WO2016015581A1 - 二甲基苯铵类长链化合物、制备、自组装结构及用途 - Google Patents

二甲基苯铵类长链化合物、制备、自组装结构及用途 Download PDF

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WO2016015581A1
WO2016015581A1 PCT/CN2015/084760 CN2015084760W WO2016015581A1 WO 2016015581 A1 WO2016015581 A1 WO 2016015581A1 CN 2015084760 W CN2015084760 W CN 2015084760W WO 2016015581 A1 WO2016015581 A1 WO 2016015581A1
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compound
long
self
product
gel
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French (fr)
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唐磊
刘进
张文胜
杨俊�
柯博文
尹芹芹
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四川大学华西医院
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Priority to SG11201700517PA priority Critical patent/SG11201700517PA/en
Priority to CA2955719A priority patent/CA2955719A1/en
Priority to RU2017103962A priority patent/RU2017103962A/ru
Priority to JP2017504006A priority patent/JP2017523175A/ja
Priority to EP15826906.8A priority patent/EP3187485A4/en
Priority to US15/327,962 priority patent/US10011562B2/en
Priority to KR1020177005646A priority patent/KR20170039258A/ko
Priority to AU2015296380A priority patent/AU2015296380A1/en
Publication of WO2016015581A1 publication Critical patent/WO2016015581A1/zh
Priority to PH12017500136A priority patent/PH12017500136A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings

Definitions

  • the present invention relates to a long-chain compound of dimethylanilinium which can have an ultra-long-acting anesthetic effect, a preparation method thereof, a self-assembled structure and use thereof.
  • Local anesthetics are drugs that can partially and reversibly block the occurrence and transmission of sensory nerve impulses in the case of keeping the patient or animal awake, causing the loss of local tissue pain.
  • the role of local anesthetics is related to the diameter of nerve cells or nerve fibers and the anatomical features of nerve tissue.
  • the general rule is that nerve fiber terminals, ganglia and synaptic parts of the central nervous system are most sensitive to local anesthetics, and fine nerve fibers are more easily blocked than coarse nerve fibers. For unmyelinated sympathetic, parasympathetic ganglion fibers can be markedly effective at low concentrations.
  • the effect of local anesthetics is generally limited to the site of administration and rapidly disappears as the drug spreads from the site of administration.
  • all clinical anesthetic drugs are non-charged molecules, which can only achieve local anesthesia and analgesia of no more than 8 hours, and can not meet the recovery of postoperative wounds, long-term pain and advanced cancer pain for more than 72 hours. The need for long-term local anesthesia. Therefore, there is a great need in the clinic for new long-acting local anesthetics that can produce more than 72 hours of action.
  • conventional local anesthetics generally contain at least one tertiary amine N atom, and then an alkyl substitution thereof can obtain a corresponding quaternary ammonium salt, so that the entire molecule has a charge and thus is not easy to pass through the cell membrane.
  • the ethyl quaternary ammonium salt of N-diethylaminoacetyl-2,6-dimethylaniline, referred to as QX314, is a previously reported quaternary ammonium salt compound having a local anesthetic effect.
  • QX314 has a strong polarity and cannot pass through the cell membrane, it cannot rapidly produce a powerful local anesthetic effect and thus cannot be directly used for clinical treatment.
  • the present invention first provides a class of long-chain compounds of dimethylanilinium which can have an ultra-long-acting anesthetic effect, and further provides a process for the preparation of the compound, as well as the self-assembled structure and use of the compound.
  • the dimethylammonium long-chain compound having the ultra-long-acting anesthetic effect of the present invention is a kind of N-diethylaminoacetyl-2,6-dimethylanilinium compound, and the structure is as shown in formula (I). Show:
  • X is a pharmaceutically acceptable anion or halogen
  • R & lt linear or branched, substituted or unsubstituted, saturated or unsaturated form of C 2 ⁇ 30 alkyl or C 2 ⁇ 30 alkoxy group
  • n An integer from 0 to 4.
  • the compound (IV) is further reacted with a corresponding linear or branched C 2-30 alkyl alcohol or a carboxylic acid compound starting material (V) to obtain the target compound (I).
  • the reaction process is as follows:
  • X is a halogen element or a pharmaceutically acceptable anion, preferably bromine
  • R 1 is a linear or branched, substituted or unsubstituted, saturated or unsaturated form of a C 2-30 alkyl or alkoxy group
  • Q is OH, COOH or COCl
  • Z is an OH or OCOCl compound
  • an integer of n 0 to 4.
  • the starting compound (IV) can be prepared by referring to the report of the publication No. CN103601650A.
  • long-chain dimethylammonium compound of the above formula (I) can be self-assembled into a micelle structure in the presence of water or an aqueous solvent, and is further used for local anesthesia.
  • the aqueous solvent is physiological saline or an organic solvent miscible with water and allowed to be used for a local injection, including ethanol, 1,2-propanediol, glycerin.
  • the micelle structure formed by self-assembly of the dimethylanilinium long-chain compound of the formula (I) of the present invention in the presence of water or an aqueous solvent can be a uniformly stable hydrogel. Tests have shown that it has a high concentration in water or an aqueous solvent and can be formed into a gel state; when the concentration is small, it can be formed into micelles.
  • micelles have been used in many fields including biomedical materials such as gene therapy.
  • the micelle structure formed by self-assembly of the dimethylanilinium long-chain compound of the structure of the formula (I) of the present invention can be preferentially applied in local anesthetics.
  • the experimental results show that the long-chain dimethylammonium compound of the above formula (I) of the present invention can be used for preparing a drug including local anesthesia, analgesia, antipruritic, and/or self-assembly of the compound.
  • the micelles or gels can produce local anesthetic effects for more than 72 hours, and thus have good application prospects in the preparation of local anesthetics or analgesics.
  • the micelle or gel formed by self-assembly of the compound can also be prepared as a carrier or delivery system for biomaterials and/or drug-encapsulated excipients as a biocompatible new formulation excipient for wrapping other drugs. Further used as a drug for local anesthesia or analgesia for related medical treatment.
  • the structural compound of the above formula (I) of the present invention may further be combined with procaine, lidocaine, and bupika.
  • Conventional anesthetic-active drugs such as ropivacaine, together constitute a drug with long-acting local anesthetic function.
  • the micelle or gel formed by self-assembly of the structural compound of the above formula (I) of the present invention may also further be subjected to transient sensitization decationization including TRPV1 and/or TRPA, capsaicin, sweet pepper, eugenol.
  • Channel agonist active compounds together constitute a drug with local anesthetic effects.
  • the onset time is shortened to 5 minutes, the sensory block time is still 80 hours, but the exercise block time is greatly reduced, which is 31 to 62 hours. Partially achieved motion-feeling separation block.
  • This feature gives the present invention a further prospect for clinical use: post-operative patients can exercise in moderate amounts without pain, which helps patients recover after surgery.
  • the structural compound of the above formula (I) is used in combination with capsaicin, sweet pepper, etc., the motor block time can be further reduced, only 11 to 20 hours, and the application can be expected to be larger.
  • the structural compound of the above formula (I) of the present invention and/or the micelle or gel formed by self-assembly of the compound in an aqueous solvent can exert a long-term local anesthetic effect in the living body, local anesthesia and/or The analgesic time can exceed 72 hours.
  • the micelle or gel and the local anesthetic biomaterial formed by self-assembly in water can also be used as a biological material for encapsulating a pharmaceutically active molecule and/or a drug carrier including symptoms for treating pain, itching and the like.
  • Formulation excipients used in delivery systems and the like have good prospects.
  • Figure 9 left TEM image of the formed hydrogel; right: hydrogel formed, 180° reversed, allowed to stand, and the fluidity is weakened.
  • Figure 10 left TEM image of the formed hydrogel; right: the formed hydrogel, 180° reversed, allowed to stand, to maintain the original shape.
  • Figure 11 left TEM image of the formed hydrogel; right: the formed hydrogel, 180° reversed, allowed to stand, to maintain the original form.
  • Figure 12 left TEM image of the formed hydrogel; right: The formed hydrogel was inverted at 180°, allowed to stand, and maintained in its original form.
  • the synthesis method was the same as in Example 3, and the yield was 36%.
  • Example 7 1.0 g of the product obtained in Example 7 was dissolved in 20 ml of dichloromethane, and a saturated aqueous solution of sodium chloride (20 ml) was eluted, and the organic layer was concentrated to dryness.
  • Methylene chloride: methanol 20:1 to 5:1 as an eluent silica gel column chromatography to give a white powdery solid.
  • reaction solution was concentrated to dryness under reduced pressure.
  • residue was purified by silica gel chromatography eluting elut elut elut elut eluting Test results:
  • reaction solution was concentrated to dryness under reduced pressure.
