WO2021227882A1 - 一种芳香类化合物、制备方法及在药物中的应用 - Google Patents

一种芳香类化合物、制备方法及在药物中的应用 Download PDF

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WO2021227882A1
WO2021227882A1 PCT/CN2021/090726 CN2021090726W WO2021227882A1 WO 2021227882 A1 WO2021227882 A1 WO 2021227882A1 CN 2021090726 W CN2021090726 W CN 2021090726W WO 2021227882 A1 WO2021227882 A1 WO 2021227882A1
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compound
group
add
dichloromethane
reduced pressure
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French (fr)
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刘力铭
邱丹
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四川道珍科技有限公司
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Priority to US17/924,985 priority Critical patent/US20230183169A1/en
Priority to EP21804434.5A priority patent/EP4151622A4/en
Publication of WO2021227882A1 publication Critical patent/WO2021227882A1/zh

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    • 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
    • C07C237/12—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 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/52—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention relates to an aromatic compound, a preparation method and application in medicine. Such compounds can be used in the preparation of local anesthetics, and produce long-acting local nerve block effects.
  • Local anesthesia is a common medical operation in clinical practice. It refers to applying local anesthetics to parts of the body when the patient is awake, so that the sensory nerve conduction function of a certain part of the body is temporarily blocked to produce analgesic effect, and the motor nerve conduction remains intact Or at the same time there is a state of being blocked in varying degrees. This block should be completely reversible.
  • the advantages of local anesthesia are that it is easy to perform, safe, awake, less complication, and little impact on the physiological function of the patient. Local anesthesia is achieved through the use of local anesthetics.
  • the action time and intensity of local anesthetics determine the duration and intensity of local anesthesia. Due to the continuous diffusion of the drug from the administered area, the local drug concentration will decrease. All the local anesthetics currently used in clinical practice have a local anesthetic time of no more than 6 hours after a single administration, even with drugs such as dexamethasone that constricts blood vessels. Combined use can reduce the loss of local anesthetics at the site of application, and the duration of local anesthesia cannot exceed 10 hours (Kyle Robert Kirkham et al, 2018, Anesthesia&Analgesia.126(1):270–279). In 2011, liposome sustained-release formulations containing bupivacaine were launched in the United States.
  • bupivacaine liposomes were shown to only provide analgesia for 24 hours after surgery, but there was no statistical difference in pain intensity between the medication group and the placebo group during the 24-72 hour period ( Uskova A et al, Curr Opin Anaesthesiol. 2015; 28(5):593-7.). It can be seen that if local anesthetics have sufficient analgesic intensity and action time, it will be expected to greatly reduce the use of opioids and avoid or reduce various systemic side effects caused by opioids.
  • Local safety mainly refers to whether the degree of tissue damage (especially nerve damage) at the drug site is within the clinically acceptable level.
  • Systemic safety refers to whether the drug will have a toxic effect on the heart if it diffuses or is injected into the systemic blood circulation by mistake, and whether it will have a toxic effect on the center after passing through the blood-brain barrier. All local anesthetics currently in clinical use have systemic toxicity. If the dose is too large or injected into the blood by mistake, it can cause arrhythmia, abnormal central nervous system activity and even death (Wadlund DL.AORN J.2017 Nov; 106(5):367 -377).
  • the present invention discloses a new class of cationic aromatic compounds, and provides a preparation method thereof and the use of such compounds in medicines.
