WO2021142577A1 - 基于苯环超分子相互作用的芳基酰胺类化合物、自组装形态及用途 - Google Patents

基于苯环超分子相互作用的芳基酰胺类化合物、自组装形态及用途 Download PDF

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WO2021142577A1
WO2021142577A1 PCT/CN2020/071782 CN2020071782W WO2021142577A1 WO 2021142577 A1 WO2021142577 A1 WO 2021142577A1 CN 2020071782 W CN2020071782 W CN 2020071782W WO 2021142577 A1 WO2021142577 A1 WO 2021142577A1
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alkyl
integer
saturated
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易天奇
艾春霞
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易天奇
艾春霞
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Definitions

  • the invention relates to an arylamide compound with long-acting anesthetic effect and low toxicity, a preparation method, self-assembly form and application.
  • Local anaesthetics are drugs that can reversibly block the generation and transmission of sensory nerve impulses while keeping the patient or animal awake, causing local tissue pain to disappear.
  • the local neuropathic toxicity caused by local anesthetics and the systemic toxicity after entering the bloodstream may cause serious risks to the safety of patients.
  • the more serious neuropathological toxicity, caused by local nerve damage may continue to even irreversibly affect the basic functions of nerves after the efficacy of the drug disappears.
  • local anesthetics are only injected locally, they may enter the circulatory system due to one or more reasons such as excessive diffusion, rich local tissues and blood vessels, and injection into the blood vessels, leading to systemic toxicity such as cardiovascular toxicity and endangering the life of patients. . Therefore, while pursuing long-acting local anesthesia, it is equally important to control and reduce the local neuropathological toxicity and systemic toxicity that may be exacerbated by long-acting local anesthesia.
  • tertiary amine N atom such as lidocaine in Figure 1.
  • these drugs quickly diffuse into nerve cell membranes in the form of free alkali.
  • the difference in pH value inside and outside the cell membrane is used to form a tertiary amine hydrochloride form, which acts on the Na + channel target in the nerve cell membrane to produce local anesthesia.
  • tertiary amine hydrochloride since the formation of tertiary amine hydrochloride is reversible, the drug will also quickly diffuse out of nerve cells in the form of free alkali and stay away from nerve tissue, so it is difficult to have a long-term effect.
  • lidocaine can obtain the corresponding quaternary ammonium salt, making the whole molecule an irreversible cation QX-314. Due to the strong polarity of QX-314 molecule, it is difficult to penetrate the cell membrane to act on the target, and cannot quickly produce powerful local anesthesia, so it cannot be directly used in clinical practice. However, once passing through the cell membrane, the sodium ion channel can be strongly inhibited in the membrane, and it is difficult to diffuse from the cell membrane to the outside of the cell, resulting in a long-lasting anesthesia effect (KRCourtney.J Pharmacol Exp Ther.1975,195,225 -236).
  • Gemini surfactants have a special molecular structure, and after self-assembly in a solvent, they can produce a surface activity that is much stronger than that of monomers (FMMenger and JSKeiper.Angew.Chem.Int.Ed.2003,39, 1906-1920).
  • Common gemini surfactants include series and parallel types, as shown in Figure 2.
  • the hydrophilic head groups are mainly quaternary ammonium cations or acid salts of primary, secondary and tertiary amines, carboxylic acid or sulfonic acid anions, and structural fragments of polyhydroxy or polynitrogen and oxygen atoms; hydrophobic tail chain Most are straight-chain alkyl or aryl groups; most of the connecting groups in the middle are straight-chain alkyl groups, as shown in Figure 3 (L.Tang.Chem.Commun.2017,53,8675-8678).
  • the tandem gemini surfactant is similar to the parallel type, except that the hydrophobic tail chain and the linking group are combined into one.
  • tertiary amino acid salt structure of common local anesthetics such as lidocaine and bupivacaine can also be used as the hydrophilic head group of surfactants; the arylamide structure can also be used as the hydrophobic tail chain.
  • the long-acting local anesthetic molecule with the structural characteristics of gemini surfactants can not only help the difficult-to-diffusion quaternary ammonium cation to diffuse into the nerve cell membrane from the local injection site, but also produce a slow-release effect through its supramolecular structure.
  • these compounds are inevitably brought about by the surfactant structure, which is significantly higher than the local neuropathological toxicity and systemic toxicity of the local anesthetics on the market, which is not conducive to further clinical use.
  • the present invention first provides a class of arylamide compounds with ultra-long-lasting anesthetic effect and low toxicity, and further provides self-assembly methods and local anesthetic applications of this class of compounds.
  • R 1 and R 2 are saturated C 1-2 alkyl groups;
  • R 3 is a hydrogen atom, saturated or unsaturated C 1-3 alkyl groups or C 1-3 substituted alkyl groups;
  • X is A carbonyl group, an oxygen atom or a nitrogen atom;
  • Y is an oxygen atom, a nitrogen atom, a methylene group, a carbonyl group or a sulfoxide group;
  • Z is a methylene group, an oxygen atom or a nitrogen atom;
  • m 1 to 2 integer;
  • n 1 An integer of ⁇ 16.
  • R 1 is a C 1-2 alkyl group;
  • R 2 is a hydrogen atom, or a substituted or unsubstituted, saturated or unsaturated C 1-3 alkyl group.
  • the compound involved in the present invention is an integral molecule composed of an anion part and a cation part.
  • the anion part is not simply replaced by the commonly used anion in pharmacy, but is designed to include the asymmetric gemini surfactant structure, which can make the supermolecular self-assembly of this type of molecule in water to form an obvious ⁇ - ⁇ stacking
  • the role of organic acid ions Using sulfonate ions to replace carboxylate ions can also produce a similar long-lasting and low-toxic local anesthetic effect.
  • the present invention relates to a compound that is a super-molecular structure formed by self-assembly in water.
  • the unique strong ⁇ - ⁇ stacking effect of this type of compound achieves sustained release, and a single drug molecule with local anesthetic effect Transported into the nerve cell membrane, using the pH difference between the inside and outside of the nerve cell membrane to achieve anion exchange, obtain the quaternary ammonium cation chloride monomer that is difficult to diffuse out of the cell, and act on the Na + channel target on the inner side of the nerve cell membrane to achieve long-term local anesthesia effect.
  • anion exchange it will quickly lose the structure of the gemini surfactant and degrade into a low-toxic substance.
  • Compound (I) has atypical structural characteristics of asymmetric gemini surfactants. Take compound A1 as an example. Compared with the traditional quaternary ammonium cationic asymmetric gemini surfactants, the quaternary ammonium cation of this compound is not covalently connected to another hydrophilic head group through a linking group, but by its anion and a linking group (sub Methyl group), another hydrophilic head group (carbonate group) and hydrophobic tail chain (n-hexyl group) are connected in sequence ( Figure 4). In short, compound (I) is a gemini surfactant that connects different hydrophilic head groups through ionic bonds instead of conventional covalent bonds.
  • Two molecules of compound (II) can also form an atypical tandem gemini surfactant structure through ⁇ - ⁇ stacking.
  • the two ⁇ - ⁇ stacked benzene rings of compound B1 can be regarded as the long hydrophobic tail chain similar to the traditional tandem gemini surfactant molecule; the tertiary amino acid salt structure is a hydrophilic head group .
  • the NOESY spectrogram detection with the same concentration as TEM reveals that the hydrogen atom of 2,6-dimethyl is related to the hydrogen atom of 3,5- on the benzene ring, indicating that the compound A1 supermolecular self-assembly in water Later, the intermolecular methyl hydrogen and aromatic ring hydrogen are close in space, and their spatial proximity is significantly higher than that of other hydrogens, as shown in Figure 6.
  • compound (II) can still self-assemble in water to form strong ⁇ - ⁇ -stacking supramolecular particles, taking lidocaine formate (compound B1) as an example.
  • lidocaine formate compound B1
  • the compound can self-assemble to form gourd-shaped Janus particles.
  • NOESY spectra with the same concentration as TEM can still be found that the hydrogen atom of 2,6-dimethyl is related to the hydrogen atom of the 3,5-benzene ring, as shown in Figure 7. This shows that lidocaine formate also has intermolecular ⁇ - ⁇ stacking.
  • lidocaine formate Two molecules of lidocaine formate will form an atypical tandem gemini surfactant structure due to ⁇ - ⁇ stacking, and further self-assemble with a single lidocaine formate molecule to form Janus particles.
  • formic acid is a weak acid
  • the charge repulsion capability of the formed two tertiary amine formate ion pairs is weaker than that of the strong acid salt, which is conducive to the realization of ⁇ - ⁇ accumulation.
  • lidocaine hydrobromide After lidocaine hydrobromide self-assembles in water, it can only form spherical micelles, and the NOESY spectrum also shows no correlation with hydrogen.
  • both the compounds (I) and (II) involved in the present invention can self-assemble in water to form an ordered supramolecular structure with strong ⁇ - ⁇ stacking action, including spherical micelles and Janus particles.
  • the present invention relates to a compound that self-assembles in water to form an ordered supramolecular structure including spherical micelles and Janus particles. When injected locally, these particles diffuse into the nerve cell membrane, and after anion exchange, a quaternary ammonium cation chloride is formed, which blocks the Na + channel inside the cell membrane and produces local anesthesia, as shown in Figure 9.
  • the present invention relates to nano micelles and/or particles formed by self-assembly of compounds, which have a unique strong ⁇ - ⁇ stacking effect, and their diffusion and slow-release abilities are stronger than common surfactants before entering nerve cell membranes. This characteristic is one of the reasons why such compounds can achieve long-term effects.
  • the compound of the present invention is a weakly acidic carboxylate
  • anion exchange is prone to occur according to the basic principle of replacing a weak acid by a strong acid.
  • the main anion in the cell is chloride
  • the compound after exchange is mainly chloride.
  • Such quaternary ammonium cation chlorides which are weak in lipophilicity, are more difficult to permeate through cell membranes, and thus are difficult to diffuse and fail. This property is another important reason for the long-term effect of this class of compounds.
  • the compound (I) involved in the present invention is a carboxylate of a quaternary ammonium cation. Its potential local neuropathological toxicity can lose the structural characteristics of its gemini surfactant through the ion exchange in nerve cells mentioned above, greatly reducing its diffusion ability, thereby reducing the damage caused by the surfactant structure. Other molecules with a surfactant structure that have been reported have a covalently connected overall structure, and do not have the unique characteristics of the compound of the present invention to quickly lose surface activity through ion exchange, so the local toxicity is relatively large.
  • the compound when the carboxylate ion is replaced by the sulfonate ion, the compound can still produce a similar low-toxicity and long-acting effect.
  • the difference is that the organic sulfonate ion is more acidic, enters the nerve cell membrane, has a weak ability to exchange chloride ions, and easily diffuses out of the nerve cell again. Therefore, the local anesthetic effect is relatively short, and the local and systemic toxicity are also increased.
  • the acid radical ion is a saturated fatty acid, because the basic structure of the gemini surfactant is lost, the long fatty chain will interfere with the ⁇ - ⁇ accumulation of the aromatic ring. This type of supramolecular structure will reduce the slow-release ability and the action time will be significantly shorter ( Example 13, Table 1).
  • the mechanism for producing low toxicity and long-acting effect is similar to that of formula (I), both of which are related to weakly acidic organic acid radicals and strong ⁇ - ⁇ accumulation.
  • the difference is that the compound of formula (II) has more stringent requirements for organic acid radicals.
  • the acidity needs to be moderate. If the acidity is too strong, such as hydrochloric acid and hydrobromic acid, it is difficult to produce long-term effects; if the acidity is insufficient, the water solubility is insufficient, such as hydrofluoric acid.
  • the volume of acid radicals should be small. For example, glacial acetic acid and a larger volume of organic acids can cause local space crowding, making it difficult to achieve effective ⁇ - ⁇ accumulation ( Figure 7), and the local anesthesia time is significantly shorter than that of formate.