  • residue was purified by silica gel chromatography eluting elut elut elut elut eluting Test results:
  • reaction solution was concentrated to dryness under reduced pressure.
  • residue was purified by silica gel chromatography eluting elut elut elut eluting Test results:
  • reaction solution was concentrated to dryness under reduced pressure.
  • residue was purified by silica gel chromatography eluting elut elut elut eluting Test results:
  • the micelle size was 40-70 nm as determined by TEM. As shown in Figure 1.
  • the micelle size was 40-70 nm as determined by TEM. as shown in picture 2.
  • the micelles were 40-80 nm by TEM. As shown in Figure 3.
  • the product Upon TEM detection, the product self-assembled in a solvent to form micelles having a particle size of 20-30 nm. As shown in Figure 4.
  • Example 15 The product of Example 15 was self-assembled in a solvent to form micelles by TEM.
  • Example 15 The product of Example 15 was self-assembled in a solvent to form micelles by TEM.
  • Example 15 The product of Example 15 was self-assembled in a solvent to form micelles by TEM.
  • Example 15 The product of Example 15 was self-assembled in a solvent to form micelles by TEM.
  • the product Upon TEM detection, the product self-assembled in a solvent to form micelles. As shown in Figure 5.
  • Example 18 The product of Example 18 was self-assembled in a solvent to form micelles by TEM. As shown in Figure 6.
  • Example 15 The product of Example 15 was self-assembled in a solvent to form micelles by TEM. As shown in Figure 7.
  • Example 15 The product of Example 15 was self-assembled in a solvent to form micelles by TEM. As shown in Figure 8.
  • the product Upon TEM detection, the product self-assembled in water to form a layered micelle deposit, thereby forming a gel.
  • Figure 9 The left image of Figure 9 shows that the product self-assembles in water to form a layered micelle stack; the right figure shows that the product forms a hydrogel at room temperature, the fluidity is significantly weakened, and it is inverted by 180°, standing still. The original gel form can still be partially maintained.
  • the product After TEM detection, the product self-assembled in a solvent to form a layered micelle accumulation, thereby forming a gel.
  • Figure 10 The left image in Figure 10 shows that the product self-assembles in water to form a layered micelle stack; the right picture shows that the product forms a hydrogel at room temperature, the fluidity is significantly weakened, and the original gel morphology is maintained after 180° inversion. .
  • the product After TEM detection, the product self-assembled in a solvent to form a layered micelle accumulation, thereby forming a gel.
  • Figure 11 The left image in Figure 11 is the self-assembly of the product in water to form a layered micelle stack; the right picture shows that the product forms a hydrogel at room temperature, the fluidity is significantly weakened, and the original gel morphology can be maintained after 180° inversion. .
  • the product Upon TEM detection, the product self-assembled in a solvent to form a layered micelle accumulation, thereby forming a gel.
  • FIG 12. The left image in Figure 12 shows that the product self-assembles in water to form a layered micelle stack; the right picture shows that the product forms a hydrogel at room temperature, the fluidity is significantly weakened, and the original gel morphology is maintained after 180° inversion. .
  • Example 26 The product of Example 26 was self-assembled in a solvent to form a gel by TEM.
  • Example 26 The product of Example 26 was self-assembled in a solvent to form a gel by TEM.
  • Example 26 The product of Example 26 was self-assembled in a solvent to form a gel by TEM.
  • Example 26 The product of Example 26 was self-assembled in a solvent to form micelles by TEM.
  • Example 26 The product of Example 26 was self-assembled in a solvent to form a gel by TEM.
  • Example 26 The product of Example 26 was self-assembled in a solvent to form a gel by TEM.
  • Example 26 The product of Example 26 was self-assembled in a solvent to form a gel by TEM.
  • Example 26 The product of Example 26 was self-assembled in a solvent to form a gel by TEM.
  • Example 26 The product of Example 26 was self-assembled in a solvent to form a gel by TEM.
  • Example 26 The product of Example 26 was self-assembled in a solvent to form a gel by TEM.
  • Example 26 The product of Example 26 was self-assembled in a solvent to form a gel by TEM.
  • Example 3-32 The product of Example 3-32 was prepared as a solution as in Example 33 and was taken.
  • the above micelles were selected, and the lidocaine-positive control group and the saline-negative control group were given 28 groups of rats completely adapted to the experimental environment, with 5 rats in each group.
  • the dose was as follows: the concentration of the lidocaine group was 2% aqueous solution (84 mmol/L), and the concentration of the drug to be tested was 5 mmol/L.
  • the injection volume of each rat administered or control was 0.2 ml, guided by a nerve locator, and injected near the rat sciatic nerve.
  • the rats to be tested were placed on the operating table to inhale 5% isoflurane, and after the righting reflex disappeared, 1.5% isoflurane was inhaled through a self-made mask to maintain anesthesia.
  • the corresponding injection area of the appendix is shaved, and the disinfection is usually carried out.
  • Two anatomical landmarks of the greater trochanter and ischial tuberosity of the femur were removed, and the midpoint of the connection was the needle insertion site. Tighten the skin, insert the needle into the vertical skin with a 1ml syringe, and stop the needle after the needle tip reaches the ischial bone. After the aspiration was not returned, 0.2 ml of the drug solution was slowly injected. Withdraw the needle and close the isoflurane. Place the animals in the observation cage until they are naturally awakened.
  • Rats were subjected to the following behavioral observations at 10 min, 30 min, 60 min after injection, every hour after 4 h, and every 2 h, 18 h, 24 h, and every day until 5 days after 12 h, and the two were subjected to the following behavioral observations.
  • the treatment received by the rats was unknown.
  • Rats were placed in a transparent observation cage with a smooth metal frit at the bottom, and the lateral skin of the rat (the sciatic nerve innervation area) was stimulated from bottom to top with a proofreading standard von frey filament.
  • the application of von frey filaments starts at 0.4g and increases to 60g step by step.
  • the filament is slightly bent, or the rat is removed from the side limb, otherwise the stimulation is stopped after 3 seconds of stimulation.
  • Each test was tested 3 times with an interval of 5 min per test to avoid sensitization.
  • a neurological block is considered to be effective when the mechanical pain threshold exceeds 60 g.
  • the time interval between the time of the injection and the first mechanical pain threshold of more than 60 g is the mechanical pain block; the time from the completion of the injection to the time when the first mechanical pain threshold falls below 60 g is mechanical pain resistance.
  • Lag time; the difference between the two is the maintenance time of mechanical pain block.
  • the rat was lifted vertically and the injection side hind limbs were placed on the electronic platform surface, at which time the hind limb muscle strength of the rat was indicated by the value displayed by the limb pedaling balance.
  • the reading is the weight of the limb itself, about 20g.
  • Half of the measured value exceeds the difference between the baseline and the limb weight as a recovery of motor function, and less than or equal to this value is considered to be a loss of motor function.
  • the time interval between the time from the completion of the injection and the measurement of the disappearance of the first movement function is the onset time of the motion block; the time interval from the completion of the injection to the time when the first movement function disappears to the recovery is the motion block. Failure time; the difference between the two is the maintenance of motion block time.
  • the local anesthetic effect is shown in Table 1.
  • Example 18 The product of Example 18 was prepared in the same manner as in Examples 33-35, 41-48, respectively, and was used.
  • the above solution was selected, and the lidocaine positive control group and the saline negative control group were respectively given 12 groups of rats which were completely adapted to the experimental environment, and 5 rats in each group.
  • the dose was as follows: the lidocaine group concentration was 2% aqueous solution (84 mmol/L).
  • the injection volume of each rat administered or control was 0.2 ml, guided by a nerve locator, and injected near the rat sciatic nerve.
  • the experimental results show that the drug can produce local anesthesia for more than 72 hours.
  • lidocaine-positive control group and saline-negative control group were given 35 groups of rats completely adapted to the experimental environment, with 5 rats in each group.
  • the positive control was administered in a dose of lidocaine 2% aqueous solution (84 mmol/L).
  • the injection volume per administration or control of each rat was 0.2 g.
  • the control group was guided by the nerve locator and injected into the rat sciatic nerve.
  • the gel was embedded in the vicinity of the rat sciatic nerve.
  • Example 60 For specific operations and local anesthetic efficacy evaluation criteria.
  • the experimental results show that the drug can produce local anesthesia for more than 72 hours.