  • R1 is arbitrarily selected from C1-5 hydrocarbon groups, alkoxy groups, hydroxyl groups, amino or substituted amino groups, carboxyl groups, halogens, cyano groups, alkoxycarbonyl groups, etc.;
  • R2 is selected from C1-8 hydrocarbon groups;
  • R3 is selected from C1-8
  • R4 is selected from C1-8 hydrocarbyl or hydrocarbylene;
  • R5 is selected from H or C1-8 hydrocarbyl or hydrocarbylene;
  • R3 and R4 can also be directly connected by a chemical bond to form a ring with the quaternary ammonium N atom;
  • R4 and R5 can also be directly connected by a chemical bond to form a ring with the quaternary ammonium N atom;
  • X is O or HN or alkyl substituted for N;
  • Y is O or OH or NH2 or alkyl substituted for N;
  • L is a carbonyl group or not present;
  • m
  • R6 is a C1-18 hydrocarbon group or the structure specified as follows:
  • R7 is a C1 to 7 hydrocarbon group
  • R8 is H or a C1 to 8 hydrocarbon group
  • Z is methylene or O
  • any carbon atom in the skeleton of R1 to R7 can be O, S, sulfone group, sulfoxide group, N atom substitution
  • R1-R7 can have one or more substituents on the skeleton, including: halogen, nitro, cyano, carboxy, ester, hydroxyl
  • M is For a pharmaceutically acceptable anion, if the molecule (I) has an internal salt structure, M may not be present.
  • the compound of the present invention can be used alone to produce rapid, potent and long-term blockade of local nerves at a relatively low concentration (0.2-0.5%). Stagnation (24 to 96 hours). It has good safety to tissues in a wide concentration range, while achieving long-acting local anesthesia, it has slight damage to nerves and muscle tissues. Within the therapeutic dose range, the compound disclosed in the present invention has no clinically unacceptable damage such as neuronecrosis and demyelination, and has no significant difference in inflammation score compared with the clinical concentration of 0.75% levobupivacaine. It shows that the compound disclosed in the present invention has better local safety.
  • the compound disclosed in the present invention also has obvious advantages in terms of systemic toxicity. It is shown that intravenous injection of an effective dose of local anesthesia will not cause animal death, and 0.75% of levobupivacaine has an effective dose of local anesthesia. After the tail vein injection, it can cause the death of most animals.
  • the above results indicate that the overall safety of the molecule disclosed in the present invention is good, and there is no concern about serious acute toxicity caused by mistaken injection into blood. More unexpectedly, when the compound of the present invention is used in combination with common clinical local anesthetics such as lidocaine, bupivacaine, or tetracaine, the dose required for its onset of action is further reduced, showing good compatibility with these drugs. This feature enhances the safety of the compound of the present invention. Finally, the compound of the present invention did not observe changes in the motor ability of animals in the sciatic nerve block experiment, showing the advantage of selective sensory block.
  • the unexpected safety improvement and high titer of the compound of the present invention greatly increase the potential of this type of drug for clinical postoperative analgesia.
  • the compounds disclosed in the present invention, pharmaceutically acceptable salts, isotopic molecules, solvates, single crystal forms or co-crystals, optical isomers, and preparations (including sustained-release preparations), pharmaceutical kits, Compounds, etc. can be used in the preparation of long-acting local anesthetics.
  • Dissolve 315 mg of compound 1 in 30 mL of dichloromethane add 156 mg of cyclohexylpropionic acid, and stir.
  • 329mg IM-16 was mixed with 1mL n-butyric anhydride, 3mL pyridine was added, and the tube was sealed and reacted overnight at 90°C. After cooling, the solvent was evaporated under reduced pressure, and ethyl acetate was added to precipitate a powdery solid. It was filtered to obtain a white solid powder, which was recrystallized twice with ethyl acetate/ethanol to obtain 105 mg of a white solid powder, namely compound 38, with a yield of 26.3%.
  • Dissolve 315 mg of compound 1 in 30 mL of dichloromethane add 157 mg of 1-piperidine propionic acid, and stir.
  • Dissolve 315 mg of compound 1 in 30 mL of dichloromethane add 159 mg of 3-(4-morpholino)propionic acid, and stir.
  • Dissolve 315 mg of compound 1 in 30 mL of dichloromethane add 186 mg of 3-(4-ethylpiperazin-1-yl)-propionic acid (CAS: 799262-18-3), and stir.
