxicity of I-Br, 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 randomly divided into 8 groups, often group 10, isoflurane fiber crops
Under liquor-saturated, percutaneous intrathecal injection 10 ul medicine as shown in table 2.Observe rat after injection and whether irritative symptoms occur: as writhing,
Shout, twitch, excited, stupor, even dead etc.(7)。
Experimental result
Result is summed up such as table 3.Intrathecal drug delivery, I-Br and I-Cl does not all result in death, and irritation incidence is low；
QX314 can cause death, and irritation incidence is high.Show that the toxicity of I-Br and I-Cl is significantly less than QX-314.
Embodiment 4
Combining with other conventional local anaesthetics, the anesthesia duration of I-Br and I-Cl is longer than QX-314, and feels-spor ts choice
Property blockage effect is preferable.
Experimental technique
According to the method for embodiment 1, use the model of rat sciatic nerve retardance, investigate 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)+lidocaine (1.15 ~ 15.38mM), Bupivacaine, lidocaine, sieve piperazine
Cacaine, the anaesthetic effect (each dosage ratio group n=10) of totokaine.Wherein, compound I is respectively I-Br and I-Cl.
Experimental result
When compound I and Bupivacaine combine, compound I with the molar percentage model in the compound preparation of Bupivacaine
Enclosing is 26.59 ~ 97.98%, and the molar percentage scope of Bupivacaine is 73.41 ~ 2.02%；Compound I with Ropivacaine
Molar percentage scope in compound preparation is 26.82 ~ 97.34%, 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 lidocaine compound preparation, lidocaine
Molar percentage scope is 92.98% ~ 12.68%；Compound I with the molar percentage scope in the compound preparation of totokaine is being
1.77 ~ 45.62%, the molar percentage scope of totokaine is 98.23 ~ 54.38%.Experimental result such as table 4.
Embodiment 5
Compound I combines with Bupivacaine, and toxicity when being applied to cavum subarachnoidale is significantly less than QX-314.
Experimental technique
According to the method for embodiment 2, use the model of rat intrathecal injection, with Bupivacaine respectively with QX-314, I-Br,
Or for subarachnoid injection after I-Cl combination, observe anaesthetic effect, excitant and the death rate (n=10).
Experimental result
Using after combining with Bupivacaine, chemical compounds I group does not occurs that death, excitant are greatly reduced；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 histology that the sciatic nerve of injection side in embodiment 4 carries out light microscopic and Electronic Speculum is seen
Examine；And calculate in maximum dose level group (being most likely to occur nervous lesion), the incidence of serious neurological damage.
Experimental result
As shown in table 6, maximum dose level polypharmacy, the neurotoxicity of I-Br Yu I-Cl is all much smaller than QX-314.
Above-mentioned test result indicate that, the monoacetylaniline cationoid compound that the present invention proposes can except when being used alone
Have outside definite local anaesthetic effect and analgesic activity, be particularly with other local anesthetic group used clinically
After the compound medicine closed, the security of use and long-acting and/or selectively retardance local anaesthesia and analgesic activity are the most more
For ideal.Above-mentioned experiment also indicates that simultaneously, the anion X's in monoacetylaniline cationoid compound of the present invention
Change, the effect that goes out embodied in experiment and/or effect can't be brought impact, and have reason to deduce, this N-acetophenone
Amine cation compound in addition to conventional other local anesthetic used with above-described embodiment institute combination, with include but not
It is limited to the local anesthetic group of other Clinical practice such as procaine, chloroprocanine, levobupivacaine, Articaine
Close, it is possible to have similar or same effect or effect.
Claims (4)
1. the monoacetylaniline cationoid compound of structure shown in formula (I) application in preparing local nerve blocking medicine,
It is characterized in that being collectively constituted by other local anesthetic of formula (I) compound Yu Clinical practice that there is local nerve blocking effect
With the composition of analgesic activity,
X in formula is halogen element.
Apply the most as claimed in claim 1, it is characterized in that the X in formula (I) structure is bromine or chlorine.
Apply the most as claimed in claim 1, it is characterized in that other described local anesthetic is Bupivacaine, benefit card
Any one in cause, Ropivacaine, totokaine, or any one in the salt compounds of these compounds.
4. the application as described in one of claims 1 to 3, is characterized in that described composition Chinese style (I) compound and other local
The portfolio ratio of anaesthetic is: the concentration of formula (I) compound is 0.5 ~ 55.7 mM/l, other local anesthetic
Concentration is 0.66 ~ 74 mM/l.
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| 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 |
| JP7436370B2 (en) * | 2018-02-11 | 2024-02-21 | ウェストチャイナホスピタル、スーチョワンユニバーシティ | Quaternary ammonium salt compounds and their preparation and use |
| WO2020156359A1 (en) * | 2019-02-01 | 2020-08-06 | 四川大学华西医院 | Quaternary ammonium salt compound, preparation method therefor and use 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 |
| WO2022037590A1 (en) * | 2020-08-17 | 2022-02-24 | 四川大学华西医院 | Quaternary ammonium salt compound for anesthesia, preparation method therefor, and use thereof |
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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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Effective date of registration: 20191122 Address after: 276006 No. 209 Hongqi Road, Shandong, Linyi Patentee after: Lunan Pharmaceutical Group Co., Ltd. Address before: 610041, Sichuan, Chengdu, Wuhou District Province, South China Sinology Lane No. 37 Patentee before: West China Hospital of Sichuan University |
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Effective date of registration: 20200325 Address after: 610041, Sichuan, Chengdu, Wuhou District Province, South China Sinology Lane No. 37 Co-patentee after: Lunan Pharmaceutical Group Corp. Patentee after: WEST CHINA HOSPITAL, SICHUAN University Address before: 610041, Sichuan, Chengdu, Wuhou District Province, South China Sinology Lane No. 37 Patentee before: WEST CHINA HOSPITAL, SICHUAN University |