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Abstract

二甲基苯铵类长链化合物、制备、自组装结构及用途。该化合物能具有超长效麻醉效应，是一种N-二乙氨基乙酰-2,6-二甲基苯铵化合物，结构如式（Ⅰ）所示。该化合物可在含水溶剂中自组装形成胶束或凝胶，在生物体内可发挥长时间局部麻醉作用，局麻和/或镇痛作用时间可超过72小时。作为在水中能自组装形成的该胶束或凝胶和具有局麻作用的生物材料，同时还可以作为包裹包括治疗疼痛、瘙痒等症状的药物活性分子和/或药物载体的生物材料及传递系统等使用的制剂辅料，都具有良好的前景。

Description

二甲基苯铵类长链化合物、制备、自组装结构及用途 技术领域
本发明涉及一种可具有超长效麻醉效应的二甲基苯铵类的长链化合物、以及其制备方法、自组装结构及用途。
背景技术
局部麻醉药(local anaesthetics，局麻药)是一类在保持病人或动物清醒的情况下，能在用药局部可逆地阻断感觉神经冲动发生与传递，引起局部组织痛觉消失的药物。局麻药的作用与神经细胞或神经纤维的直径大小及神经组织的解剖特点有关。一般规律是神经纤维末梢、神经节及中枢神经系统的突触部位对局麻药最为敏感，细神经纤维比粗神经纤维更易被阻断。对无髓鞘的交感、副交感神经节后纤维在低浓度时可显效。对混合神经产生作用时，首先消失的是持续性钝痛(如压痛)，其次是短暂性锐痛，继之依次为冷觉、温觉、触觉、压觉消失，最后发生运动麻痹。局部麻醉药物的作用机制，目前公认的是阻断神经细胞膜上的电压门控性Na+通道，使传导阻滞，产生局麻作用。
局麻药的作用一般局限于给药部位并随药物从给药部位扩散而迅速消失。若需要获得长效的局部麻醉作用，除了改进局部麻醉药物的分子结构外，还需要提高用药的剂量。目前，临床上所有的局部麻醉药物均为不带有电荷的分子，只能实现不超过8小时的局麻与镇痛，不能满足术后创口恢复、长期疼痛和晚期癌痛等对超过72小时长效局麻的需求。因此，临床上非常需要能够产生超过72小时作用的新型长效局部麻醉药物。
目前的常规局部麻醉药物中一般都含有至少一个叔胺N原子，再对其进行一次烷基取代能得到相应的季铵盐，使整个分子具有了电荷，从而不易穿过细胞膜。被称为QX314的N-二乙氨基乙酰-2,6-二甲基苯胺的乙基季铵盐，就是较早报道的一个具有局麻作用的季铵盐化合物。但由于QX314分子极性较强，不能穿过细胞膜，因而无法快速地产生有力的局部麻醉作用，因而无法直接用于临床治疗。但是其对靶点位于细胞膜内侧的钠离子通道的抑制却十分强。一旦穿过细胞膜，就能在膜内对钠离子通道进行有力的抑制，并难于从细胞膜内扩散到细胞外，从而产生持久的麻醉作用(Courtney KR.J Pharmacol Exp Ther.1975,195:225–236)。目前已有许多研究发现，QX314能经TRPV1阳离子通道进入细胞膜，引起持久麻醉作用(Craig R.Ries.Anesthesiology.2009；111:122–126)。最新研究表明，在外加表面活性剂条件下，亦可通过形成胶束，帮助带电荷的QX314进入细胞膜，引起超过8小时的局麻作用(Daniel S.Kohane，PNAS.2010；107:3745-3750)。
发明内容
鉴于此，本发明首先提供了一类可具有超长效麻醉效应的二甲基苯铵类的长链化合物，并进一步提供该化合物的制备方法，以及该化合物的自组装结构和用途。
本发明所述的具有超长效麻醉效应的二甲基苯铵类长链化合物，是一类N-二乙氨基乙酰-2,6-二甲基苯铵化合物，结构如式(Ⅰ)所示：
Figure PCTCN2015084760-appb-000001
式中的X为卤素或药学上可接受的阴离子；R为直链或支链、取代或未取代、饱和或不饱和形式的C2～30烷基或C2～30烷氧基；n＝0～4的整数。
上述通式化合物中，可作为优选结构的化合物包括有：一类是式(Ⅰ)结构中的R为C12～30烷氧基或烷基；n＝1。另一类是式(Ⅰ)结构中的R为C2～11烷氧基或烷基；n＝1。
本发明上述式(Ⅰ)化合物的基本制备方法，按按下述方式进行：
由化合物(Ⅳ)再与相应的直链或支链C2～30烷基醇或羧酸化合物类原料(Ⅴ)反应，得到目标化合物(Ⅰ)，反应过程如下：
Figure PCTCN2015084760-appb-000002
式中的X为卤元素或药学上可接受的阴离子，优选为溴；R1为直链或支链、取代或未取代、饱和或不饱和形式的C2～30烷基或烷氧基；Q为OH，COOH或COCl；Z为OH或OCOCl化合物；n＝0～4的整数。其中，原料化合物(Ⅳ)可参照公开号CN103601650A文献的报道制备得到。
进一步的研究还发现，本上述式(Ⅰ)结构的二甲基苯铵类长链化合物，在水或含水溶剂存在的条件下，可以自组装形成为胶束结构，进一步用于局部麻醉。
其中，所述的含水溶剂为生理盐水或能与水混溶且允许用于局部注射剂的有机溶剂，包括乙醇、1,2-丙二醇、甘油。
所述由本发明式(Ⅰ)结构的二甲基苯铵类长链化合物在水或含水溶剂存在条件下自组装所形成的胶束结构，可成为一种均一稳定的水凝胶。试验显示，其在水或含水溶剂中浓度大，可形成为凝胶状态；浓度小，则可形成为胶束。
目前，胶束类物质在包括如基因治疗等生物医学材料领域已有了较多的应用。实验表明，本发明所述式(Ⅰ)结构的二甲基苯铵类长链化合物自组装所形成的该胶束结构，则可优先在局部麻醉药物中被应用。
实验结果表明，本发明上述式(Ⅰ)结构的二甲基苯铵类长链化合物，可用于制备包括局部麻醉、镇痛、止痒在内的药物，和/或由该化合物自组装形成的所述胶束或凝胶，能产生超过72小时的局部麻醉作用，因而在用于制备局部麻醉药物或镇痛药物中具有良好的应用前景。此外，由该化合物自组装形成的所述胶束或凝胶，还可作为生物相容的新型制剂辅料而制备成生物材料和/或药物包裹辅料的载体或传递系统，用于包裹其它药物后，进一步作为局麻或镇痛等药物而用于相关的医学治疗。
在此基础上，本发明上述式(Ⅰ)结构化合物进一步还可以与包括普鲁卡因、利多卡因、布比卡 因、罗哌卡因在内的常规具有麻醉活性的药物，共同组成具有长效局部麻醉功能的药物。由本发明上述式(Ⅰ)结构化合物自组装形成的所述胶束或凝胶，同样也可以进一步与包括TRPV1和/或TRPA、辣椒素、甜椒素、丁香酚在内的瞬态感受去阳离子通道激动剂活性化合物共同组成具有局部麻醉作用的药物。
其中，本发明上述式(Ⅰ)结构化合物与常规局麻药合用后，起效时间缩短至5分钟，感觉阻滞时间仍为80小时，但运动阻滞时间大幅度降低，为31～62小时，部分实现了运动-感觉分离阻滞。该特性使本发明具有进一步运用于临床的前景：术后患者能够在不痛的情况下适量运动，有助于患者术后康复。而当上述式(Ⅰ)结构化合物与辣椒素、甜椒素等合用时，运动阻滞时间可进一步降低，仅为11～20小时，可应用预期更大。
实验结果已表明，本发明上述式(Ⅰ)结构化合物和/或由该化合物在含水溶剂中自组装形成的胶束或凝胶，在生物体内可发挥长时间局部麻醉作用，局麻和/或镇痛作用时间可超过72小时。此外，作为在水中能自组装形成的该胶束或凝胶和具有局麻作用的生物材料，同时还可以作为包裹包括治疗疼痛、瘙痒等症状的药物活性分子和/或药物载体的生物材料及传递系统等使用的制剂辅料，都具有良好的前景。
以下通过实施例的具体实施方式再对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。在不脱离本发明上述技术思想情况下，根据本领域普通技术知识和惯用手段做出的各种替换或变更，均应包括在本发明的范围内。
附图说明
图1形成的胶束的透射电镜图片
图2形成的胶束的透射电镜图片
图3形成的胶束的透射电镜图片
图4形成的胶束的透射电镜图片
图5形成的胶束的透射电镜图片
图6形成的胶束的透射电镜图片
图7形成的胶束的透射电镜图片
图8形成的胶束的透射电镜图片
图9左图：形成的水凝胶的透射电镜图片；右图：形成的水凝胶经，180°反转，静置，流动性减弱。
图10左图：形成的水凝胶的透射电镜图片；右图：形成的水凝胶经，180°反转，静置，保持原形态。
图11左图：形成的水凝胶的透射电镜图片；右图：形成的水凝胶经，180°反转，静置，保持原形态。
图12左图：形成的水凝胶的透射电镜图片；右图：形成的水凝胶经，180°反转，静置，保持原形态。
具体实施方式
实施例1
中间化合物(Ⅳ)的制备
Figure PCTCN2015084760-appb-000003
将5g N-二乙氨基乙酰-2,6-二甲基苯胺溶于50ml 2-溴乙醇，在密闭容器中于90℃反应24h，之后将反应液缓慢滴加到200ml无水乙醚中并不断搅拌，析出白色固体，过滤，烘干，得产物(Ⅳ)2.37g，产率31％。
实施例2
中间化合物(Ⅳ)的制备
Figure PCTCN2015084760-appb-000004
将4.5g N-二乙氨基乙酰-2,6-二甲基苯胺和2.4g 2-溴乙醇，均匀混合于30ml 1,2-二氯乙烷中，在密闭容器中于100℃封管反应12h，之后将反应液缓慢滴加到200ml无水乙醚中并不断搅拌，析出白色固体，过滤，烘干，得产物(Ⅳ)2.06g，收率30％。