  • Dissolve 329 mg of IM-21 in 20 mL of dichloromethane, add 315 mg of compound 1, and stir. Dissolve 210 mg of DCC in 10 mL of dichloromethane, drip into the above reaction solution with stirring, and react at room temperature overnight after the dripping is completed. After filtration, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (dichloromethane/methanol 20/1) to obtain 103 mg of white solid powder, namely compound 44, yield: 16.5%.
  • the compound of the example was dissolved in water for injection at a concentration of 0.2-0.5g/100mL (0.2-0.5%), or a mixed solution with a specific ratio of common clinical local anesthetics on the market, with 0.75% levobupivaca as positive Control compound.
  • the experimental method is: male SD rats weighing 180-300 grams, shave their back hair one day before the experiment, and expose a round skin area with a diameter of 4 cm. Use a 1 mL syringe to inject 0.4 mL of the drug solution subcutaneously into the round center of the exposed back to form a skin hill.
  • the skin and muscle of the experimental animal were taken from the administration site, and the pathological section was prepared by HE staining to observe the inflammation score of the tissue.
  • the scoring standard is: 0 points (no inflammation); 1 point (local mild inflammation); 2 points ( Moderate edema, moderate inflammation); 3 points (diffuse edema, severe inflammation).
  • the pathological results showed that when the molecules of the present invention were administered in 0.2%, 0.5% and mixed solutions with common local anesthetics, the inflammation scores of skin and muscle tissues were not statistically significant with those of the 0.75% levobupivacaine control group. Differences and damage scores are all 0 to 1, showing that the local safety of the compound of the present invention is equivalent to that of bupivacaine at a clinical concentration, and has good local safety.
  • the compound of the example was dissolved in water for injection at a concentration of 0.5 ⁇ 2.0g/100mL (0.5% ⁇ 2%), or a mixed solution with a specific ratio of commercially available clinical local anesthetics, with 0.75% levobupivacaine
  • the injection is a positive control compound.
  • the experimental method was as follows: male SD rats weighing 180-300 grams were anesthetized with isoflurane, and 0.2 mL of the drug-containing solution was injected near the left sciatic nerve. Each drug was tested using 8 rats. After the rat wakes up, start the first measurement, and then take the measurement every 2 hours. If there is still anesthesia after the six measurements, the measurement is performed every 6 hours until the anesthesia disappears.
  • the method for judging whether anesthesia is present is as follows: use Von Frey fiber filaments (60g) to stimulate the skin of the plantar and side of the hind limbs on the side where the drug is injected. If there is no such behavior, it is deemed that the local anesthetic effect exists.
  • the test results are shown in Table 2.
  • the drugs to be tested all produced local anesthesia during the first test.
  • 0.75% of bupivacaine can only produce sciatic nerve anesthesia for 2 to 6 hours, while most of the compounds described in the present invention can produce sciatic nerve anesthesia for up to 160 hours at a concentration range of 0.5% to 2.0%.
  • a mixed solution formed by the compound of the present invention at a low concentration and lidocaine, bupivacaine, levobupivacaine, and tetracaine at a low concentration can significantly prolong the sciatic nerve anesthesia time and exhibit strong synergy effect.
  • levobupivacaine hydrochloride not only caused sensory block on the hindlimb on the side where the drug was injected, but also significantly blocked the motor function of the hindlimb on the side of the rat. It is basically the same as the duration of sensory block.
  • none of the compounds disclosed in the present invention has been found to block the locomotor ability of the hind limbs of rats, which indicates that the compounds of the present invention have the advantage of selective sensory block.
  • the scoring standard is: 0 points (slightly congested, dilated, and no inflammatory cell infiltration of the epineurium); 1 point (Slightly congested and dilated adventitial blood vessels, accompanied by a small amount of inflammatory cell infiltration); 2 points (obviously congested and dilated adventitia vessels, accompanied by inflammatory cell infiltration); 3 points (adventitious blood vessels congested, dilated, and spinal cord parenchyma with inflammatory cell infiltration) .