  • micellar biomaterial that can be self-assembled in water, it can also be used as a preparation auxiliary material for packaging biomaterials and delivery systems that include pharmacologically active molecules and/or drug carriers for the treatment of pain, itching and other symptoms. Good prospects.
  • Figure 1 is a schematic diagram of the mechanism of action of local anesthetics
  • Figure 2 is a schematic diagram of "parallel type” and "series type” gemini surfactants
  • Figure 3 is a schematic diagram of the structure of a parallel asymmetric gemini surfactant with local anesthetic activity
  • Figure 4 is a schematic diagram of the structure of the "parallel type" gemini surfactant A1 connected by ionic bonds;
  • Figure 5 is a schematic diagram of the structure of tandem gemini surfactant B1 with ⁇ - ⁇ stacking connection of benzene rings;
  • Figure 6 is a TEM picture of self-assembly of compound A1 in water and a NOESY spectrum in heavy water;
  • Figure 7 is a TEM picture of self-assembly of compound B1 in water and a NOESY spectrum in heavy water;
  • Figure 8 is a TEM photograph of lidocaine acetate self-assembly in water and a NOESY spectrum in heavy water;
  • Figure 9 is a schematic diagram of the diffusion and slow-release mechanism of the present invention.
  • Figure 10 is a schematic diagram of the principle of rapid degradation of the compounds involved in the present invention in blood
  • Figure 11 is a TEM photograph of Example 12
  • FIG. 12 is a NOESY spectrum chart of Example 13.
  • FIG. 12 is a NOESY spectrum chart of Example 13.
  • Example 1 The organic carboxylic acid in Example 1 was accurately weighed 1.00 g into a 50 mL round bottom flask, and 30 mL of dichloromethane was dissolved.
  • the quaternary ammonium base obtained in Example 5 and Example 6 was slowly added under stirring at 0°C, and the amount of other substances was accurately weighed, and then concentrated to dryness.
  • Dichloromethane-methanol silica gel column chromatography, concentration, and vacuum drying to obtain the final product for preparing the chemical solution.
  • the obtained compound and its structure data are as follows:
  • Compound 72 1 H NMR (400MHz, CDCl 3 ) ⁇ : 7.03 ⁇ 7.06(m,3H), 4.52(br,2H), 4.36(br,2H), 4.05(br,2H), 3.79 ⁇ 3.82(m, 2H), 3.40 ⁇ 3.43(m,2H), 3.30 ⁇ 3.32(m,9H),2.21(br,6H), 1.52 ⁇ 1.57(m,2H),1.35 ⁇ 1.42(m,6H),0.89 ⁇ 0.92( m,3H).
  • the structure data is as follows:
  • the solution was aseptically filtered with a 220 ⁇ m water phase microporous filter membrane into another sterilized vial, stoppered and sealed, and allowed to stand for later use.
  • the control group is a 0.75% levobupivacaine hydrochloride aqueous solution (32mmol/L).
  • the rat is placed in a transparent observation cage with a smooth metal sieve plate at the bottom, and the von frey filament of the proofreading standard is used to stimulate the outer skin (sciatic nerve innervation area) of the rat's foot from bottom to top.
  • the application of von frey filaments started from 0.4g and gradually increased to 60g.
  • the rat removes the limb, or the stimulation is artificially stopped after the stimulation time reaches 3s.
  • Each test point is tested 3 times, and the interval between each test is 5 minutes to avoid sensitization.
  • the nerve block is considered effective.
  • the time interval from the completion of the injection to the time when the first mechanical pain threshold exceeds 60g is the onset time of mechanical pain block; the time from the completion of the injection to the first mechanical pain threshold falling below 60g is the mechanical pain block Delay time; the difference between the two is the maintenance time of mechanical analgesia.
  • the experimental rats were euthanized by injecting bupivacaine into the heart under isoflurane anesthesia. Take the sciatic nerve about 1.5cm from the injection site, store it in 10% formaldehyde solution for 48h, HE stain and cut into 5 ⁇ m thick sections.
  • the degree of demyelination is scored as follows:
  • the vascular proliferation score is as follows:
  • the measured data are as follows:
  • the injection concentration of bupivacaine hydrochloride is 32mmol/L.
  • the injection concentration of QX-314 was 25mmol/L. Due to insufficient local blocking strength, the sensory block was not completely achieved under the test conditions of the present invention, so it was recorded as ineffective.
  • the injection concentration of the control compound was 25 mmol/L. No accurate determination of the compound LD 50, but has been reported to significantly greater than the long-term toxicity of compound (Comparative Compound 8 and 9) of the LD 10.00mg / kg body weight 50 as a test standard.

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Abstract

基于苯环超分子作用的芳基酰胺类化合物、自组装形态及用途。该类化合物结构如式(Ⅰ)和(Ⅱ)所示，可在含水溶剂中自组装形成具有分子间强π-π堆积作用的球形胶束和Janus粒子，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48小时，局部神经病理毒性和全身毒性显著低于已公开的长效局麻分子。作为在水中能自组装形成胶束且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

基于苯环超分子相互作用的芳基酰胺类化合物、自组装形态及用途 技术领域
本发明涉及一种具有长效麻醉效应和低毒性的芳基酰胺类化合物、制备方法、自组装形态及用途。
背景技术
长效局部麻醉药开发的技术瓶颈
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。
局麻药的作用一般局限于给药部位，并随药物从给药部位扩散而迅速失效。目前，临床上所有的局部麻醉药物只能实现不超过4小时的强效局麻与镇痛，不能满足如牙科根管治疗后疼痛、关节骨痛、带状疱疹疼痛、术后创口恢复和晚期癌痛等对12～72小时长效局麻的需求。因此，临床上非常需要能够产生超过12小时作用的新型长效局部麻醉药物。
在临床实践中，局部麻醉药产生的注射局部的神经病理毒性和进入血液后产生的全身毒性，均可能对患者的安全造成严重隐患。其中较为严重的神经病理毒性，造成的局部神经损伤，可能在药效消失后，持续的乃至于不可逆的影响神经的基本功能。而尽管局部麻醉药仅仅是局部注射，但仍可能由于扩散能力过强、局部组织血管丰富、注射误入血管等一个或多个原因进入循环系统，导致心血管毒性等全身毒性，危及患者生命安全。因此，在追求 长效局麻的同时，控制和降低长效局麻可能加剧的局部神经病理毒性和全身毒性同样重要。
目前的常规局部麻醉药物含有至少一个叔胺N原子，如图1中的利多卡因。该类药物注射于局部组织后，以游离碱形式快速扩散进入神经细胞膜内。再利用细胞膜内外的pH值差，形成叔胺盐酸盐形式，作用于神经细胞膜内的Na +通道靶点，产生局部麻醉作用。但由于叔胺盐酸盐的形成是可逆的，药物同样会快速以游离碱的形式扩散出神经细胞并远离神经组织，因而很难长效。
再对利多卡因行一次烷基取代能得到相应的季铵盐，使整个分子成为不可逆的阳离子QX-314。由于QX-314分子极性较强，很难穿过细胞膜作用于靶点，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。然而一旦穿过细胞膜，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(K.R.Courtney.J Pharmacol Exp Ther.1975,195，225-236)。目前已有许多研究发现，QX-314能经TRPV1阳离子通道进入细胞膜，引起持久麻醉作用(C.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QX-314进入细胞膜，引起超过8小时的局麻作用(D.S.Kohane.PNAS.2010,107,3745-3750)。然而，由于该类季铵阳离子化合物的扩散能力较弱，进入神经细胞膜内作用于钠通道靶点的分子占注射总量的比例较低，只能引起不超过7小时的局麻作用，仍不满足临床实践中对超过12小时长效局麻的需求。由此可见，目标化合物的扩散过程对长效局部麻醉十分关键。
双子表面活性剂与局部麻醉
双子表面活性剂(gemini surfactant)具有特殊的分子结构，在溶剂中自组装后可产生远远强于单体的表面活性(F.M.Menger and J.S.Keiper.Angew.Chem.Int.Ed.2003,39,1906-1920)。常见的双子表面活性剂包括串联型和并联型，如图2。
并联型双子表面活性剂，亲水头基主要为季铵阳离子或伯、仲、叔胺的酸式盐、羧酸或磺酸阴离子以及多羟基或多氮、氧原子的结构片段；疏水尾链多为直链烷基或芳基；中间的连接基团多为直链烷基,如图3(L.Tang.Chem.Commun.2017,53,8675-8678)。串联型双子表面活性剂与并联型类似，只是疏水尾链与连接基团合二为一。利多卡因、布比卡因等常见局麻药的叔胺酸式盐结构，亦可作为表面活性剂的亲水头基；其芳基酰胺结构亦可作为疏水尾链。