1H NMR(400MHz,CD3OD)δ：7.11～7.16(m,3H),4.50～4.51(m,2H),4.05～4.07(m,2H),3.75～3.87(m,6H),2.26(s,6H),1.43(t,J＝7.2Hz,6H)。
13C NMR(100MHz,CD3OD)δ：8.28,18.65,56.81,56.93,58.48,61.63,128.92,129.31,134.19,136.80,164.15。
HRMS:[C16H27N2O2]+，279.2075。
实施例3
Figure PCTCN2015084760-appb-000005
将3.0g N-二乙氨基乙酰-2,6-二甲基苯胺和等当量的2-溴乙酸甲酯，均匀混合于30ml 1,2-二氯乙烷中，在密闭容器中于100℃封管反应6h，之后将反应液缓慢滴加到200ml无水乙醚中并不断搅拌，析出白色固体，过滤，烘干，得产物1.96g，收率40％。
1H NMR(400MHz,CDCl3)δ：7.11～7.16(m,3H),6.03～6.07(m,2H),4.15～4.21(m,2H),3.75～3.87(m,6H),2.26(s,3H),2.15(s,6H),1.25(t,J＝7.2Hz,6H)。
13C NMR(100MHz,CDCl3)δ：8.28,18.65,20.4,56.81,56.93,58.48,61.63,128.92,129.31,134.19,136.80,164.15,170.2。
HRMS:[C17H27N2O3]+，307.4135。
实施例4
Figure PCTCN2015084760-appb-000006
合成方法同实施例3，收率36％。
1H NMR(400MHz,CDCl3)δ：7.11～7.16(m,3H),6.03～6.07(m,2H),4.15～4.21(m,2H),3.75～3.87(m,6H),2.35(t,J＝6.8Hz,2H),2.26(s,6H),2.12(s,6H),1,79(m,2H),1.25(t,J＝7.2Hz,6H),0.90(t,J＝7.0Hz,3H)。
13C NMR(100MHz,CDCl3)δ：7.32,13.50,18.40,18.65,35.82,56.81,56.93,58.48,61.63,128.92,129.31,134.19,136.80,164.15,170.2。
HRMS:[C19H31N2O3]+，335.4625。
实施例5
Figure PCTCN2015084760-appb-000007
合成方法同实施例3，收率32％。
1H NMR(400MHz,CDCl3)δ：7.11～7.16(m,3H),6.03～6.07(m,2H),4.15～4.21(m,2H),3.75～3.87(m,6H),2.26(s,6H),2.12(s,6H),1.25(t,J＝7.2Hz,6H),1.28(s,9H)。
13C NMR(100MHz,CDCl3)δ：7.32,18.65,27.43,38.42,56.81,56.93,58.48,61.63,128.92,129.31,134.19,136.80,164.15,170.2。
HRMS:[C20H33N2O3]+，349.4895。
实施例6
Figure PCTCN2015084760-appb-000008
于100ml圆底瓶中加入化合物(Ⅳ)3g，二氯甲烷50ml，吡啶0.7g，室温搅拌均匀。滴加乙酰氯0.7g的10ml二氯甲烷溶液，室温搅拌6h。
反应液减压浓缩至干。二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.06g，收率32％。检测结果：
1H NMR(400MHz，CDCl3)δ：10.36(s,1H),7.03～7.11(m,3H),4.99(br,2H),4.61(t,J＝4.8Hz,2H),4.01(t,J＝4.9Hz,2H),3.68～3.77(m,4H),2.26(br,6H),2.10(br,3H),1.49(t,J＝7.2Hz,3H).
13C NMR(100MHz,CDCl3)δ：8.47,18.92,20.87,56.43,57.48,57.77,57.82,127.61,128.19,132.84, 135.10,161.80,170.03.
HRMS:[C18H29N2O3]+，321.2177.
实施例7
Figure PCTCN2015084760-appb-000009
于100ml圆底瓶中加入正十二烷酸1.7g，二氯甲烷20ml，氯化亚砜2ml，回流搅拌1h。减压浓缩至干。残余物用二氯甲烷20ml溶解，备用。
于另一100ml圆底瓶中加入化合物(Ⅳ)3.0g，吡啶0.7g，室温搅拌均匀。缓慢滴加上述备用残余物的二氯甲烷溶液20ml，室温搅拌12h。
反应液减压浓缩至干。二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.58g，收率35％。检测结果：
1H NMR(400MHz，CDCl3)δ：10.43(br，1H),7.03～7.11(m,3H),5.06(br,2H),4.61～4.63(m,2H),4.00～4.02(m,2H),3.71～3.77(m,2H),2.34(t,J＝7.4Hz,2H),2.77(br,6H),1.59(t,J＝7.0Hz,2H),1.52(t,J＝7.0Hz,2H),1.26(br,16H),0.88(t,J＝6.5Hz,3H)。
13C NMR(100MHz,CDCl3)δ：8.51,14.11,18.90,18.93,22.67,24.61,26.90,29.08,29.22,29.32,29.43,29.58,31.89,33.95,56.45,57.18,57.77,127.60,128.19,132.82,135.08,161.81,172.90。
HRMS:[C28H49N2O3]+，461.3734.
实施例8
Figure PCTCN2015084760-appb-000010
参照实施例7方法，得到白色粉末状固体1.54g，收率31％。
1H NMR(400MHz，CDCl3)δ：10.48(s,1H),7.04～7.11(m,3H),5.13(s,2H),4.64(t,J＝5.2Hz,2H),3.98(t,J＝5.2Hz,2H),3.68～3.79(m,4H),2.35(t,J＝7.6Hz,2H),2.28(br,6H),1.61～1.73(m,2H),1.57(t,J＝7.2Hz,2H),1.26(br,24H),0.88(t,J＝7.0Hz,3H).
13C NMR(100MHz,CDCl3)δ：8.52,14.13,18.97,22.70,24.62,29.90,29.23,29.36,29.44,29.60, 29.66,29.69,31.92,33.95,56.49,57.06,57.87,127.67,128.23,132.73,135.01,161.63,172.89。
HRMS:[C32H57N2O3]+，517.4368.
实施例9
Figure PCTCN2015084760-appb-000011
将实施例7所得产品1.0g，溶解于20ml二氯甲烷中，饱和氯化钠水溶液20ml x 5萃洗，分液，有机层浓缩至干。二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体0.98g，收率90％。
1H NMR(400MHz，CDCl3)δ：10.43(br，1H),7.03～7.11(m,3H),5.06(br,2H),4.61～4.63(m,2H),4.00～4.02(m,2H),3.71～3.77(m,2H),2.34(t,J＝7.4Hz,2H),2.77(br,6H),1.59(t,J＝7.0Hz,2H),1.52(t,J＝7.0Hz,2H),1.26(br,16H),0.88(t,J＝6.5Hz,3H)。
离子色谱检测，氯离子含量99.9％。
实施例10
Figure PCTCN2015084760-appb-000012
将实施例8所得产品1.0g，溶解于20ml二氯甲烷中，饱和氯化钠水溶液20ml x 5萃洗，分液，有机层浓缩至干。二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体0.98g，收率91％。
1H NMR(400MHz，CDCl3)δ：10.48(s,1H),7.04～7.11(m,3H),5.13(s,2H),4.64(t,J＝5.2Hz,2H),3.98(t,J＝5.2Hz,2H),3.68～3.79(m,4H),2.35(t,J＝7.6Hz,2H),2.28(br,6H),1.61～1.73(m,2H),1.57(t,J＝7.2Hz,2H),1.26(br,24H),0.88(t,J＝7.0Hz,3H).