  • Example 51 the compound of the present invention can produce a local infiltration anesthesia effect for 24 to 66 hours at a concentration of 0.2% and an injection volume of 0.4 mL. Will not cause the death of rats. However, 0.4 mL 0.75% of levobupivacaine can only produce a local infiltration anesthetic effect for 4-6 hours. If all of this dose of levobupivacaine is injected into the blood by mistake, 70% of the rats will die. It can be seen that the compound of the present invention has high potency and good safety, and the overall safety at an effective dose is much higher than that of the control drug levobupivacaine.
  • the present invention is not limited to the above optional embodiments.
  • anyone can derive other products in various forms under the enlightenment of the present invention, but regardless of any changes in its shape or structure, all that fall into the scope of the claims of the present invention The technical solutions within the scope fall within the protection scope of the present invention.

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Abstract

一种芳香类化合物，该类化合物可在局部产生持久的神经阻滞作用，产生镇痛、止痒等效果，可用于长效局部麻醉药物、局部镇痛药物和止痒药物的制备。

Description

一种芳香类化合物、制备方法及在药物中的应用 技术领域
本发明涉及一种芳香类化合物、制备方法及在药物中的应用。该类化合物可在制备局部麻醉药物中应用，产生长效的局部神经阻滞效果。
背景技术
大部分手术伤口引起的中度至重度疼痛将持续48～72小时，因此术后疼痛的处理通常是给予全身性阿片类镇痛药物，但因此引起的成瘾、便秘和呼吸抑制等问题困扰患者。如何在减少阿片类药物使用的同时确保术后镇痛的安全有效成为需要解决的重大临床问题。
临床上，某些伤口较小的手术可使用局部麻醉药物控制疼痛，从而避免或减少使用阿片类全身麻醉药物。局部麻醉是临床常见的医疗操作，是指在患者清醒状态下，将局部麻醉药物应用于身体局部，使机体某一部分的感觉神经传导功能暂时被阻断而产生镇痛效果，运动神经传导保持完好或同时有程度不等的被阻滞状态。这种阻滞应完全可逆。局部麻醉的优点在于简便易行、安全、患者清醒、并发症少和对患者生理功能影响小。局部麻醉是通过使用局部麻醉药物得以实现，局部麻醉药物的作用时间和作用强度决定了局部麻醉的持续时间和镇痛强度。由于药物会从给药局部不断扩散导致局部药物浓度降低，目前临床使用的所有局部麻醉药物单次给药后产生的局部麻醉时间均不超过6小时，即便是与收缩血管的地塞米松等药物合用，降低局部麻醉药物在用药部位的扩散损失，局部麻醉的持续时间也无法超过10小时(Kyle Robert Kirkham et al,2018,Anesthesia&Analgesia.126(1):270–279)。