具有双子表面活性剂结构特征的长效局麻分子，不仅能够协助难于扩散的季铵阳离子从局部注射位点扩散进入神经细胞膜内，还能通过其超分子结构产生缓释作用。然而，该类化合物都不可避免的带由表面活性剂结构带来的，显著高于已上市局麻药的局部神经病理毒性和全身毒性，不利于进一步的临床使用。
发明内容
本发明首先提供了一类具有超长效麻醉效应和低毒性的芳基酰胺类化合物，并进一步提供该类化合物的自组装方式和局部麻醉应用。
本发明所述的具有长效局部麻醉作用的芳基酰胺类化合物，结构如下：
Figure PCTCN2020071782-appb-000001
(Ⅰ)式中R 1和R 2为饱和形式的C 1～2烷基；R 3为氢原子、饱和或不饱和形式的C 1～3烷基或C 1～3取代烷基；X为羰基、氧原子或氮原子；Y为氧原子、氮原子、亚甲基、羰基或亚砜基团；Z为亚甲基、氧原子或氮原子；m＝1～2的整数；n＝1～16的整数。(Ⅱ)式中的R 1为C 1～2烷基；R 2为氢原子，或者取代或未取代、饱和或不饱和形式的C 1～3烷基。
本发明所涉及的化合物，是由阴离子部分和阳离子部分构成的整体分子。其中阴离子部分并非简单的以药学常用阴离子替换得到，而是出于包括不对称双子表面活性剂结构设计在内的，能够使该类分子在水中超分子自组装后形成产生明显的π-π堆积作用的有机酸根离子。使用磺酸根离子替换羧酸根离子，也能产生类似长效低毒的局部麻醉作用。
本发明涉及化合物为通过在水中自组装形成的超分子结构，通过双子表面活性剂的固有性质以该类化合物特有的强π-π堆积作用实现缓释，并将具有局部麻醉作用的单个药物分子运送进入神经细胞膜内，利用神经细胞膜内外的pH值差异，实现阴离子交换，得到难扩散出细胞的季铵阳离子氯化物单体，作用于神经细胞膜内侧的Na +通道靶点，实现长效局部麻醉作用。而该类化合物进入血液后，通过阴离子交换，会迅速失去双子表面活性剂的结构，降解为低毒性物质。
本发明的系列化合物(Ⅰ)和(Ⅱ)具有以下基本特性：
(1)具有非典型的不对称双子表面活性剂结构特征。
(2)能够在水中自组装形成包括Janus粒子在内的有序的超分子结构。
(3)由于π-π堆积影响，该类分子自组装形成的超分子体系缓释能力更强。
(4)该类分子在进入神经细胞后，受到细胞膜内、外pH值差异影响，形成了阴离子不同(主要为细胞内最常见的氯离子)而扩散能力降低的季铵阳离子氯化物作用于靶点，容易进却难于出神经细胞，作用时间更持久，局部损伤也降低。
(5)进入血液后，能够产生强π-π堆积作用的结构立刻消失，因而全身毒性低。
以上全部或部分特性决定了本发明涉及化合物能产生低毒的长效局麻作用。
双子表面活性剂结构
化合物(Ⅰ)具有非典型的不对称双子表面活性剂结构特征。以化合物A1为例。与传统的季铵阳离子型不对称双子表面活性剂相比，该化合物的季铵阳离子并未通过连接基团与另一亲水头基共价连接，而是由其阴离子与连接基团(亚甲基)、另一亲水头基(碳酸酯基)以及疏水尾链(正己基)依次相连(图4)。简言之，化合物(Ⅰ)是通过离子键而非常规的共价键连接不同亲水头基的双子表面活性剂。
两分子的化合物(Ⅱ)通过π-π堆积，也可形成非典型的串联型双子表面活性剂结构。如图5所示，化合物B1的两个π-π堆积的苯环，可以看作类似于传统串联型双子表面活性剂分子的长疏水尾链；叔胺酸式盐结构则是亲水头基。
π-π堆积与Janus粒子
仍然以化合物A1为例，其在蒸馏水中可自组装形成葫芦型的Janus粒子。此前文章中提到，该类Janus粒子的形成与π-π堆积作用密切相关(L.Tang. Chem.Commun.2017,53,8675-8678.)。以重水为溶剂，进行与TEM等浓度的NOESY谱图检测，可发现2,6-二甲基的氢原子与苯环上3,5-的氢原子相关，说明化合物A1在水中超分子自组装后，分子间的甲基氢与芳环氢在空间位置上接近，且其空间接近程度显著高于其他位置的氢，如图6。
由于芳环和甲基的刚性结构和键角导致同一分子中的两个氢原子无法在空间位置上接近，因而有且仅有芳环以“side by side”的方式发生了π-π堆积才会出现不同分子上的两种氢原子在空间位置上的接近。
尽管不具备双子表面活性剂的结构特征，化合物(Ⅱ)仍然可在水中自组装形成强π-π堆积的超分子粒子，以甲酸利多卡因(化合物B1)为例。在蒸馏水中，该化合物可自组装形成葫芦型的Janus粒子。以重水为溶剂，进行与TEM等浓度的NOESY谱图检测，仍可发现2,6-二甲基的氢原子与3,5-的苯环上的氢原子相关，如图7。从而说明甲酸利多卡因也存在分子间的π-π堆积作用。两分子的甲酸利多卡因会因π-π堆积形成一个非典型的串联型双子表面活性剂结构的超分子体，进一步与单个甲酸利多卡因分子共同自组装形成Janus粒子。同时，由于甲酸为弱酸，形成的两个叔胺甲酸盐离子对的电荷相互排斥能力相对强酸盐较弱，因而有利于实现π-π堆积。
用同样的方法对等浓度的醋酸利多卡因进行了TEM和NOESY检测，发现该化合物无法形成Janus粒子，只能形成球形胶束；2,6-二甲基的氢原子与3,5-位的苯环上的氢原子无相关性，因而没有或没有足够强的π-π堆积作用，如图8。原因在于有机酸根离子的体积过大时，很难形成有效的π-π堆积。类似的情况也出现在氢溴酸利多卡因的自组装中。氢溴酸利多卡因在水中自组装后，只能形成球形胶束，NOESY谱图也无相关氢的响应。
综上，本发明所涉及的化合物(Ⅰ)和(Ⅱ)，均能够在水中自组装形成π-π堆积作用强的，包括球形胶束和Janus粒子在内的有序的超分子结构。
扩散与缓释机制
本发明涉及化合物，在水中自组装形成包括球形胶束和Janus粒子在内的有序的超分子结构。注射于局部，该类粒子扩散至神经细胞膜内，经阴离子交换后，形成季铵阳离子氯化物，阻滞细胞膜内侧的Na +通道，产生局麻作用，如图9。
本发明涉及化合物自组装形成的纳米胶束和/或粒子，具有其特有的强π-π堆积作用，在进入神经细胞膜之前，扩散和缓释能力都强于常见表面活性剂。此特性为该类化合物能实现长效的原因之一。
进入神经细胞后，由于细胞内pH值低于细胞外，而本发明涉及化合物为酸性较弱的羧酸盐，根据强酸置换弱酸的基本原理，容易发生阴离子交换。又因为细胞内主要的阴离子为氯离子，因而交换后的化合物主要为氯化物。亲脂性弱的该类季铵阳离子氯化物较难透过细胞膜，从而也很难扩散失效。此性质为该类化合物实现长效的另一重要原因。
低毒性机理
本发明所涉及的化合物(Ⅰ)为季铵阳离子的羧酸盐。其潜在的局部神经病理毒性，可通过前面提及的，神经细胞内的离子交换而失去其双子表面活性剂的结构特征，大幅降低其扩散能力，进而减少了表面活性剂结构带来的损伤。其它已报道的具有表面活性剂结构的分子，整体结构为共价连接，不具备本发明化合物所独有的通过离子交换快速失去表面活性的特性，因而局部毒性相对较大。
全身毒性的情况类似。由于血液中主要的阴离子为氯离子，且相对本化合物的阴离子大大过量，因而可快速实现离子交换，如图10。同时由于血液的pH为7.35～7.45，相对于本发明所涉及的季铵羧酸类化合物偏酸性，更加促进了该类强碱弱酸盐向强酸强碱盐的离子交换变化。如图10所示，其中的一个化合物LD 50(大鼠静脉注射)仅为15.2mg/kg，与已上市最长效的盐酸布比卡因(LD 50＝6.0mg/kg，大鼠静脉注射)相比，全身毒性大幅降低。而该化合物的LD 50又与相对低毒性的该类季铵氯化物十分接近。该结果说明此类化合物确实可在血液中快速实现离子交换，也通过实施例中更多该类化合物的LD 50结果得到验证。
根据以上原理，当羧酸根离子替换为磺酸根离子时，化合物仍能产生近似的低毒长效作用。不同之处在于，有机磺酸根离子的酸性较强，进入神经细胞膜内，交换氯离子能力较弱，容易再次扩散出神经细胞，因而局麻作用时间相对较短，局部毒性和全身毒性也有所增加。而当酸根离子为饱和脂肪酸时，由于失去了双子表面活性剂的基本结构，脂肪长链会干扰芳环的π-π堆积作用，该类超分子结构缓释能力降低，作用时间显著变短(实施例13，表1)。
对于式(Ⅱ)化合物，其产生低毒长效的机理与式(Ⅰ)类似，均与弱酸性的有机酸根和强π-π堆积作用有关。不同之处在于，式(Ⅱ)化合物对有机酸根要求更苛刻。首先酸性需要适中。酸性过强，如盐酸、氢溴酸，则很难产生长效；酸性不足，则水溶性不足，如氢氟酸。其次酸根的体积要小。如冰醋酸以及更大体积的有机酸，会导致局部空间拥挤，难以实现有效的π-π堆积作用(图7)，从而局麻时间较甲酸盐显著缩短。
实验结果已表明，本发明上述式(Ⅰ)和(Ⅱ)结构化合物在水中自组装形成强π-π堆积的纳米粒子后，在生物体内可发挥长时间局部麻醉作用，局部毒性和全身毒性较已报道的长效局麻分子明显降低。此外，作为在水中能自组装形成的该胶束生物材料，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，具有良好的前景。
附图说明
图1是局部麻醉药物的作用机理示意图；
图2是“并联型”和“串联型”双子表面活性剂示意图；
图3是具有局麻活性的并联型不对称双子表面活性剂结构示意图；
图4是离子键连接的“并联型”双子表面活性剂A1结构示意图；
图5是苯环π-π堆积连接的串联型双子表面活性剂B1结构示意图；
图6是化合物A1在水中自组装的TEM照片和重水中的NOESY谱图；
图7是化合物B1在水中自组装的TEM照片和重水中的NOESY谱图；
图8是醋酸利多卡因在水中自组装的TEM照片和重水中的NOESY谱图；
图9是本发明的扩散与缓释机理示意图；
图10是本发明所涉及化合物在血液中快速降解原理示意图；
图11是实施例12的TEM照片；
图12是实施例13的NOESY谱图。
具体实施方式
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。
实施例1
Figure PCTCN2020071782-appb-000002
于100mL圆底烧瓶中，加入羟基羧酸钠5mmol，吡啶5mmol，无水乙腈30mL，冰浴下搅拌0.5h。缓慢滴加对应的有机酰氯5mmol的25mL无水乙腈溶液，15min滴毕。过滤，滤液加入1N氯化氢的乙醇溶液10mL，减压浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到对应的羧酸，如下：
Figure PCTCN2020071782-appb-000003
实施例2
Figure PCTCN2020071782-appb-000004
方法一：
于100mL圆底烧瓶中，加入羟基羧酸钠5mmol，1，2-二氯乙烷30mL。室温搅拌下加入三聚光气2mmol。缓慢滴加吡啶5mmol，室温搅拌1h。滴加对应的脂肪醇或脂肪胺5mmol，50℃搅拌16h。冷却至室温，过滤。滤液加入1N氯化氢的乙醇溶液10mL，浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到对应的羧酸，如下：
Figure PCTCN2020071782-appb-000005
方法二：
于100mL圆底烧瓶中，加入羟基羧酸钠5mmol，1,2-二氯乙烷30mL。冰浴搅拌下滴加二氯亚砜5mmol的1,2-二氯乙烷10mL，15min滴毕。撤去冰浴，室温搅拌30min。滴加对应的脂肪醇5mmol，室温搅拌24h。过滤，滤液加入1N氯化氢的乙醇溶液10mL，减压浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到对应的羧酸如下：
Figure PCTCN2020071782-appb-000006
实施例3
Figure PCTCN2020071782-appb-000007
于50mL圆底烧瓶中，加入羟基羧酸乙酰胺10mmol，脂肪醇10mmol，室温搅拌下加入70％硫酸10mL，80℃下搅拌加热4h。冷却至室温，残余物倾倒至装有冰水混合物约100mL的烧杯中，二氯甲烷50mL x 4萃取。合并有机相，水20mL x 2萃洗，无水硫酸钠干燥，浓缩。残余物加入4mmol/L的氢氧化钠水溶液，回流搅拌6h。残余物用1N盐酸酸化至pH＝5.0,二氯甲烷50mL x 4萃取，浓缩。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到对应的羧酸如下：
Figure PCTCN2020071782-appb-000008
实施例4
Figure PCTCN2020071782-appb-000009
于100mL圆底烧瓶中，加入二羧酸单苄酯5mmol，草酰氯5mmol，室温搅拌2h。滴加脂肪醇5mmol的二氯甲烷溶液30mL，室温搅拌24h。浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，得到二羧酸二酯。将得到的该二羧酸酯置于50mL圆底瓶中，加入1mmol 5％Pd/C，甲醇20mL，通入1atm氢气，室温搅拌24h。过滤，浓缩。二氯甲烷-甲醇硅胶柱层析，真空干燥，得到对应的羧酸如下：
Figure PCTCN2020071782-appb-000010
实施例5
Figure PCTCN2020071782-appb-000011
于80mL厚壁玻璃容器中，分别加入利多卡因25mmol和有机溴代物25mmol，100℃封管加热24h，冷却至室温。二氯甲烷-甲醇硅胶柱层析，分离得到对应的季铵溴化物。该类季铵溴化物在5℃下，通过强碱性离子交换树脂
Figure PCTCN2020071782-appb-000012
1X2(CAS:69011-19-4)进行离子交换，得到的水溶液在5℃下用二氯甲烷50mL x 5萃取，有机相合并，用10mL水萃洗，浓缩至干。真空干燥，得到的季铵碱如下：
Figure PCTCN2020071782-appb-000013
实施例6
Figure PCTCN2020071782-appb-000014
于80mL厚壁玻璃容器中，分别加入α-氯代酰胺25mmol和对应的叔胺25mmol，100℃封管加热24h，冷却至室温。二氯甲烷-甲醇硅胶柱层析，分离得到对应的季铵氯化物。该类季铵溴化物在5℃下，通过强碱性离子交换树脂
Figure PCTCN2020071782-appb-000015
1X2(CAS:69011-19-4)进行离子交换，得到的水溶液在5℃下用二氯甲烷50mL x 5萃取，浓缩至干。真空干燥，得到对应的季铵碱如下：
Figure PCTCN2020071782-appb-000016
实施例7
将实施例1中的有机羧酸分别精密称量1.00g至50mL圆底烧瓶中，30mL二氯甲烷溶解。0℃搅拌下分别缓慢加入对应的实施例5和实施例6中得到的，经精密称量等物质的量的季铵碱，浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到用于配置药液的终产物。得到的化合物及其结构数据如下：
Figure PCTCN2020071782-appb-000017
化合物1： 1H NMR(400MHz，CDCl 3)δ:7.02～7.05(m,3H),4.92(br,2H),4.46(br,2H),3.63(q,J＝7.3Hz,6H),2.24(s,6H),2.10(s,3H),1.42(t,J＝7.3Hz,9H). 13C NMR(100MHz,CDCl 3)δ:7.85,18.52, 21.18,54.08,56.20,60.64,64.13,127.02,127.99,132.88,133.71,134.96,162.37,171.20,172.97.