离子色谱检测，氯离子含量99.9％。
实施例11
Figure PCTCN2015084760-appb-000013
于100ml圆底瓶中加入化合物(Ⅳ)3.0g，三聚光气0.84g，二氯甲烷30ml，室温搅拌均匀。缓慢滴加吡啶0.6g，室温搅拌2h。
滴加乙醇2.0g的二氯甲烷溶液40ml，室温搅拌12h。
反应液减压浓缩至干。残余物以二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.55g，收率43％。检测结果：
1H NMR(400MHz，CDCl3)δ：10.48(s,1H),7.04～7.11(m,3H),5.05(br,2H),4.68(br,2H),4.22(t,J＝7.1Hz,2H),4.06(br,2H),3.74(br,2H),2.27(br,6H),1.52(br,6H),1.30(t,J＝7.1Hz,3H)。
13C NMR(100MHz,CDCl3)δ：8.52,14.16,18.90,56.59,57.88,60.64,65.08,127.57,128.17,132.88,135.12,154.15,161.79。
HRMS:[C19H31N2O4]+，351.2650.
实施例12
Figure PCTCN2015084760-appb-000014
于100ml圆底瓶中加入化合物(Ⅳ)3.0g，三聚光气0.84g，二氯甲烷30ml，室温搅拌均匀。缓慢滴加吡啶0.6g，室温搅拌2h。
滴加丁醇2.0g的二氯甲烷溶液40ml，室温搅拌12h。
反应液减压浓缩至干。残余物以二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.30g，收率35％。检测结果：
1H NMR(400MHz，CDCl3)δ：11.04(s,1H),7.02～7.10(m,3H),5.05(br,2H),4.68(br,2H),4.14(t,J＝6.8Hz,2H),4.04(br,2H),3.66～3.77(m,4H),2.27(s,6H),1.66(m,2H),1.52(t,J＝6.8Hz,6H),1.30(t, J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ：8.34,13.62,18.84,30.47,56.43,57.58,57.84,60.59,68.9076.77,127.42,128.12,133.11,135.01,154.31,161.75。
HRMS:[C21H35N2O4]+，379.2601.
实施例13
Figure PCTCN2015084760-appb-000015
于100ml圆底瓶中加入化合物(Ⅳ)3.0g，三聚光气0.84g，二氯甲烷30ml，室温搅拌均匀。缓慢滴加吡啶0.6g，室温搅拌2h。
滴加正己醇2.0g的二氯甲烷溶液40ml，室温搅拌12h。
反应液减压浓缩至干。残余物以二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.30g，收率34％。检测结果：
1H NMR(400MHz，CDCl3)δ：10.89(s,1H),7.03～7.10(m,3H),5.07(br,2H),4.68(br,2H),4.16(t,J＝6.8Hz,2H),4.04(m,2H),3.67～3.80(m,4H),2.28(s,6H),1.66(m,2H),1.54(t,J＝6.8Hz,6H),1.31(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ：8.42,14.00,14.21,18.89,22.49,25.26,28.45,31.32,56.54,57.71,57.88,60.42,60.53,69.33,76.73,127.52,128.17,132.96,135.02,154.31,161.71。
HRMS:[C23H39N2O4]+，407.3347.
实施例14
Figure PCTCN2015084760-appb-000016
于100ml圆底瓶中加入化合物(Ⅳ)3.0g，三聚光气0.84g，二氯甲烷30ml，室温搅拌均匀。缓慢滴加吡啶0.6g，室温搅拌2h。
滴加正庚醇2.0g的二氯甲烷溶液40ml，室温搅拌12h。
反应液减压浓缩至干。残余物以二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.30g，收率34％。检测结果：
1H NMR(400MHz，CDCl3)δ：10.34(s,1H),7.00～7.08(m,3H),5.00(m,2H),4.64(br,2H),4.16(t,J＝6.8Hz,2H),4.04(m,2H),3.66～3.76(m,4H),2.24(s,6H),1.60～1.63(m,2H),1.54～1.56(m,8H),0.86(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ：8.33,14.06,14.19,18.82,21.06,22.54,25.53,26.89,28.48,28.81,31.64,56.40,57.56,57.82,60.39,60.59,69.33,76.79,127.42,128.12,133.11,135.04,154.31,161.77。
HRMS:[C24H41N2O4]+，421.3070.
实施例15
Figure PCTCN2015084760-appb-000017
将实施例14所得产品1.0g，溶解于20ml二氯甲烷中，饱和氯化钠水溶液20ml x 5萃洗，分液，有机层浓缩至干。二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.0g，收率92％。
1H NMR(400MHz，CDCl3)δ：10.34(s,1H),7.00～7.08(m,3H),5.00(m,2H),4.64(br,2H),4.16(t,J＝6.8Hz,2H),4.04(m,2H),3.66～3.76(m,4H),2.24(s,6H),1.60～1.63(m,2H),1.54～1.56(m,8H),0.86(t,J＝7.2Hz,3H)。
离子色谱检测，氯离子含量大于99.9％。
实施例16
Figure PCTCN2015084760-appb-000018
于100ml圆底瓶中加入化合物(Ⅳ)3.0g，三聚光气0.84g，二氯甲烷30ml，室温搅拌均匀。缓慢滴加吡啶0.6g，室温搅拌2h。
滴加正辛醇2.0g的二氯甲烷溶液40ml，室温搅拌12h。
反应液减压浓缩至干。残余物以二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状 固体1.40g，收率35％。检测结果：
1H NMR(400MHz，CDCl3)δ：11.04(s,1H),7.02～7.10(m,3H),5.05(m,2H),4.68(br,2H),4.16(t,J＝6.8Hz,2H),4.04(m,2H),3.66～3.76(m,4H),2.27(s,6H),1.65～1.69(m,2H),1.52(t,J＝5.4Hz,6H),1.24～1.31(m,10H),0.89(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ：8.49,14.09,14.19,18.92,22.62,25.58,28.48,29.12,31.74,56.54,57.81,60.59,69.24,76.77,127.57,128.16,132.87,135.13,154.29,161.78。
HRMS:[C25H43N2O4]+，435.3223.
实施例17
Figure PCTCN2015084760-appb-000019
将实施例16所得产品1.0g，溶解于20ml二氯甲烷中，饱和氯化钠水溶液20ml x 5萃洗，分液，有机层浓缩至干。二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.0g，收率92％。
1H NMR(400MHz，CDCl3)δ：11.04(s,1H),7.02～7.10(m,3H),5.05(m,2H),4.68(br,2H),4.16(t,J＝6.8Hz,2H),4.04(m,2H),3.66～3.76(m,4H),2.27(s,6H),1.65～1.69(m,2H),1.52(t,J＝5.4Hz,6H),1.24～1.31(m,10H),0.89(t,J＝7.2Hz,3H)。
离子色谱检测，氯离子含量大于99.9％。
实施例18
Figure PCTCN2015084760-appb-000020
于100ml圆底瓶中加入化合物(Ⅳ)3.0g，三聚光气0.84g，二氯甲烷30ml，室温搅拌均匀。缓慢滴加吡啶0.6g，室温搅拌2h。
滴加正壬醇1.2g的二氯甲烷溶液40ml，室温搅拌12h。
反应液减压浓缩至干。残余物以二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.73g，收率39％。检测结果：
1H NMR(400MHz，CDCl3)δ：10.47(br，1H),7.03～7.11(m,3H),5.08(s,2H),4.66～4.69(m,2H),4.15(t,J＝6.7Hz,2H),4.04～4.11(m,2H),3.67-3.83(m,4H),2.28(br,6H),1.99(br,2H),1.63-1.70(m,2H),1.54(t,J＝7.2Hz,6H),1.30～1.37(m,4H),0.90(t,J＝4.0Hz,3H).
13C NMR(100MHz,CDCl3)δ：8.50,13.92,18.92,18.94,22.24,27.69,28.18,56.57,57.85,60.54,69.30,127.62,128.19,132.80,135.11,154.30,161.75.
HRMS:[C26H45N2O4]+，449.3387.
实施例19
Figure PCTCN2015084760-appb-000021
将实施例18所得产品1.0g，溶解于20ml二氯甲烷中，饱和氯化钠水溶液20ml x 5萃洗，分液，有机层浓缩至干。二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.0g，收率92％。
1H NMR(400MHz，CDCl3)δ：10.47(br，1H),7.03～7.11(m,3H),5.08(s,2H),4.66～4.69(m,2H),4.15(t,J＝6.7Hz,2H),4.04～4.11(m,2H),3.67-3.83(m,4H),2.28(br,6H),1.99(br,2H),1.63-1.70(m,2H),1.54(t,J＝7.2Hz,6H),1.30～1.37(m,4H),0.90(t,J＝4.0Hz,3H).