2011年，含有布比卡因的脂质体缓释制剂在美国上市，虽然该制剂声称可以产生72小时的局部麻醉效果，但已经有报道证实其不稳定的剂量-药效依赖(Christopher Wahal,Indian J Anaesth.2018；62(2):94–102.)和有限的镇痛效果(Malik O et al,J Anaesthesiol Clin Pharmacol.2017；33(2):151-156)，表明该制剂并不能独立地应对术后48～72小时的疼痛，仅能减少全身性阿片类镇痛药物的使用。在后续的一些临床试验中，布比卡因脂质体显示仅能提供术后24小时的镇痛效果，但在24～72小时期间用药组与安慰剂组的疼痛强度并无统计学差异(Uskova A et al,Curr Opin Anaesthesiol.2015；28(5):593-7.)。可见，局部麻醉药物如果具备足够的镇痛强度和作用时间，将有望大幅减少阿片类药物的使用，避免或减少因阿片类药物产生的各种全身副作用。
长效局部麻醉药物的另一个挑战是药物的安全性，包括局部和全身安全性。局部安全性主要是指用药部位的组织损伤(尤其是神经损伤)程度是否在临床可接受的程度之内。而全身安全性是指药物如果扩散或误注进入全身血液循环是否对心脏产生毒害作用，若透过血脑屏障后是否对中枢产生毒害作用。目前临床使用的所有局部麻醉药物均具有全身毒性，若剂量过大或误注入血，可引起心率失常、中枢神经活动异常甚至导致死亡(Wadlund DL.AORN J.2017 Nov；106(5):367-377)。
为了获得更长效的局部麻醉药物，一些针对传统局部麻醉药物因扩散导致药效不能持久的改良分子陆 续出现，如QX-314和QX-314-OH，它们是传统局部麻醉药物利多卡因的季铵盐衍生物，具备与利多卡因相似的结构，但分子带有永久的正电荷，正电荷使得分子的扩散减慢，使它们能够产生的局部麻醉时间较之利多卡因显著延长(2 hours VS 6～8hours)。值得注意的是，阳离子的引入虽使分子的局部麻醉时间延长，但从注射部位扩散至神经细胞的能力欠佳，QX-314和QX-314-OH的起效时间也明显延长，注射后需要20～30分钟方能起效(Anesthesiology,2009,111:122～6)。此外，要充分发挥上述带电分子的作用，需借助一定的离子通道开放剂，才能将上述分子送入胞内而发挥作用(CN201680057337.3)。
另一些具有表面活性，可自组装形成缓释材料的利多卡因季铵盐衍生物随后被报道，这些单体分子在溶液中经组装之后可产生长效(24～90小时)局部麻醉效果(中国发明申请：201510423735.X)，但这类分子对局部神经可造成中度至重度神经损伤(中国发明申请：201810104560.X)。随后，又出现了一些新的阳离子型长效局部麻醉药物的报道(201910100568.3、201910101369.4)，这类化合物在大鼠坐骨神经阻滞模型中的剂量较大，说明其效价较低，且这些分子的整体安全性并不清楚。
由此可见，单次给药起效迅速、效价高、局部损伤小，用药后整体安全性好的长效局部麻醉药物仍需要进一步的研发。
发明内容
针对目前长效局部麻醉药物或类药分子的不足，本发明披露了一类新的阳离子芳香族化合物，并提供其制备方法以及这类化合物在药物中的用途。
本发明所称的酰胺化化合物，其结构如式(Ⅰ)所示：
Figure PCTCN2021090726-appb-000001
其中，R1任意选自C1～5的烃基、烷氧基、羟基、氨基或取代氨基、羧基、卤素、氰基、烷氧羰基等；R2选自C1～8的烃基；R3选自C1～8的烃基或亚烃基；R4选自C1～8的烃基或亚烃基；R5选自H或C1～8的烃基或亚烃基；R3和R4还可以由化学键直接相连，与季铵N原子形成环；R4和R5还可以由化学键直接相连，与季铵N原子形成环；X为O或HN或烷基取代N；Y为O或OH或NH2或烷基取代N；L为羰基或不存在；m＝0或1；n＝0～4的整数；
R6为C1～18的烃基或如下指定结构：
Figure PCTCN2021090726-appb-000002
上述指定结构中p＝1～16的整数，R7为C1～7的烃基，R8为H或C1～8的烃基，Z为亚甲基或O；R1～R7的骨架中任一碳原子可被O，S，砜基，亚砜基，N原子替换；R1～R7的骨架上可具有1个或多个取代基，包括：卤素，硝基，氰基，羧基，酯基，羟基；M为药学上可以接受的阴离子，若分子(Ⅰ)具备内盐结构，M可以不存在。