化合物2： 1H NMR(400MHz，CDCl 3)δ:6.99～7.05(m,3H),4.90(br,2H),4.36～4.41(m,2H),3.49～3.59(m,6H),2.26～2.34(m,2H),2.19～2.22(m,6H),1.54～1.59(m,2H),1.30～1.37(m,9H),1.22～1.26(m,2H),0.84～0.87(m,3H). 13C NMR(100MHz,CDCl 3)δ:7.70,13.85,18.54,22.22,24.53,31.21,54.01,63.86,126.97,127.92,133.68,134.96,162.13,172.86,173.91.
化合物3： 1H NMR(400MHz，CDCl 3)δ:7.02～7.05(m,3H),4.91(br,2H),4.46(br,2H),3.63(q,J＝7.3Hz,6H),2.36(t,J＝7.7Hz,2H),2.24(s,6H),1.58～1.63(m,2H),1.42(t,J＝7.3Hz,9H),1.26～1.30(m,4H),0.86(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.84,13.90,18.53,22.31,24.61,31.30,34.26,54.05,56.18,63.97,126.99,127.96,133.71,134.95,162.37,173.08,174.02.
化合物4： 1H NMR(400MHz，CDCl 3)δ:7.01～7.09(m,3H),4.78～4.82(m,2H),4.43～4.45(m,2H),3.55～3.64(m,6H),2.31～2.37(m,2H),2.24(s,6H),1.54～1.63(m,2H),1.35～1.41(m,9H),1.25～1.32(m,6H),0.85～0.89(m,3H). 13C NMR(100MHz,CDCl 3)δ:7.75,13.98,18.46,22.39,24.82,28.75,31.42,34.20,54.03,56.04,63.64,126.98,127.93,133.71,135.00,162.39,172.86,173.90.
化合物5： 1H NMR(400MHz，CDCl 3)δ:6.97～7.02(m,3H),4.86～4.89(m,2H),4.42(br,2H),3.56～3.62(m,6H),2.32(t,J＝7.7Hz,2H),2.20 (br,6H),1.52～1.59(m,2H),1.36～1.40(m,9H),1.21～1.27(m,8H),0.83(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.85,14.05,18.54,22.58,24.93,28.94,29.10,31.62,34.31,54.05,56.19,63.97,126.99,127.97,133.79,134.94,162.37,173.08,174.02.
化合物6： 1H NMR(400MHz，CDCl 3)δ:7.01～7.06(m,3H),4.89～4.91(m,2H),4.42(br,2H),3.56～3.62(m,6H),2.32(t,J＝7.7Hz,2H),2.20(br,6H),1.52～1.59(m,2H),1.36～1.41(m,9H),1.22～1.29(m,12H),0.85(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.78,14.02,18.50,22.58,24.93,28.94,29.04,29.11,29.18,31.42,34.30,54.12,56.24,63.97,126.99,127.97,133.79,134.92,173.08,174.02.
化合物7： 1H NMR(400MHz，CDCl 3)δ:7.01～7.06(m,3H),4.88～4.91(m,2H),4.45(br,2H),3.52～3.60(m,6H),2.26～2.29(m,2H),2.23(br,6H),1.52～1.59(m,2H),1.36～1.41(m,9H),1.23～1.30(m,16H),0.79～0.82(m,3H). 13C NMR(100MHz,CDCl 3)δ:7.70,14.11,18.50,22.49,24.90,28.92,28.99,29.06,29.12,29.15,29.17,31.62,34.30,54.12,56.24,63.97,127.02,127.95,133.76,134.89,173.18,174.06.
化合物8： 1H NMR(400MHz，CDCl 3)δ:6.99～7.06(m,3H),4.87～4.92(m,2H),4.39(br,2H),3.51～3.57(m,6H),2.32～2.36(m,2H),2.25(br,6H),1.52～1.58(m,2H),1.37～1.41(m,9H),1.21～1.31(m,24H),0.82～0.86(m,3H). 13C NMR(100MHz,CDCl 3)δ:7.83,14.21,18.52,22.53,24.90,28.93,28.99,29.02,29.04,29.06,29.10,29.12,29.15,29.16,29.18,31.65,34.30,54.12,56.24,63.97,127.02,127.95,133.76, 134.89,173.18,174.06.
化合物9： 1H NMR(400MHz，CDCl 3)δ:6.99～7.06(m,3H),4.31～4.35(m,2H),4.39(br,2H),3.51～3.57(m,6H),2.49～2.52(m,2H),2.32～2.36(m,2H),2.28～2.31(m,2H),2.25(br,6H),1.63～1.68(m,2H),1.52～1.58(m,2H),1.37～1.41(m,9H),1.26～1.31(m,12H),0.89(t,J＝6.9Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.85,18.52,22.72,24.86,29.02,29.18,29.32,29.37,29.64,31.81,33.72,33.88,54.08,59.79,64.13,127.99,132.88,133.71,134.96,162.37,173.12,177.30.
化合物11： 1H NMR(400MHz，CDCl 3)δ:6.98～7.06(m,3H),5.61～5.72(m,1H),5.14～5.24(m,2H),4.88(m,2H),4.78～4.82(m,2H),3.52～3.71(m,6H),2.58～2.61(m,3H),2.31～2.37(m,2H),2.23(s,6H),1.54～1.63(m,2H),1.43(t,J＝6.4Hz,6H),1.25～1.32(m,6H),0.85～0.89(m,3H). 13C NMR(100MHz,CDCl 3)δ:8.20,13.92,18.82,22.36,24.76,26.82,28.77,31.42,34.20,55.37,57.04,58.26,63.64,119.82,127.33,128.13,130.85,133.11,134.96,161.77,172.88,173.92.
化合物12： 1H NMR(400MHz，CDCl 3)δ:10.96(s,1H),6.99～7.02(m,3H),4.90(br,2H),5.61～5.71(m,1H),5.20(d,J＝17.1Hz,1H),5.14(d,J＝10.1Hz,1H),4.82(br,1H),3.51～3.60(m,6H),2.56～2.62(m,2H),2.26～2.34(m,2H),2.22(s,6H),1.54～1.59(m,2H),1.41(t,J＝6.4Hz,6H),1.22～1.26(m,2H),0.84～0.87(m,3H). 13C NMR(100MHz,CDCl 3)δ:8.18,13.85,18.81,22.22,26.81,24.53,31.21,57.26,55.29,56.97,58.20,63.86,127.38,128.09,130.86,133.08,135.00,161.81,172.86, 173.91.
化合物13： 1H NMR(400MHz，CDCl 3)δ:7.00～7.04(m,3H),4.91(s,2H),4.61(s,2H),4.02(s,2H),3.68(m,4H),2.36(t,J＝7.7Hz,2H),2.22(s,6H),1.58～1.63(m,2H),1.45(s,6H),1.26～1.30(m,4H),0.86(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.23,13.90,18.81,22.31,24.61,31.30,34.26,56.43,57.58,57.84,60.86,63.97,127.49,128.12,132.90,135.05,154.69,161.75,173.08,174.02.
化合物14： 1H NMR(400MHz，CDCl 3)δ:10.96(s,1H),7.00～7.03(m,3H),5.63～5.71(m,1H),5.18(d,J＝17.1Hz,1H),5.12(d,J＝10.1Hz,1H),4.93(br,2H),4.82(br,1H),3.51～3.60(m,6H),2.56～2.62(m,2H),2.35(t,J＝7.7Hz,2H),2.22(s,6H),1.59～1.63(m,2H),1.43(t,J＝6.4Hz,6H),1.27～1.31(m,4H),0.87(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.98,13.92,18.80,22.32,24.58,26.83,31.32,34.20,57.26,55.29,56.95,58.21,63.98,127.39,128.12,130.84,133.07,135.02,161.79,173.10,174.03.
化合物15： 1H NMR(400MHz，CDCl 3)δ:7.00～7.04(m,3H),4.79～4.82(m,2H),4.61(s,2H),4.02(s,2H),3.68(m,4H),2.31～2.36(m,2H),2.22(s,6H),1.55～1.62(m,2H),1.45(s,6H),1.25～1.32(m,6H),0.85～0.89(m,3H). 13C NMR(100MHz,CDCl 3)δ:8.15,13.92,18.82,22.37,24.82,28.81,31.39,34.23,56.43,57.58,57.84,60.86,63.59,127.49,128.12,132.90,135.05,154.69,161.75,172.83,173.88.
化合物16： 1H NMR(400MHz，CDCl 3)δ:7.01～7.04(m,3H),4.96(br, 2H),4.90(br,2H),3.91(H a,1H),3.83(H b,1H),3.62～3.81(m,6H),3.40(s,3H),2.26～2.34(m,2H),2.22(s,6H),2.08(br,2H),1.54～1.60(m,2H),1.47(t,J＝7.1Hz,6H),1.23～1.28(m,2H),0.86(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.28,13.86,18.80,22.22,24.52,31.23,56.27,57.35,58.84,59.32,66.07,63.83,127.35,128.09,133.10,134.97,162.03,172.85,173.92.
化合物17： 1H NMR(400MHz，CDCl 3)δ:7.01～7.05(m,3H),4.95(br,2H),4.87(br,2H),3.87(H a,1H),3.81(H b,1H),3.65～3.76(m,6H),3.42(s,3H),2.34(t,J＝7.7Hz,2H),2.23(s,6H),2.08(br,2H),1.58～1.63(m,2H),1.26～1.30(m,4H),1.46(t,J＝7.1Hz,6H),0.86(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.26,18.79,56.28,13.90,22.33,24.58,31.32,34.26,57.37,58.82,59.33,66.05,63.97,127.36,128.09,133.08,134.98,162.00,173.11,174.03.
化合物18： 1H NMR(400MHz，CDCl 3)δ:7.01～7.05(m,3H),4.97(br,2H),4.86～4.88(m,2H),3.89(H a,1H),3.82(H b,1H),3.62～3.78(m,6H),3.40(s,3H),2.33(t,J＝7.7Hz,2H),2.26(s,6H),2.09(br,2H),1.46(t,J＝7.1Hz,6H),1.21～1.27(m,8H),0.86(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.31,14.03,18.81,22.56,24.92,28.92,29.13,31.60,34.31,56.28,57.36,58.86,59.36,66.08,63.96,127.33,128.08,133.11,134.95,162.01,173.08,174.05.
化合物19： 1H NMR(400MHz，CDCl 3)δ:7.00～7.05(m,3H),4.96(br,2H),4.89～4.91(m,2H),3.88(H a,1H),3.83(H b,1H),3.63～3.76(m,6H),3.39 (s,3H),2.31(t,J＝7.7Hz,2H),2.26(s,6H),2.09(br,2H),1.46(t,J＝7.1Hz,6H),1.22～1.29(m,12H),0.85(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.29,14.05,18.80,22.58,24.91,28.97,29.05,29.12,29.20,31.59,34.31,56.31,57.38,58.87,59.35,66.02,63.96,127.36,128.13,133.05,134.93,162.02,173.09,174.03.