离子色谱检测，氯离子含量大于99.9％。
实施例20
Figure PCTCN2015084760-appb-000022
将实施例18所得产品1.0g，溶解于20ml二氯甲烷中，饱和甲磺酸钠水溶液20ml x 5萃洗，分液，有机层浓缩至干。二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.0g，收率92％。
1H NMR(400MHz，CDCl3)δ：10.47(br，1H),7.03～7.11(m,3H),5.08(s,2H),4.66～4.69(m,2H),4.15(t,J＝6.7Hz,2H),4.04～4.11(m,2H),3.67-3.83(m,4H),2.28(br,6H),1.99(br,2H),1.63-1.70(m,2H),1.54(t,J＝7.2Hz,6H),1.30～1.37(m,4H),0.90(t,J＝4.0Hz,3H).
离子色谱检测，甲磺酸离子含量大于99.9％。
实施例21
Figure PCTCN2015084760-appb-000023
将实施例18所得产品1.0g，溶解于20ml二氯甲烷中，饱和三氟乙酸钠水溶液20ml x 5萃洗，分液，有机层浓缩至干。二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.0g，收率92％。
1H NMR(400MHz，CDCl3)δ：10.47(br，1H),7.03～7.11(m,3H),5.08(s,2H),4.66～4.69(m,2H),4.15(t,J＝6.7Hz,2H),4.04～4.11(m,2H),3.67-3.83(m,4H),2.28(br,6H),1.99(br,2H),1.63-1.70(m,2H),1.54(t,J＝7.2Hz,6H),1.30～1.37(m,4H),0.90(t,J＝4.0Hz,3H).
离子色谱检测，三氟乙酸离子含量大于99.9％。
实施例22
Figure PCTCN2015084760-appb-000024
将实施例18所得产品1.0g，溶解于20ml二氯甲烷中，饱和硫酸钠水溶液20ml x 5萃洗，分液，有机层浓缩至干。二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.0g，收率92％。
1H NMR(400MHz，CDCl3)δ：10.47(br，1H),7.03～7.11(m,3H),5.08(s,2H),4.66～4.69(m,2H),4.15(t,J＝6.7Hz,2H),4.04～4.11(m,2H),3.67-3.83(m,4H),2.28(br,6H),1.99(br,2H),1.63-1.70(m,2H),1.54(t,J＝7.2Hz,6H),1.30～1.37(m,4H),0.90(t,J＝4.0Hz,3H).
离子色谱检测，硫酸根离子含量大于99.9％。
实施例23
Figure PCTCN2015084760-appb-000025
参照实施例18方法，得到白色粉末状固体，收率40％。
1H NMR(400MHz，CDCl3)δ：10.58(br，1H),7.02～7.10(m,3H),5.07(s,2H),4.66～4.69(m,2H),4.15(t,J＝6.8Hz,2H),4.04～4.07(m,2H),3.68～3.79(m,4H),2.27(br,6H),1.65(t,J＝7.1Hz,2H),1.53(t,J＝7.2Hz,6H),1.27-1.30(m,14H),0.88(t,J＝6.6Hz,3H).
13C NMR(100MHz,CDCl3)δ：8.49,14.13,18.92,22.68,25.60,28.50,29.18,29.30,29.48,29.52,31.88,56.56,57.81,57.89,60.56,69.29,127.57,128.18,132.87,135.10,154.30,161.75.
HRMS:[C27H47N2O4]+，463.3553.
实施例24
Figure PCTCN2015084760-appb-000026
将实施例23所得产品1.0g，溶解于20ml二氯甲烷中，饱和氯化钠水溶液20ml x 5萃洗，分液，有机层浓缩至干。二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.0g，收率92％。
1H NMR(400MHz，CDCl3)δ：10.58(br，1H),7.02～7.10(m,3H),5.07(s,2H),4.66～4.69(m,2H),4.15(t,J＝6.8Hz,2H),4.04～4.07(m,2H),3.68～3.79(m,4H),2.27(br,6H),1.65(t,J＝7.1Hz,2H),1.53(t,J＝7.2Hz,6H),1.27-1.30(m,14H),0.88(t,J＝6.6Hz,3H).
离子色谱检测，氯离子含量大于99.9％。
实施例25
Figure PCTCN2015084760-appb-000027
参照实施例18方法，得到白色粉末状固体，收率42％。
1H NMR(400MHz，CDCl3)δ：10.54(br，1H),7.03～7.11(m,3H),5.08(s,2H),4.66～4.69(m,2H),4.15(t,J＝6.8Hz,2H),4.04～4.06(m,2H),3.68-3.80(m,4H),2.28(br,6H),1.96(br,1H),1.65(t,J＝7.1Hz,2H),1.54(t,J＝7.2Hz,6H),1.26-1.30(m,16H),0.88(t,J＝6.6Hz,3H).
13C NMR(100MHz,CDCl3)δ：8.48,14.13,18.91,22.68,25.59,28.50,29.18,29.32,29.48,29.57,29.59,31.90,56.57,57.82,57.87,60.52,69.34,127.60,128.18,132.82,135.09,154.30,161.74.
HRMS:[C28H49N2O4]+，477.3694.
实施例26
Figure PCTCN2015084760-appb-000028
参照实施例18方法，得到白色粉末状固体，收率46％。
1H NMR(400MHz，CDCl3)δ：10.52(br，1H),7.03～7.11(m,3H),5.08(s,2H),4.67(t,J＝4.6Hz,2H),4.14(t,J＝6.8Hz,2H),4.04～4.06(m,4H),2.28(s,6H),2.03(br,2H),1.67(t,J＝6.8Hz,2H),1.53(t,J＝7.2Hz,6H),1.26～1.30(m,18H),0.88(t,J＝6.8Hz,3H).
13C NMR(100MHz,CDCl3)δ：8.49,14.14,18.92,22.70,28.50,29.19,29.35,29.49,29.58,29.64,31.92,56.57,57.82,57.87,60.54,69.32,127.60,128.18,132.83,135.11,154.30,161.76。
HRMS:[C29H51N2O4]+，491.3642.
实施例27
Figure PCTCN2015084760-appb-000029
将实施例26所得产品1.0g，溶解于20ml二氯甲烷中，饱和氯化钠水溶液20ml x 5萃洗，分液，有机层浓缩至干。二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.0g，收率92％。
1H NMR(400MHz，CDCl3)δ：10.52(br，1H),7.03～7.11(m,3H),5.08(s,2H),4.67(t,J＝4.6Hz,2H),4.14(t,J＝6.8Hz,2H),4.04～4.06(m,4H),2.28(s,6H),2.03(br,2H),1.67(t,J＝6.8Hz,2H),1.53(t,J＝7.2Hz,6H),1.26～1.30(m,18H),0.88(t,J＝6.8Hz,3H).
离子色谱检测，氯离子含量大于99.9％。
实施例28
Figure PCTCN2015084760-appb-000030
参照实施例18方法，得到白色粉末状固体，收率51％。
1H NMR(400MHz，CDCl3)δ：10.52(br，1H),7.02～7.10(m,3H),5.05(s,2H),4.67(t,J＝4.4Hz,2H),4.13(t,J＝6.8Hz,2H),4.05～4.07(m,2H),3.68～3.78(m,4H),2.27(s,6H),1.64(t,J＝6.9Hz,2H),1.51(t,J＝7.2Hz,6H),1.26～1.30(m,22H),0.88(t,J＝6.8Hz,3H).
13C NMR(100MHz,CDCl3)δ：8.49,14.13,18.91,22.69,25.60,28.50,29.20,29.36,29.50,29.57,29.65,29.67,29.69,31.92,56.53,57.80,57.87,60.59,69.25,76.76,127.56,128.16,132.88,135.12,154.30,161.79.
HRMS:[C31H55N2O4]+，519.4166.
实施例29
Figure PCTCN2015084760-appb-000031
参照实施例18方法，得到白色粉末状固体，收率59％。
1H NMR(400MHz，CDCl3)δ：10.60(br，1H),7.04～7.09(m,3H),5.12(s,2H),4.68(t,J＝4.5Hz,2H),4.16(t,J＝6.8Hz,2H),4.02～4.05(m,2H),3.64～3.82(m,4H),2.28(s,6H),1.64～1.68(m,2H),1.56(t,J＝7.2Hz,6H),1.26～1.31(m,26H),0.88(t,J＝6.4Hz,3H).
13C NMR(100MHz,CDCl3)δ：8.48,14.13,18.96,22.70,25.60,28.51,29.37,29.49,29.59,29.70,31.93,56.63,57.95,60.48,69.42,127.63,128.20,132.78,135.03,154.27,161.62.
HRMS:[C33H59N2O4]+，547.4478.
实施例30
Figure PCTCN2015084760-appb-000032
将实施例29所得产品1.0g，溶解于20ml二氯甲烷中，饱和氯化钠水溶液20ml x 5萃洗，分液，有机层浓缩至干。二氯甲烷:甲醇＝20:1至5:1为洗脱剂硅胶柱层析，得白色粉末状固体1.0g，收率92％。
1H NMR(400MHz，CDCl3)δ：10.60(br，1H),7.04～7.09(m,3H),5.12(s,2H),4.68(t,J＝4.5Hz,2H),4.16(t,J＝6.8Hz,2H),4.02～4.05(m,2H),3.64～3.82(m,4H),2.28(s,6H),1.64～1.68(m,2H),1.56(t,J＝7.2Hz,6H),1.26～1.31(m,26H),0.88(t,J＝6.4Hz,3H).
离子色谱检测，氯离子含量大于99.9％。
实施例31
Figure PCTCN2015084760-appb-000033
参照实施例18方法，得到白色粉末状固体，收率49％。
1H NMR(400MHz，CDCl3)δ：10.52(br，1H),7.03～7.11(m,3H),5.12(s,2H),4.68(t,J＝4.6Hz,2H),4.15(t,J＝6.8Hz,2H),4.04～4.06(m,2H),3.68～3.80(m,4H),2.28(s,6H),1.63～1.67(m,2H),1.54(t,J＝7.2Hz,6H),1.26～1.30(m,30H),0.88(t,J＝6.6Hz,3H).
13C NMR(100MHz,CDCl3)δ：8.50,14.14,18.94,22.70,25.60,28.50,29.21,29.37,29.51,29.60,29.67,29.71,31.93,56.58,57.84,57.80,60.54,69.33,127.60,128.19,132.83,135.10,154.30,161.74.
HRMS:[C35H63N2O4]+，575.4791.
实施例32
Figure PCTCN2015084760-appb-000034
参照实施例18方法，得到白色粉末状固体，收率48％。
1H NMR(400MHz，CDCl3)δ：10.53(br，1H),7.02～7.10(m,3H),5.08(s,2H),4.68(t,J＝4.5Hz,2H),4.14(t,J＝6.8Hz,2H),4.04～4.06(m,2H),3.66～3.81(m,4H),2.27(s,6H),1.63～1.67(m,2H),1.53(t,J＝7.2Hz,6H),1.26～1.30(m,34H),0.88(t,J＝6.6Hz,3H).
13C NMR(100MHz,CDCl3)δ：8.50,14.14,18.92,22.70,25.60,28.51,29.20,29.37,29.51,29.61,29.67,29.72,31.93,56.57,57.83,60.56,69.30,127.58,128.18,132.85,135.10,154.30,161.76.
HRMS:[C37H67N2O4]+，603.5096.
实施例33
于装有实施例14产物5mmol的西林瓶中，加入1ml蒸馏水，40℃振摇均匀，得到均一透明溶液。
经TEM检测，胶束粒径为40-70nm。如图1所示。
实施例34
于装有实施例19产物5mmol的西林瓶中，加入1ml生理盐水，40℃振摇均匀，得到均一透明溶液。
经TEM检测，胶束粒径为40-70nm。如图2所示。
实施例35
于装有实施例22产物5mmol的西林瓶中，加入1ml 5％乙醇溶液，40℃振摇均匀，得到均一透明溶液。
经TEM检测，胶束粒径为40-80nm。如图3所示。
实施例36
于装有实施例24产物5mmol的西林瓶中，加入1ml 5％1,2-丙二醇溶液，40℃振摇均匀，得到均一透明溶液。
经TEM检测，产物在溶剂中自组装形成了粒径为20-30nm的胶束。如图4所示。
实施例37
于装有实施例15产物5mmol的西林瓶中，加入1ml 5％1,2-丙二醇溶液，40℃振摇均匀，得到均一透明溶液。
经TEM检测，实施例15产物在溶剂中自组装形成了胶束。
实施例38
于装有实施例15产物5mmol的西林瓶中，加入1ml 5％甘油溶液，40℃振摇均匀，得到均一透明溶液。
经TEM检测，实施例15产物在溶剂中自组装形成了胶束。
实施例39
于装有实施例15产物5mmol和普鲁卡因3mmol的西林瓶中，加入1ml 5％乙醇溶液，40℃振摇均匀，得到均一透明溶液。
经TEM检测，实施例15产物在溶剂中自组装形成了胶束。
实施例40
于装有实施例15产物5mmol和利多卡因3mmol的西林瓶中，加入1ml 5％乙醇溶液，40℃振摇均匀，得到均一透明溶液。
经TEM检测，实施例15产物在溶剂中自组装形成了胶束。
实施例41
于装有实施例17产物25mmol和布比卡因3mmol的西林瓶中，加入1ml 5％乙醇溶液，40℃振摇均匀，得到均一透明溶液。
经TEM检测，产物在溶剂中自组装形成了胶束。如图5所示。
实施例42
于装有实施例18产物25mmol和罗哌卡因3mmol的西林瓶中，加入1ml 5％乙醇溶液，40℃振摇均匀，得到均一透明溶液。
经TEM检测，实施例18产物在溶剂中自组装形成了胶束。如图6所示。
实施例43
于装有实施例15产物25mmol和辣椒素3mmol的西林瓶中，加入2ml 5％乙醇溶液，40℃振摇均匀，得到均一透明溶液。
经TEM检测，实施例15产物在溶剂中自组装形成了胶束。如图7所示。
实施例44
于装有实施例15产物25mmol和甜椒素3mmol的西林瓶中，加入2ml 5％乙醇溶液，40℃振摇均匀，得到均一透明溶液。
经TEM检测，实施例15产物在溶剂中自组装形成了胶束。如图8所示。
实施例45
于装有实施例7产物25mmol的PV管中，加入1ml水，40℃振摇均匀，得到均一透明的凝胶。
经TEM检测，产物在水中自组装形成了层状胶束堆积，从而形成凝胶。如图9所示。图9中左图所示的是产物在水中自组装形成了层状胶束堆积；右图所示的是产物在室温形成了水凝胶，流动性显著减弱，经180°倒转，静置，仍能部分维持原有凝胶形态。
实施例46
于装有实施例19产物25mmol的PV管中，加入1ml水，40℃振摇均匀，得到均一透明的凝胶。
经TEM分别检测，产物在溶剂中自组装形成了层状胶束堆积，从而形成凝胶。如图10所示。图10中的左图是产物在水中自组装形成了层状胶束堆积；右图是产物在室温形成了水凝胶，流动性显著减弱，经180°倒转，仍能维持原有凝胶形态。
实施例47
于装有实施例22产物25mmol的PV管中，加入1ml水，40℃振摇均匀，得到均一透明的凝胶。
经TEM分别检测，产物在溶剂中自组装形成了层状胶束堆积，从而形成凝胶。如图11所示。图11中的左图是产物在水中自组装形成了层状胶束堆积；右图是产物在室温形成了水凝胶，流动性显著减弱，经180°倒转，仍能维持原有凝胶形态。
实施例48
于装有实施例26产物25mmol的PV管中，加入1ml水，40℃振摇均匀，得到均一透明的凝胶。
经TEM检测，产物在溶剂中自组装形成了层状胶束堆积，从而形成凝胶。如图12所示。图12中的左图是产物在水中自组装形成了层状胶束堆积；右图是产物在室温形成了水凝胶，流动性显著减弱，经180°倒转，仍能维持原有凝胶形态。
实施例49
于装有实施例26产物25mmol的西林瓶中，加入1ml生理盐水，40℃振摇均匀，得到均一透明的凝胶。
经TEM检测，实施例26产物在溶剂中自组装形成了凝胶。
实施例50
于装有实施例26产物25mmol的西林瓶中，加入1ml 5％乙醇溶液，40℃振摇1h，得到均一 透明的凝胶。
经TEM检测，实施例26产物在溶剂中自组装形成了凝胶。
实施例51
于装有实施例26产物25mmol的西林瓶中，加入1ml 5％1,2-丙二醇溶液，40℃振摇1h，得到均一透明的凝胶。
经TEM检测，实施例26产物在溶剂中自组装形成了凝胶。
实施例52
于装有实施例26产物25mmol的西林瓶中，加入1ml 5％甘油溶液，40℃振摇均匀，得到均一透明凝胶。
经TEM检测，实施例26产物在溶剂中自组装形成了胶束。
实施例53
于装有实施例26产物25mmol和普鲁卡因3mmol的西林瓶中，加入1ml 5％乙醇溶液，40℃振摇均匀，得到均一透明凝胶。