化合物20： 1H NMR(400MHz，CDCl 3)δ:6.99～7.04(m,3H),4.93(br,2H),4.88(br,2H),3.86(br,2H),3.80(br,2H),3.64～3.73(m,4H),3.49～3.56(m,2H),2.37(t,J＝7.7Hz,2H),2.32(s,6H),1.58～1.63(m,2H),1.44(t,J＝6.8Hz,6H),1.26～1.30(m,4H),1.15(t,J＝6.9Hz,3H),0.86(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.26,13.90,14.95,18.81,22.32,24.59,31.33,34.26,56.17,57.26,58.82,63.97,67.19,127.35,128.07,133.09,135.01,162.06,173.07,174.05.
化合物22： 1H NMR(400MHz，CDCl 3)δ:7.02～7.06(m,3H),4.94(br,2H),4.86(br,2H),4.19～4.21(m,2H),3.73～3.88(m,4H),3.65～3.68(m,2H),2.24(s,6H),2.36(t,J＝7.7Hz,2H),1.58～1.63(m,2H),1.43(t,J＝7.1Hz,6H),1.26～1.31(m,4H),0.86(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.15,13.90,18.74,22.33,24.61,31.29,34.18,35.53,55.57,56.04,57.21,59.38,63.89,127.33,128.06,133.21,134.96,161.56,173.08,174.01.
化合物23： 1H NMR(400MHz，CDCl 3)δ:7.02～7.08(m,3H),4.88(br,2H),4.78～4.83(m,2H),4.19～4.21(m,2H),3.73～3.88(m,4H),3.65～3.68(m,2H),2.31～2.36(m,2H),2.23(s,6H),1.56～1.63(m,2H),1.43(t, J＝7.1Hz,6H),1.25～1.32(m,6H),0.86(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.13,13.97,18.72,22.38,24.85,28.72,31.42,34.21,35.50,55.56,56.07,57.19,59.40,63.64,127.32,128.09,133.18,134.93,161.57,172.87,173.92.
化合物24： 1H NMR(400MHz，CDCl 3)δ:7.01～7.05(m,3H),4.90(br,2H),4.86～4.88(m,2H),4.19～4.23(m,2H),3.77～3.85(m,4H),3.63～3.67(m,2H),2.32(t,J＝7.7Hz,2H),2.22(s,6H),1.45(t,J＝7.1Hz,6H),1.20～1.27(m,8H),0.84(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.19,14.03,22.56,24.88,28.92,29.10,31.58,34.29,18.70,35.51,55.56,56.03,57.19,59.38,127.30,128.01,133.19,134.99,161.57.63.97,173.09,174.02.
化合物25： 1H NMR(400MHz，CDCl 3)δ:7.02～7.10(m,3H),4.89～4.92(m,2H),4.87(br,2H),4.19～4.22(m,2H),3.73～3.88(m,4H),3.65～3.68(m,2H),2.32(t,J＝7.7Hz,2H),2.24(s,6H),1.43(t,J＝7.1Hz,6H),1.21～1.28(m,10H),0.86(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.12,14.06,18.77,22.56,24.91,28.98,29.07,29.16,31.62,34.27,35.5655.54,56.03,57.22,59.36,63.94,127.31,128.11,133.24,134.93,161.55,173.08,174.00.
化合物26： 1H NMR(400MHz，CDCl 3)δ:6.99～7.05(m,3H),4.92(br,2H),4.84(br,2H),4.59(H a,1H),4.47(H b,1H),3.57～3.70(m,6H),2.36(t,J＝7.7Hz,2H),2.32(H a,1H),2.27(H b,1H),2.21(s,6H),1.58～1.63(m,2H),1.39(t,J＝6.9Hz,6H),1.26～1.31(m,4H),0.86(t,J＝6.7 Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.04,13.88,18.74,22.27,24.00(d,J＝19.6Hz,),24.61,31.30,34.26,55.33,56.31,56.99,63.94,79.65,81.32,127.44,128.12,133.02,135.01,161.82,173.05,174.01.化合物27：7.00～7.05(m,3H),4.82(br,2H),4.78(br,2H),4.58(H a,1H),4.45(H b,1H),3.56～3.67(m,6H),2.32(H a,1H),2.28(H b,1H),2.33～2.37(m,2H),2.22(s,6H),1.56～1.62(m,2H),1.39(t,J＝6.9Hz,6H),1.26～1.33(m,6H),0.85～0.89(m,3H). 13C NMR(100MHz,CDCl 3)δ:8.03,14.00,18.70,22.41,24.02(d,J＝19.6Hz,),24.77,28.76,31.42,34.23,55.32,56.30,56.97,63.61,79.68,81.34,127.42,128.09,133.05,135.04,161.86,172.88,173.92.
化合物28：7.01～7.05(m,3H),4.87～4.90(m,2H),4.83(br,2H),4.58(H a,1H),4.45(H b,1H),3.60～3.70(m,6H),2.33(H a,1H),2.25(H b,1H),2.30(t,J＝7.7Hz,2H),2.22(s,6H),1.40(t,J＝6.9Hz,6H),1.21～1.26(m,8H),0.84(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.02,14.07,18.75,22.56,24.02(d,J＝19.6Hz,),24.91,28.92,29.13,31.61,34.33,55.32,56.28,57.01,63.98,79.63,81.29,127.42,128.13,133.07,135.04,161.79,173.09,174.00.
化合物29：6.98～7.05(m,3H),4.86～4.90(m,2H),4.83(br,2H),4.58(H a,1H),4.48(H b,1H),3.57～3.67(m,6H),2.33(H a,1H),2.25(H b,1H),2.31(t,J＝7.7Hz,2H),2.22(s,6H),1.41(t,J＝6.9Hz,6H),1.21～1.27(m,10H),0.85(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.04,14.02,18.74,22.57,24.01(d,J＝19.6Hz,),24.93,28.94,29.10,29.18, 31.62,34.31,55.33,56.31,56.99,63.96,79.65,81.32,127.44,128.12,133.02,135.01,161.82,173.08,174.02.
化合物30：6.99～7.05(m,3H),4.90(br,2H),4.83(br,2H),3.78(m,2H),3.57～3.70(m,6H),2.36(m,2H),2.26～2.32(m,2H),2.21(s,6H),1.55～1.59(m,2H),1.43(t,J＝6.9Hz,6H),1.22～1.26(m,2H),0.84～0.87(m,3H). 13C NMR(100MHz,CDCl 3)δ:8.02,13.83,18.74,43.19,55.33,56.31,56.99,79.65,81.32,127.44,128.12,133.02,135.01,161.82.22.22,24.53,31.21,63.86,172.86,173.91.
化合物31：6.99～7.05(m,3H),4.84(br,2H),4.78～4.81(m,2H),3.78(m,2H),3.57～3.70(m,6H),2.29～2.34(m,2H),2.36(br,2H),2.21(s,6H),1.55～1.62(m,2H),1.42(t,J＝6.9Hz,6H),1.25～1.31(m,6H),0.86～0.90(m,3H). 13C NMR(100MHz,CDCl 3)δ:8.12,13.98,18.84,22.39,24.82,28.75,31.42,34.20,43.19,55.30,56.30,56.96,63.60,79.63,81.30,127.42,128.10,133.03,135.02,161.85,172.86,173.90.
实施例8
参照实施例7，精密称定部分实施例2～4和实施例5的有机酸、碱，制备得到用于配置药液的终产物。化合物及其结构数据如下：
Figure PCTCN2020071782-appb-000018
化合物32： 1H NMR(400MHz，CDCl 3)δ:6.98～7.05(m,3H),4.87(br,2H),4.44(br,2H),4.02(t,J＝6.8Hz,2H),3.61(q,J＝7.3Hz,6H),2.21(s,6H),1.56～1.63(m,2H),1.40(q,J＝7.3Hz,9H),1.24～1.27(m,4H),0.85(t,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.86,13.91,18.63,22.26,27.78,28.92,54.12,56.20,66.07,67.77,127.06,128.00,133.61,134.96,155.55,162.35,172.72.
化合物33： 1H NMR(400MHz，CDCl 3)δ:7.08～7.14(m,3H),4.86～4.87(m,2H),4.77～4.79(m,1H),4.62(br,1H),4.20(t,J＝6.7Hz,1H),4.12 (t,J＝6.8Hz,1H),3.69(q,J＝6.8Hz,6H),2.29(s,6H),1.66～1.74(m,2H),1.48(t,J＝6.7Hz,9H),1.31～1.43(m,6H),0.92～0.96(m,3H). 13C NMR(100MHz,CDCl 3)δ:7.83,13.95,13.97,18.51,22.47,25.25,25.32,28.50,28.56,31.32,31.37,54.17,56.15,63.37,67.93,68.47,127.15,128.03,133.47,135.01,154.77,155.46,162.30,167.75.
化合物34： 1H NMR(400MHz，CDCl 3)δ:7.00～7.05(m,3H),4.87(br,2H),4.46(br,2H),4.02(t,J＝6.8Hz,2H),3.63(q,J＝7.3Hz,6H),2.25(s,6H),1.59～1.65(m,2H),1.43(q,J＝7.3Hz,9H),1.24～1.30(m,10H),0.87(t,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.86,13.91,18.63,22.26,27.78,28.92,29.09,29.30,54.15,56.24,66.13,67.72,127.08,128.05,133.64,134.98,155.59,162.32,172.72.
化合物35： 1H NMR(400MHz，CDCl 3)δ:7.02～7.05(m,3H),5.01(br,2H),4.46(br,2H),3.63(q,J＝7.3Hz,6H),3.16～3.19(m,2H),2.24(s,6H),1.50～1.53(m,2H),1.42(t,J＝7.3Hz,9H),1.28～1.33(m,10H),0.88(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.85,14.12,18.52,22.73,26.41,26.73,2933,29.39,31.78,40.29,54.08,61.55,64.13,127.99,132.88,133.71,134.96,155.86,162.37,172.99.
化合物36： 1H NMR(400MHz，CDCl 3)δ:7.01～7.05(m,3H),5.02(br,2H),4.43(br,2H),3.61(q,J＝7.3Hz,6H),3.16～3.19(m,2H),2.22(s,6H),1.50～1.54(m,2H),1.43(t,J＝7.3Hz,9H),1.26～1.34(m,18H),0.87(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.89,14.08,18.60,22.73,26.44,26.76,29.33,29.36,29.61,29.64,29.67,29.69, 31.83,40.32,54.13,61.49,64.12,127.96,132.85,133.78,134.98,155.89,162.41,172.92.
化合物37： 1H NMR(400MHz，CDCl 3)δ:7.02～7.05(m,3H),4.49(br,2H),4.43(br,2H),4.02(br,2H),3.60(q,J＝7.3Hz,6H),2.22(s,6H),1.50～1.57(m,2H),1.41(t,J＝7.3Hz,9H),1.35～1.42(m,10H),0.89～0.92(m,3H). 13C NMR(100MHz,CDCl 3)δ:7.79,14.12,18.52,22.61,26.11,29.20,29.35,29.60,31.77,54.08,64.13,69.39,72.45,128.01,132.86,133.73,134.92,162.37,172.88.
化合物38： 1H NMR(400MHz，CDCl 3)δ:7.02～7.05(m,3H),4.46(br,2H),4.30(br,2H),3.63(q,J＝7.3Hz,6H),3.36(t,J＝8.0Hz,2H),2.24(s,6H),1.48～1.52(m,2H),1.43(t,J＝7.3Hz,9H),1.40～1.43(m,2H),1.25～1.30(m,4H),0.88(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.76,14.08,18.47,22.65,29.66,31.78,54.05,64.11,64.50,67.36,127.97,132.86,133.68,135.01,162.35,173.01.
化合物39： 1H NMR(400MHz，CDCl 3)δ:7.01～7.05(m,3H),4.43(br,2H),4.28(br,2H),3.63(q,J＝7.3Hz,6H),3.37(t,J＝8.0Hz,2H),2.24(s,6H),1.48～1.53(m,2H),1.42～1.45(m,2H),1.41(t,J＝7.3Hz,9H),1.26～1.33(m,10H),0.89(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.78,14.12,18.50,22.69,29.18,29.26,29.35,29.63,29.68,29.76,54.11,64.15,64.38,67.42,127.96,132.84,133.71,134.93,162.39,173.01.