经TEM检测，实施例26产物在溶剂中自组装形成了凝胶。
实施例54
于装有实施例26产物25mmol和利多卡因3mmol的西林瓶中，加入1ml 5％乙醇溶液，40℃振摇均匀，得到均一透明凝胶。
经TEM检测，实施例26产物在溶剂中自组装形成了凝胶。
实施例55
于装有实施例26产物25mmol和布比卡因3mmol的西林瓶中，加入1ml 5％乙醇溶液，40℃振摇均匀，得到均一透明凝胶。
经TEM检测，实施例26产物在溶剂中自组装形成了凝胶。
实施例56
于装有实施例26产物25mmol和罗哌卡因3mmol的西林瓶中，加入1ml 5％乙醇溶液，40℃振摇均匀，得到均一透明凝胶。
经TEM检测，实施例26产物在溶剂中自组装形成了凝胶。
实施例57
于装有实施例26产物25mmol和辣椒素10mg的西林瓶中，加入1ml 5％乙醇溶液，40℃振摇均匀，得到均一透明凝胶。
经TEM检测，实施例26产物在溶剂中自组装形成了凝胶。
实施例58
于装有实施例26产物25mmol和甜椒素10mg的西林瓶中，加入1ml 5％乙醇溶液，40℃振摇均匀，得到均一透明凝胶。
经TEM检测，实施例26产物在溶剂中自组装形成了凝胶。
实施例59
于装有实施例26产物和甜椒素10mg的西林瓶中，加入2ml 5％乙醇溶液，40℃振摇1h，得到均一透明的凝胶。
经TEM检测，实施例26产物在溶剂中自组装形成了凝胶。
实施例60
将实施例3-32产物，按实施例33方法配制为溶液，备用。
选取上述胶束，利多卡因阳性对照组、生理盐水阴性对照组分别给予28组完全适应实验环境的受试大鼠，每组5只。给药剂量为：利多卡因组浓度为2％水溶液(84mmol/L)，待测药物浓度均为5mmol/L。每只大鼠给药或对照的注射体积为0.2ml，通过神经定位器导向定位，注射于大鼠坐骨神经附近。
具体操作及局麻药效评判标准如下：
坐骨神经阻滞：
将待测大鼠至于操作台上，使其吸入5％异氟烷，翻正反射消失后继续经自制面罩吸入1.5％异氟烷以维持麻醉。左侧卧位，骶尾部相应注射区域剃毛，常规消毒铺巾。扪出股骨大转子及坐骨结节两个骨性解剖标志，两者连线中点为进针部位。绷紧皮肤，以1ml注射器垂直皮肤进针，针尖抵至坐骨后，停止进针。抽吸无回血后，缓慢注射药液0.2ml。退针，关闭异氟烷。将动物放至观察笼中待其自然苏醒。
神经阻滞效果观察：
注射后10min、30min、60min、以后4h内每个小时、以后至12h内每2h、18h、24h、此后每天直至5天，专由两人对大鼠进行如下行为学观察，该两人对大鼠所接受的处理均不知情。
机械痛阈(VFH)：
大鼠置于底部为光滑金属筛板的透明观察笼内，用校对标准的von frey filament由下至上刺激大鼠足部外侧皮肤(坐骨神经支配区域)。von frey filaments的应用自0.4g开始，逐级增加至60g。每次刺激时，filament有轻微弯曲为准，要么大鼠移开该侧肢体，否则刺激时间达3s后人为停止刺激。每个测试时点测试3次，每次测试间隔时间为5min以避免敏化。
机械痛阈超过60g即认为神经阻滞有效。自注射完毕至第一次机械痛阈超过60g的测量时点之间的时间间隔为机械痛觉阻滞起效时间；自注射完毕至第一次机械痛阈降至60g以下的时间为机械痛觉阻滞失效时间；两者的差值为机械痛觉阻滞维持时间。
运动功能：
由后肢蹬踏试验(Postural Extensor Thrust,PET)评价。垂直提起大鼠并使注射侧后肢蹬在电子天平台面上，此时大鼠后肢肌力由肢体蹬踏天平而显示出的数值表示。肢体完全麻痹时，读数为肢体自身重量，约20g。测量值超过基线与肢体重量差值的一半视为运动功能恢复，小于或等于该值视为运动功能消失。
自注射完毕至第一次运动功能消失的测量时点之间的时间间隔为运动阻滞起效时间；自注射完毕至第一次运动功能由消失到恢复的时点之时间间隔为运动阻滞失效时间；两者的差值为运动阻滞维持 时间。局麻效果如表1所示。
表1 大鼠局麻效果实验1
Figure PCTCN2015084760-appb-000035
上述实验结果表明，实施例3-5的产物能够产生大于7小时的局部麻醉作用，实施例6-32的产物则都能够产生大于72小时的局部麻醉作用。
实施例61
将实施例产物18，分别按实施例33-35，41-48方法配制溶液，备用。
选取上述溶液，利多卡因阳性对照组、生理盐水阴性对照组分别给予12组完全适应实验环境的受试大鼠，每组5只。给药剂量为：利多卡因组浓度为2％水溶液(84mmol/L)。每只大鼠给药或对照的注射体积为0.2ml，通过神经定位器导向定位，注射于大鼠坐骨神经附近。
具体操作及局麻药效评判标准同实施例60。
局麻效果，如表2所示。
表2 大鼠局麻效果实验2
Figure PCTCN2015084760-appb-000036
实验结果表明，该类药物能够产生大于72小时的局部麻醉作用。
实施例62
将实施例7～10，13～32产物，按照实施例45方法，无菌条件下配置为25mmol/L，均一透明的水凝胶，备用。
取上述凝胶，利多卡因阳性对照组，生理盐水阴性对照组分别给予35组完全适应实验环境的受试大鼠，每组5只。阳性对照给药剂量为：利多卡因2％水溶液(84mmol/L)。每只大鼠给药或对照的注射体积为0.2g。其中对照组通过神经定位器导向定位，注射于大鼠坐骨神经附近；实验组大鼠，在七氟醚全麻后，通过手术，将凝胶包埋于大鼠坐骨神经附近。
具体操作及局麻药效评判标准参照实施例60。
待其苏醒后，观测局麻效果如表3。
表3 大鼠局麻效果实验3
Figure PCTCN2015084760-appb-000037
实验结果表明，该类药物能够产生大于72小时的局部麻醉作用。

Claims (10)

  1. 具有超长效麻醉效应的二甲基苯铵类长链化合物，是一类N-二乙氨基乙酰-2,6-二甲基苯铵化合物，结构如式(Ⅰ)所示：
    Figure PCTCN2015084760-appb-100001
    式中的X为卤素或药学上可接受的阴离子，优选为溴；R为直链或支链、取代或未取代、饱和或不饱和形式的C2～30烷基或烷氧基；n＝0～4的整数。
  2. 如权利要求1所述的化合物，其特征是所述式(Ⅰ)结构中的R为C12～30烷氧基或烷基；n＝1。
  3. 如权利要求1所述的化合物，其特征是所述式(Ⅰ)结构中的R为C2～11烷氧基或烷基；n＝1。
  4. 权利要求1至3之一所述的式(Ⅰ)结构二甲基苯铵类长链化合物的制备方法，其特征是按下述方式进行：
    由化合物(Ⅳ)与相应的直链或支链C2～30烷基醇或羧酸化合物类原料(Ⅴ)反应，得到目标化合物(Ⅰ)，反应过程如下：
    Figure PCTCN2015084760-appb-100002
    式中的X为卤元素或药学上可接受的阴离子，优选为溴；R1为直链或支链、取代或未取代、饱和或不饱和形式的C2～30烷基或烷氧基；Q为OH，COOH或COCl；Z为OH或OCOCl化合物；n＝0～4的整数。
  5. 权利要求1至3之一所述的二甲基苯铵类长链化合物，其特征是在水或含水溶剂存在的条件下，由其自组装形成的胶束结构，优选在局部麻醉中的应用。
  6. 如权利要求5所述的二甲基苯铵类长链化合物，其特征是所述的含水溶剂为生理盐水或能与水混溶且允许用于局部注射剂的有机溶剂，包括乙醇、1,2-丙二醇、甘油。
  7. 如权利要求5或6所述的二甲基苯铵类长链化合物，其特征是所述的自组装形成的胶束结构为均一稳定的水凝胶。
  8. 权利要求1至7之一所述的二甲基苯铵类长链化合物，其特征是在用于制备包括局部麻醉、镇痛、止痒在内的药物中的应用。
  9. 如权利要求5至7之一所述的二甲基苯铵类长链化合物，其特征是所述的自组装形成的胶束结构在用于制备生物材料和/或药物包裹辅料的载体或传递系统中的应用。
  10. 如权利要求8或9的应用，其特征是由所述的式(Ⅰ)结构化合物与包括普鲁卡因、利多 卡因、布比卡因、罗哌卡因在内的常规具有麻醉活性的药物共同组成具有长效局部麻醉功能的药物；或者是由所述的自组装形成的胶束结构与包括TRPV1和/或TRPA、辣椒素、甜椒素、丁香酚在内的瞬态感受去阳离子通道激动剂活性化合物共同组成具有局部麻醉作用的药物。
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