化合物40： 1H NMR(400MHz，CDCl 3)δ:7.00～7.04(m,3H),4.43(br, 2H),4.13(t,J＝7.8Hz,2H),3.60(q,J＝7.3Hz,6H),2.80～2.84(m,2H),2.71～2.75(m,2H),2.21(s,6H),1.60～1.63(m,2H),1.42～1.45(m,2H),1.40(t,J＝7.3Hz,9H),0.88(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.88,13.90,18.54,18.95,29.05,29.15,54.06,64.10,64.89,128.03,132.78,133.69,135.01,162.35,173.22,174.64.
化合物41： 1H NMR(400MHz，CDCl 3)δ:7.00～7.04(m,3H),4.43(br,2H),3.61(q,J＝7.3Hz,6H),3.00～3.05(m,2H),2.71～2.74(m,2H),2.45～2.48(m,2H),1.50～1.53(m,2H),2.23(s,6H),1.42(t,J＝7.3Hz,9H),1.28～1.32(m,10H),0.90(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.79,14.02,18.50,22.46,26.49,29.08,29.22,29.29,29.33,29.36,29.98,30.24,31.82,39.23,54.12,64.11,127.97,132.86,133.75,134.94,162.36,172.18,173.84.
化合物42： 1H NMR(400MHz，CDCl 3)δ:6.98～7.04(m,3H),5.61～5.72(m,1H),5.18～5.23(m,2H),5.02(br,2H),4.86～4.90(m,2H),3.57～3.71(m,6H),3.16(t,J＝7.8Hz,2H),2.58～2.63(m,3H),2.23(s,6H),1.42(t,J＝6.4Hz,6H),1.49～1.53(m,2H),1.28～1.32,(m,2H),0.90(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.18,13.72,18.80,19.81,26.81,32.15,40.03,55.33,57.02,58.30,61.52,119.82,127.36,128.07,130.83,133.14,134.92,155.89,161.75,172.94.
化合物43： 1H NMR(400MHz，CDCl 3)δ:6.99～7.05(m,3H),5.64～5.73(m,1H),5.16～5.22(m,2H),4.88～4.92(m,2H),4.47(br,2H),4.05(br,2H),3.52～3.71(m,6H),2.58～2.61(m,3H),2.23(s,6H),1.50～1.56(m, 2H),1.43(t,J＝6.4Hz,6H),1.36～1.42(m,6H),0.88～0.91(m,3H). 13C NMR(100MHz,CDCl 3)δ:8.17,14.12,18.80,22.54,26.15,26.81,29.16,31.80,55.33,57.09,58.30,69.43,73.12,119.83,127.32,128.06,130.80,133.13,135.01,161.74,172.53.
化合物44： 1H NMR(400MHz，CDCl 3)δ:11.05(s,1H),7.01～7.05(m,3H),5.01(br,2H),4.93(br,2H),3.86(H a,1H),3.80(H b,1H),3.65～3.76(m,6H),3.41(s,3H),3.15～3.18,(m,2H),2.25(s,6H),2.08(br,2H),1.50～1.54(m,2H),1.45(t,J＝7.1Hz,6H),1.27～1.34(m,10H),0.89(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.33,14.10,18.78,22.73,26.41,26.70,29.26,29.32,31.81,40.26,56.24,57.33,58.82,59.37,61.54,66.08,127.34,128.11,133.08,134.96,155.86,162.02,172.96.
化合物45： 1H NMR(400MHz，CDCl 3)δ:7.01～7.06(m,3H),4.96(br,2H),4.30(br,2H),3.88(H a,1H),3.81(H b,1H),3.68～3.77(m,6H),3.41(s,3H),3.36(t,J＝8.0Hz,2H),2.23(s,6H),2.07(br,2H),1.48～1.52(m,2H),1.46(t,J＝7.1Hz,6H),1.42～1.45(m,2H),1.24～1.29(m,4H),0.88(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.32,14.10,18.80,22.63,29.66,31.78,56.28,57.37,58.85,59.35,64.50,66.08,67.35,127.36,128.09,133.08,134.96,162.01,173.01.
化合物46： 1H NMR(400MHz，CDCl 3)δ:7.01～7.05(m,3H),4.96(br,2H),4.86(br,2H),4.05(t,J＝6.8Hz,2H),3.88(H a,1H),3.84(H b,1H),3.70～3.80(m,6H),3.40(s,3H),2.26(s,6H),2.09(br,2H),1.61～1.65 (m,2H),1.46(t,J＝7.1Hz,6H),1.26～1.31(m,6H),0.87(t,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.28,13.91,18.79,22.33,27.69,28.95,29.07,56.24,57.35,58.83,59.35,66.02,67.80,127.36,128.11,133.06,134.97,162.02,172.73.
化合物47： 1H NMR(400MHz，CDCl 3)δ:7.00～7.05(m,3H),4.95(br,2H),4.13(t,J＝7.8Hz,2H),3.86(H a,1H),3.84(H b,1H),3.70～3.79(m,6H),3.41(s,3H),2.81～2.84(m,2H),2.70～2.75(m,2H),2.24(s,6H),2.07(br,2H),1.60～1.63(m,2H),1.46(t,J＝7.1Hz,6H),1.42～1.45(m,2H),0.88(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.27,13.90,18.76,18.95,29.05,29.15,56.33,57.39,58.86,59.38,64.89,66.08,127.37,128.11,133.09,134.99,162.01,173.22,174.64.
化合物48： 1H NMR(400MHz，CDCl 3)δ:7.02～7.10(m,3H),4.90(br,2H),4.84(br,2H),4.19～4.21(m,2H),4.03(t,J＝6.8Hz,2H),3.73～3.88(m,4H),3.65～3.68(m,2H),2.24(s,6H),1.60～1.65(m,2H),1.43(t,J＝7.1Hz,6H),1.26～1.30(m,6H),0.88(t,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.15,13.90,18.74,22.32,27.69,28.97,29.07,35.5355.57,56.04,57.21,59.38,67.82,127.33,128.06,133.21,134.96,161.56,172.70.
化合物49： 1H NMR(400MHz，CDCl 3)δ:7.02～7.06(m,3H),5.01(br,2H),4.88(br,2H),4.18～4.21(m,2H),3.79～3.88(m,4H),3.65～3.68(m,2H),3.16～3.19,(m,2H),2.23(s,6H),1.50～1.54(m,2H),1.43(t,J＝7.1Hz,6H),1.28～1.33(m,10H),0.88(t,J＝7.0Hz,3H). 13C NMR (100MHz,CDCl 3)δ:8.11,14.12,18.70,22.71,26.43,26.76,29.35,29.40,31.78,35.56,40.33,55.55,56.02,57.26,59.43,61.57,127.29,128.09,133.18,134.93,155.86,161.55,172.98.
化合物50： 1H NMR(400MHz，CDCl 3)δ:7.01～7.06(m,3H),4.88(br,2H),4.49(br,2H),4.19～4.22(m,2H),4.02(br,2H),3.77～3.86(m,4H),3.64～3.67(m,2H),2.24(s,6H),1.49～1.55(m,2H),1.43(t,J＝7.1Hz,6H),1.35～1.42(m,10H),0.89～0.92(m,3H). 13C NMR(100MHz,CDCl 3)δ:8.12,14.06,18.71,22.58,26.11,29.20,29.35,29.60,31.77,35.52,55.59,56.06,57.23,59.35,69.39,72.45,127.31,128.07,133.21,134.95,161.54,172.88.
化合物51： 1H NMR(400MHz，CDCl 3)δ:7.02～7.06(m,3H),4.88(br,2H),4.30(br,2H),4.17～4.20(m,2H),3.79～3.87(m,4H),3.65～3.68(m,2H),3.37(t,J＝8.0Hz,2H),2.22(s,6H),1.48～1.53(m,2H),1.42～1.45(m,2H),1.40(t,J＝7.1Hz,6H,1.26～1.33(m,8H),0.89(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.13,14.12,18.73,22.69,29.18,29.26,29.35,29.68,29.76,35.51,55.57,56.02,57.18,59.40,64.38,67.42,127.32,128.08,133.19,134.94,161.55,173.00.化合物52： 1H NMR(400MHz，CDCl 3)δ:7.00～7.07(m,3H),4.88(br,2H),4.18～4.22(m,2H),4.12(t,J＝7.8Hz,2H),3.74～3.86(m,4H),3.65～3.69(m,2H),2.82～2.86(m,2H),2.73～2.79(m,2H),2.23(s,6H),1.56～1.62(m,2H),1.45(t,J＝7.1Hz,6H).1.38～1.42(m,6H),0.90(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.10,14.09,18.72, 22.69,25.72,28.86,29.10,29.17,35.52,55.52,56.03,57.20,59.42,65.00,127.31,128.04,133.21,134.93,161.54,173.24,174.62.
化合物53： 1H NMR(400MHz，CDCl 3)δ:7.03～7.08(m,3H),4.88(br,2H),4.18～4.21(m,2H),3.78～3.87(m,4H),3.64～3.68(m,2H),3.03～3.05(m,2H),2.70～2.74(m,2H),2.45～2.48(m,2H),2.24(s,6H),1.42(t,J＝7.1Hz,6H),1.50～1.53(m,2H),1.28～1.32(m,4H),0.89(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.11,13.98,18.69,22.39,28.90,29.14,29.73,30.21,35.50,55.58,56.02,57.23,59.42,127.36,128.04,133.19,134.93,161.52,172.22,173.86.
化合物54： 1H NMR(400MHz，CDCl 3)δ:7.00～7.06(m,3H),4.90(br,2H),4.80(br,2H),4.57(H a,1H),4.48(H b,1H),4.05(t,J＝6.8Hz,2H),3.60～3.70(m,6H),2.34(H a,1H),2.26(H b,1H),2.21(s,6H),1.60～1.64(m,2H),1.39(t,J＝6.9Hz,6H),1.28～1.30(m,6H),0.86(t,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.02,13.90,18.74,22.33,24.00(d,J＝19.6Hz,),27.66,28.98,29.12,55.33,56.31,56.99,67.80,79.65,81.32,127.44,128.12,133.02,135.01,161.82,172.71.
化合物55： 1H NMR(400MHz，CDCl 3)δ:6.99～7.05(m,3H),5.00(br,2H),4.81(br,2H),4.59(H a,1H),4.47(H b,1H),3.59～3.70(m,6H),3.15～3.18(m,2H),2.31(H a,1H),2.23(H b,1H),2.21(s,6H),1.49～1.53(m,2H),1.40(t,J＝6.9Hz,6H),1.27～1.33(m,10H),0.89(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.98,14.07,18.72,22.70,24.01(d,J＝19.6Hz,),26.37,26.73,29.36,29.42,31.78,40.26,55.33, 56.32,56.96,61.55,79.64,81.30,127.42,128.13,133.05,135.04,155.86,161.79,173.02.
化合物56： 1H NMR(400MHz，CDCl 3)δ:6.98～7.05(m,3H),4.84(br,2H),4.59(H a,1H),4.47(H b,1H),4.30(br,2H),3.63～3.71(m,6H),3.36(t,J＝8.0Hz,2H),2.32(H a,1H),2.25(H b,1H),2.21(s,6H),1.48～1.52(m,2H),1.42～1.45(m,2H),1.38(t,J＝6.9Hz,6H),1.25～1.30(m,4H),0.88(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.00,14.08,18.76,22.65,24.03(d,J＝19.6Hz,),29.66,31.78,55.31,56.30,56.96,64.50,67.36,79.62,81.30,127.41,128.12,133.05,135.03,161.80,173.01.
化合物57： 1H NMR(400MHz，CDCl 3)δ:7.00～7.06(m,3H),4.82(br,2H),4.59(H a,1H),4.47(H b,1H),4.12(t,J＝7.8Hz,2H),3.60～3.69(m,6H),2.34(H a,1H),2.82～2.86(m,2H),2.73～2.79(m,2H),2.24(H b,1H),2.21(s,6H),1.56～1.62(m,2H),1.42～1.47(m,6H),1.39(t,J＝6.9Hz,6H),0.90(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.02,14.09,18.73,22.72,24.01(d,J＝19.6Hz,),25.70,28.87,29.06,29.13,55.30,56.33,57.02,65.02,79.68,81.29,127.42,128.10,133.00,135.04,161.83,173.25,174.60.
实施例9
参照实施例7，精密称定部分实施例1～4和实施例6的有机酸、碱，制备得到用于配置药液的终产物。化合物及其结构数据如下：
Figure PCTCN2020071782-appb-000019
化合物58： 1H NMR(400MHz，CDCl 3)δ:7.05～7.09(m,3H),4.85～4.89(m,2H),4.40(br,2H),3.31(br,9H),2.32(t,J＝7.7Hz,2H),2.20(br,6H),1.52～1.59(m,2H),1.36～1.40(m,9H),1.21～1.27(m,8H),0.83(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.88,14.05,18.54,22.58,24.93,28.94,29.10,31.62,34.31,54.05,56.19,63.97,126.99,127.97,133.79,134.94,162.37,173.08,174.02.
化合物59： 1H NMR(400MHz，CDCl 3)δ:7.05～7.08(m,3H),4.88(br,2H),4.42(br,2H),3.31(br,9H),2.33(t,J＝7.7Hz,2H),2.22(br,6H),1.51～1.58(m,2H),1.37～1.41(m,9H),1.20～1.27(m,12H),0.84(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.88,14.02,18.54,22.57, 24.93,28.96,29.11,29.18,29.22,31.60,34.27,54.02,56.21,63.95,127.04,128.03,133.82,134.98,162.35,173.06,174.01.
化合物60： 1H NMR(400MHz，CDCl 3)δ:7.06～7.11(m,3H),4.90(br,2H),4.45(br,2H),4.03(t,J＝6.8Hz,2H),2.21(br,6H),1.60～1.64(m,2H),1.26～1.29(m,6H),0.87(t,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.78,13.91,18.53,22.29,27.67,28.93,29.05,54.15,63.92,67.82,127.02,127.95,133.76,134.90,162.30,172.73.
化合物61： 1H NMR(400MHz，CDCl 3)δ:7.05～7.09(m,3H),4.99(br,2H),4.42(br,2H),3.15～3.19(m,2H),2.21(br,6H),1.50～1.53(m,2H),1.26～1.32(m,10H),0.89(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.82,14.10,18.53,22.73,26.41,26.75,29.33,29.36,31.75,40.33,54.03,61.57,63.92,126.99,127.97,133.79,134.94,155.84,162.37,173.01.
化合物62： 1H NMR(400MHz，CDCl 3)δ:7.05～7.09(m,3H),4.43(br,2H),4.10(t,J＝7.8Hz,2H),2.82～2.86(m,2H),2.73～2.79(m,2H),2.23(br,6H),1.57～1.61(m,2H),1.37～1.42(m,6H),0.89(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.88,14.11,18.54,22.72,25.74,28.83,29.09,29.17,54.05,63.97,65.02,126.99,127.97,133.79,134.94,162.37,173.25,174.60.
化合物63： 1H NMR(400MHz，CDCl 3)δ:7.03～7.08(m,3H),4.89(br,2H),4.45(br,2H),3.58～3.62(m,4H),3.33(br,3H),2.32(t,J＝7.7Hz,2H),2.20(br,6H),1.52～1.59(m,2H),1.37～1.40(m,9H),1.22～1.27 (m,8H),0.85(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.93,14.16,18.49,22.59,24.96,28.90,29.14,31.65,34.33,54.07,56.23,64.02,126.95,128.03,133.76,134.90,162.35,173.09,174.04.
化合物64： 1H NMR(400MHz，CDCl 3)δ:7.05～7.09(m,3H),5.59～5.63(m,1H),5.07～5.12(m,2H),4.40(br,2H),4.12(t,J＝7.8Hz,2H),3.31(br,6H),2.82～2.86(m,2H),2.73～2.79(m,2H),2.20(br,6H),1.56～1.62(m,2H),1.38～1.43(m,6H),0.90(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.98,14.09,18.63,22.72,25.70,28.86,29.09,29.17,54.06,63.78,65.00,65.30,125.42,127.03,127.99,128.56,133.84,134.92,162.38,173.25,174.61.
化合物65： 1H NMR(400MHz，CDCl 3)δ:7.05～7.09(m,3H),5.61～5.64(m,1H),5.08～5.12(m,2H),4.85(br,2H),4.40(br,2H),3.30(br,6H),2.31～2.35(m,2H),2.21(br,6H),1.55～1.63(m,2H),1.26～1.32(m,6H),0.86～0.89(m,3H). 13C NMR(100MHz,CDCl 3)δ:8.02,13.98,18.60,22.36,24.80,28.73,31.45,34.20,54.01,63.58,63.72,65.33,125.43,127.05,128.02,128.57,133.84,134.96,162.30,172.85,173.92.
化合物66： 1H NMR(400MHz，CDCl 3)δ:7.05～7.09(m,3H),5.59～5.63(m,1H),5.07～5.12(m,2H),4.40(br,2H),4.28(br,2H),3.37(t,J＝8.0Hz,2H),3.30(br,6H),2.23(br,6H),1.48～1.53(m,2H),1.42～1.46(m,2H),1.25～1.32(m,10H),0.88(t,J＝6.7Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.01,14.10,18.60,22.67,29.16,29.24,29.33,29.62,29.69,29.77,54.11,63.74,64.38,65.35,67.45,125.41,127.07,127.98, 128.57,133.82,134.93,162.42,173.00.
化合物67： 1H NMR(400MHz，CDCl 3)δ:7.05～7.09(m,3H),5.59～5.63(m,1H),5.07～5.12(m,2H),5.01(br,2H),4.40(br,2H),3.31(br,6H),3.16～3.20(m,2H),2.20(br,6H),1.50～1.53(m,2H),1.28～1.33(m,10H),0.88(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.97,14.11,18.60,22.73,26.41,26.77,29.34,29.42,31.76,40.33,54.04,63.80,65.32,61.58,125.41,127.02,128.03,128.59,133.82,134.93,155.84,162.37,173.02.
化合物68： 1H NMR(400MHz，CDCl 3)δ:7.05～7.09(m,3H),4.93(br,2H),4.42(br,2H),5.65～5.69(m,1H),5.01～5.05(m,2H),3.31(br,6H),2.39～2.43(m,2H),2.22(br,6H),2.10(s,3H). 13C NMR(100MHz,CDCl 3)δ:7.98,18.62,21.18,26.01,54.01,63.74,64.13,65.32,116.56,127.03,127.99,133.84,134.62,134.92,162.38.
化合物70： 1H NMR(400MHz，CDCl 3)δ:7.03～7.06(m,3H),4.90(br,2H),4.36(br,2H),3.79～3.82(m,2H),3.40～3.43(m,2H),3.30～3.32(m,9H),2.35(t,J＝7.7Hz,2H),2.21(br,6H),1.57～1.62(m,2H),1.27～1.30(m,4H),0.87(t,J＝6.7Hz,3H).. 13C NMR(100MHz,CDCl 3)δ:7.89,13.93,18.52,22.31,24.63,31.32,34.28,54.04,59.23,63.92,64.00,67.32,69.94,126.93,127.96,133.82,134.92,162.35,173.08,174.02.化合物71： 1H NMR(400MHz，CDCl 3)δ:7.02～7.06(m,3H),4.89(br,2H),4.35(br,2H),4.04(t,J＝6.8Hz,2H),3.76～3.80(m,2H),3.40～3.43(m,2H),3.30～3.32(m,9H),1.57～1.61(m,2H),2.23(br,6H),1.24～1.28 (m,4H),0.86(t,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.93,13.91,18.51,22.24,27.79,28.90,54.14,59.23,63.99,67.32,67.83,70.01,126.99,127.94,133.84,134.91,162.35,172.72.
化合物72： 1H NMR(400MHz，CDCl 3)δ:7.03～7.06(m,3H),4.52(br,2H),4.36(br,2H),4.05(br,2H),3.79～3.82(m,2H),3.40～3.43(m,2H),3.30～3.32(m,9H),2.21(br,6H),1.52～1.57(m,2H),1.35～1.42(m,6H),0.89～0.92(m,3H). 13C NMR(100MHz,CDCl 3)δ:7.94,14.12,18.50,22.58,26.15,29.13,31.80,54.09,59.23,63.81,67.36,69.43,70.03,73.15,127.01,127.98,133.82,134.91,162.35,172.52.
化合物73： 1H NMR(400MHz，CDCl 3)δ:7.03～7.06(m,3H),4.98(br,2H),4.36(br,2H),3.78～3.82(m,2H),3.40～3.42(m,2H),3.30～3.33(m,9H),3.16～3.19(m,2H),2.21(br,6H),1.50～1.53(m,2H),1.28～1.34(m,10H),0.87(t,J＝7.0Hz,3H).. 13C NMR(100MHz,CDCl 3)δ:7.90,14.12,18.52,22.74,26.41,26.72,29.31,29.39,31.80,40.32,54.01,59.17,61.52,63.99,67.37,70.03,126.99,127.97,133.79,134.94,155.86,162.37,172.99.
化合物74： 1H NMR(400MHz，CDCl 3)δ:7.03～7.06(m,3H),4.39(br,2H),4.31～4.35(m,2H),3.79～3.83(m,2H),3.41～3.43(m,2H),3.30～3.32(m,9H),2.50～2.53(m,2H),2.30(t,J＝7.6Hz,2H),2.21(br,6H),1.62～1.65(m,2H),1.28～1.32(m,4H),0.90(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:7.87,14.18,18.52,22.42,31.12,31.24,33.75,33.88,54.05,59.19,59.69,63.95,67.33,69.98,127.01,127.96, 133.83,134.94,162.35,173.10,177.32.
化合物75： 1H NMR(400MHz，CDCl 3)δ:7.03～7.06(m,3H),4.36(br,2H),4.10(t,J＝7.8Hz,2H),3.79～3.82(m,2H),3.40～3.43(m,2H),3.30～3.33(m,9H),2.82～2.85(m,2H),2.72～2.77(m,2H),2.21(br,6H),1.56～1.62(m,2H),1.37～1.42(m,6H),0.90(t,J＝7.0Hz,3H).. 13C NMR(100MHz,CDCl 3)δ:7.88,14.09,18.54,22.69,25.74,28.90,29.11,29.18,54.07,59.21,63.98,65.02,67.35,69.98,126.96,127.94,133.77,134.92,162.38,173.26,174.62.
化合物76： 1H NMR(400MHz，CDCl 3)δ:7.04～7.07(m,3H),4.78～4.82(m,2H),4.42(br,2H),3.95(m,2H),3.42(t,J＝7.1Hz,2H),3.26～3.31(m,5H),2.32～2.37(m,2H),2.21(br,6H),1.54～1.63(m,2H),1.40(t,J＝6.8Hz,3H),1.25～1.32(m,6H),0.85～0.89(m,3H). 13C NMR(100MHz,CDCl 3)δ:7.99,14.01,18.50,22.36,24.82,28.73,31.39,34.22,54.03,57.82,63.61,63.97,64.58,126.96,127.93,133.80,134.90,162.34,172.84,173.91.
化合物77： 1H NMR(400MHz，CDCl 3)δ:7.05～7.09(m,3H),4.40(br,2H),3.95(m,2H),3.42(t,J＝7.1Hz,2H),3.27～3.31(m,5H),3.02～3.06(m,2H),2.70～2.74(m,2H),2.44～2.47(m,2H),2.20(br,6H),1.50～1.54(m,2H),1.40(t,J＝6.8Hz,3H),1.26～1.33(m,10H),0.90(t,J＝7.0Hz,3H). 13C NMR(100MHz,CDCl 3)δ:8.03,14.06,18.46,22.46,26.48,29.07,29.21,29.27,29.32,29.38,30.01,30.27,31.80,39.24,54.11,57.83,63.99,64.63,126.97,127.98,133.77,134.93,162.32, 172.16,173.81.
实施例10
Figure PCTCN2020071782-appb-000020
于100mL圆底瓶中，加入α-氯代酰胺25mmol，三乙胺30mmol，1,2-二氯乙烷30mL，40℃缓慢滴加二取代仲胺25mmol的1,2-二氯乙烷20mL，30min滴毕。60℃搅拌16h，冷却至室温。二氯甲烷-甲醇硅胶柱层析，分离得到对应叔胺。精密称定该叔胺，加入冷却的二氯甲烷20ml，缓慢滴加等物质的量的甲酸，低温浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到对应的叔胺甲酸盐如下：
Figure PCTCN2020071782-appb-000021
其结构数据如下：
化合物78： 1H NMR(400MHz,D 2O)δ:7.21～7.10(m,3H),4.24(s,2H),3.29(qd,J＝7.3,1.8Hz,4H),2.12(s,6H),1.29(t,J＝7.3Hz,6H).
化合物79： 1H NMR(400MHz，CDCl 3)δ:7.16～7.19(m,3H),5.82～5.85(m,1H),5.18～5.23(m,2H),3.34(br,2H),3.04～3.07(m,2H),2.25(s,3H),2.12(s,6H). 13C NMR(100MHz,CDCl 3)δ:17.58,42.79,59.37,59.56,117.40,126.82,127.75,130.72,137.08,165.76,168.48.
化合物80： 1H NMR(400MHz，CDCl 3)δ:7.16～7.20(m,3H),5.85～5.88(m,1H),5.18～5.23(m,2H),3.33(br,2H),3.03～3.07(m,2H),2.64(q,J＝6.7Hz,2H),2.12(s,6H),1.02(t,J＝6.8Hz,3H). 13C NMR(100MHz, CDCl 3)δ:12.71,17.60,48.92,56.88,57.03,117.40,126.82,127.73,130.72,137.09,165.76,168.50,168.46.
化合物81： 1H NMR(400MHz，CDCl 3)δ:7.16～7.19(m,3H),5.85～5.88(m,1H),5.18～5.23(m,2H),3.78(br,2H),3.39(br,2H),2.63～2.67(m,5H),2.12(s,6H),1.02(t,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3)δ:11.74,17.58,45.09,47.65,55.72,73.21,126.79,127.72,130.73,137.12,165.70,168.49.
化合物82： 1H NMR(400MHz，CDCl 3)δ:7.16～7.19(m,3H),3.49(br,2H),3.32(br,2H),2.64(q,J＝6.8Hz,2H),2.12(s,6H),1.01(t,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3)δ:11.81,17.62,45.01,47.72,55.81,114.83,126.79,127.74,130.73,137.11,165.68,168.49.
实施例11
精密称量有机羧酸1.00g至50mL圆底烧瓶中，30mL二氯甲烷溶解。0℃搅拌下分别缓慢加入经精密称量等物质的量的季铵碱，浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到用于配置药液的终产物。得到的对照化合物如下：
Figure PCTCN2020071782-appb-000022
实施例12
精密称定对照化合物2、化合物14、22、44、52、65、7215x 10 -3mmol至5mL玻璃瓶中，精确加入去离子水1mL，室温搅拌2h，静置至泡沫消失。另精密称取化合物7480x 10 -3mmol至5mL玻璃瓶中，精确加入去离子水1mL，室温搅拌3h。溶液以220μm水相微孔滤膜过滤,磷钨酸染色，TEM检测，如图11所示。除对照化合物2外，其余7个样品均能形成葫芦型的Janus粒子。
实施例13
精密称定对照化合物2、化合物14、22、52、65、7215x 10 -3mmol至5mL玻璃瓶中，精确加氘水1mL，室温搅拌2h，静置至泡沫消失。另精密称取化合物7480x 10 -3mmol至5mL玻璃瓶中，精确加入氘水1mL，室温搅拌3h。NOESY检测，结果如图12所示。除了对照化合物2外，其余样品均能检测出芳环上的甲基氢与芳环氢的相关作用。
实施例14
待测试溶液制备的一般方法：
精密称取上述实施例得到产物75x 10 -3mmol，加入蒸馏水3mL，25℃下以1200rpm转速磁力搅拌3小时，室温静置至气泡消失。
溶液以220μm水相微孔滤膜无菌过滤至另一经灭菌处理的西林瓶中，加塞密封，静置备用。
动物实验的一般方法：
选取200～300g体重的大鼠，雌雄各半。待其完全适应环境后，随机分组，每组8只。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。
其中对照组为0.75％盐酸左布比卡因的水溶液(32mmol/L)。
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、1h、2h、4h、8h、12h、16h、24h测定。此后以28h、32h、36h、40h、48h测定，每天重复直至大鼠完全恢复。
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。
神经病理损伤评估：
坐骨神经注射后第14天，将实验大鼠异氟醚麻醉下心脏注射布比卡因安乐死。取注射部位坐骨神经约1.5cm，保存于10％甲醛溶液中48h，HE染色并切成5μm厚度的切片。
光镜下观察并评分如下：
0分：无炎症；1分：局部轻微炎症；2分：中度水肿及炎症；3分：弥 漫性水肿及重度炎症反应。
脱髓鞘程度评分如下：
0分：无脱髓鞘；1分：轻度脱髓鞘；2分：中度脱髓鞘；3分：重度脱髓鞘。
血管增生评分如下：
0分：无血管增生；1分：每个切片1～2个增生血管(cuffed vessel)；2分：每个切片3～5个增生血管；3分：每个切片增生血管大于5个。
全身毒性测定方法：
选取200～300g体重的大鼠，雌雄各半。随机分组，每组8只。尾静脉注射浓度为25mmol/L的本类化合物纯水溶液，采用序贯法测得半数致死量(LD 50)。
测得数据如下：
表1化合物(I)的坐骨神经阻滞时间和毒性数据
Figure PCTCN2020071782-appb-000023
Figure PCTCN2020071782-appb-000024
Figure PCTCN2020071782-appb-000025
*盐酸布比卡因的注射浓度为32mmol/L。QX-314注射浓度为25mmol/L，由于导致的局部阻滞强度不足，在本发明的测试条件下仍未达到完全的感觉阻滞，故记录为未起效。对照化合物的注射浓度均为25mmol/L。部分化合物未精确测定LD 50，而是以显著大于已报道的长效低毒化合物(对照化合物8和9)的LD 50的10.00mg/kg体重作为测试标准。
Figure PCTCN2020071782-appb-000026
实施例15
精密称取表2中的化合物，其中盐酸利多卡因、醋酸利多卡因和正丙酸利多卡因，配制为2％的水溶液；盐酸布比卡因配制为0.75％的水溶液；实施例10中的化合物，配制为32mmol/L的水溶液。参照实施例14，进行大鼠坐骨神经阻滞实验，并测定神经损伤和LD 50，结果如表2。其中大鼠神经阻滞的测试时间点为1h,2h,4h，此后每2h测试至16h此后的测试时间点为24h。
表2化合物(Ⅱ)的坐骨神经阻滞时间和毒性数据
Figure PCTCN2020071782-appb-000027
Figure PCTCN2020071782-appb-000028
*化合物82在16h时间点局麻作用均有效，在24h时间点局麻作用消失。部分化合物未精确测定LD 50，而是以显著大于盐酸布比卡因2倍LD 50的12.00mg/kg体重作为测试标准。

Claims (17)

  1. 具有长效麻醉效应的二甲基苯铵长链羧酸盐类化合物，结构如式(Ⅰ)所示：
    Figure PCTCN2020071782-appb-100001
    式中的R1和R2为C1～2烷基；R3为氢原子、饱和或不饱和形式的C1～3烷基或取代烷基；X为羰基、氧原子或氮原子；Y为氧原子、氮原子、亚甲基、羰基或亚砜基团；Z为亚甲基、氧原子或氮原子；m＝1～2的整数；n＝1～16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R1和R2为C1～2烷基；R3为氢原子、饱和或不饱和形式的C1～3烷基、C1～3取代烷基；X为羰基或氧原子；Y为氧原子、氮原子、亚甲基、羰基或亚砜基团；Z为亚甲基、氧原子或氮原子；m＝1～2的整数；n＝1～12的整数。
  3. 如权利要求1所述的化合物，其特征如式(Ⅰa)所示：
    Figure PCTCN2020071782-appb-100002
    其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
  4. 如权利要求1所述的化合物，其特征如式(Ⅰb)所示：
    Figure PCTCN2020071782-appb-100003
    其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
  5. 如权利要求1所述的化合物，其特征如式(Ⅰc)所示：
    Figure PCTCN2020071782-appb-100004
    其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
  6. 如权利要求1所述的化合物，其特征如式(Ⅰd)所示：
    Figure PCTCN2020071782-appb-100005
    其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
  7. 如权利要求1所述的化合物，其特征如式(Ⅰe)所示：
    Figure PCTCN2020071782-appb-100006
    其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
  8. 如权利要求1所述的化合物，其特征如式(Ⅰf)所示：
    Figure PCTCN2020071782-appb-100007
    其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
  9. 如权利要求1所述的化合物，其特征如式(Ⅰg)所示：
    Figure PCTCN2020071782-appb-100008
    其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；Y为氧原子或氮原子；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
  10. 如权利要求1所述的化合物，其特征如式(Ⅰh)所示：
    Figure PCTCN2020071782-appb-100009
    其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；X为羰基、氧原子或氮原子；Y为氧原子、氮原子、亚甲基、羰基或亚砜基团；Z为亚甲基、氧原子或氮原子；m＝1～2的整数；n＝1～16的整数。
  11. 如权利要求1所述的化合物，其特征如式(Ⅰi)所示：
    Figure PCTCN2020071782-appb-100010
    其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；X为羰基、氧原子或氮原子；Y为氧原子、氮原子、亚甲基、羰基或亚砜基团；Z为亚甲基、氧原子或氮原子；m＝1～2的整数；n＝1～16的整数。
  12. 如权利要求1所述的化合物，其特征如式(Ⅰj)所示：
    Figure PCTCN2020071782-appb-100011
    其中R1为饱和形式的C1～2烷基；R2为氢原子、取代或未取代、饱和或不 饱和形式的C1～3烷基或烷氧基；X为羰基、氧原子或氮原子；Y为氧原子、氮原子、亚甲基、羰基或亚砜基团；Z为亚甲基、氧原子或氮原子；m＝1～2的整数；n＝1～16的整数。
  13. 具有长效麻醉效应的二甲基苯胺甲酸盐类化合物，结构如式(Ⅱ)所示：
    Figure PCTCN2020071782-appb-100012
    式中的R1为饱和形式的C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～4烷基。
  14. 权利要求13所述的具体化合物78、79、80、81、82，结构如下：
    Figure PCTCN2020071782-appb-100013
  15. 权利要求1至12之一所述的二甲基苯铵长链羧酸盐类化合物，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。
  16. 权利要求13～14之一所述的二甲基苯胺甲酸盐类化合物，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。
  17. 如权利要求1至14之一所述的化合物，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。
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ZHANG YUJUN; GONG DEYING; ZHENG QINGSHAN; LIU JIN; ZHANG WENSHENG: "LC–MS/MS method for preclinical pharmacokinetic study of QX-OH, a novel long-acting local anesthetic, in sciatic nerve blockade in rats", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 146, 1 January 1900 (1900-01-01), AMSTERDAM, NL, pages 161 - 167, XP085239371, ISSN: 0731-7085, DOI: 10.1016/j.jpba.2017.07.028 *

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