符合上述结构特点的优选化合物包括但不限于：
Figure PCTCN2021090726-appb-000003
Figure PCTCN2021090726-appb-000004
Figure PCTCN2021090726-appb-000005
这类化合物的合成通常是分别合成得到含有A和B结构片段的分子，然后用共价键或经lingker将A,B片段键合得到：
Figure PCTCN2021090726-appb-000006
当Linker为
Figure PCTCN2021090726-appb-000007
时，目标物的通常的合成路线为：
Figure PCTCN2021090726-appb-000008
当Linker为
Figure PCTCN2021090726-appb-000009
时，目标物的通常的合成路线为：
Figure PCTCN2021090726-appb-000010
当Linker为
Figure PCTCN2021090726-appb-000011
时(R10为H或烷基)，目标物的通常的合成路线为：
Figure PCTCN2021090726-appb-000012
当Linker为
Figure PCTCN2021090726-appb-000013
时(R11为H或烷基)，目标物的通常的合成路线为：
Figure PCTCN2021090726-appb-000014
当lingke为
Figure PCTCN2021090726-appb-000015
时，目标物的通常的合成路线为(X为卤素或磺酸酯)：
Figure PCTCN2021090726-appb-000016
本发明所述的化合物在大鼠坐骨神经阻滞和皮下浸润麻醉两项实验中，单独使用即可在较低的浓度下(0.2～0.5％)对局部神经产生快速、强效和长时间的阻滞(24～96小时)。在较宽的浓度范围下对组织的安全性好，在实现长效局部麻醉的同时对神经、肌肉组织损伤轻微。在治疗剂量范围内，本发明所披露的化合物未出现神经坏死和脱髓鞘等临床不能接受的损伤，同时在炎症评分上与临床浓度的0.75％左布比卡因相比无显著差异。说明本发明所披露的化合物具有较好的局部安全性。此外，本发明所披露的化合物在全身毒性方面也具有明显的优势，表现在静脉注射局部麻醉有效剂量的化合物，不会引起动物的死亡，而0.75％的左布比卡因其局部麻醉有效剂量经尾静脉注射后，可引起大部分动物的死亡。上述结果说明本发明所披露的分子整体安全性良好，没有误注入血后产生严重急性毒性的担忧。更为意想不到的是，本发明所述的化合物与利多卡因、布比卡因或丁卡因等临床常见局部麻醉药物合用时，其起效所需剂量进一步降低，表现出与这些药物良好的协同效应，这种特点加强了本发明所述化合物的安全性。最后，本发明所述的化合物在坐骨神经阻滞实验中并未观察到动物的运动能力改变，显示出选择性感觉阻滞的优势。
本发明所述化合物意想不到的安全性改善和高效价，极大地提高了这类药物用于临床术后镇痛的潜力。本发明所披露的化合物，药学上可接受的盐，同位素分子，溶剂合物，单一晶型或共晶，光学异构体，以及含有上述物质的制剂(含缓释制剂)、药物试剂盒、复方等，可在制备长效局部麻醉药物中应用。
下面结合实施例来说明本发明所述的发明内容及其优越性。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 PCTCN2021090726-appb-000017
将13.7克4-氨基-3,5-二甲基苯酚和40克三乙胺溶于150mL二氯甲烷中，冰浴下缓慢滴加11.3克氯乙酰氯。滴毕后搅拌反应2小时，减压蒸干溶剂，加入150mL乙酸乙酯，用50mL稀盐酸洗涤有机层，分出有机层。减压蒸干乙酸乙酯，得棕黑色油状物，柱层析纯化产物(石油醚/乙酸乙酯＝3/1)，得黄色固体粉末4.89克(IM-1)。产率22.9％。
将300mg IM-1溶解在3mL无水乙醇中，加入2mL三乙胺，外温95℃封管搅拌反应3小时，析出白色固体，冷却后加入5mL乙醇，用2滴浓盐酸调pH值至3以下，减压蒸干乙醇，得灰白色固体粉末，柱层析纯化(二氯甲烷/甲醇＝10/1)得122mg白色粉末，即化合物1，产率：27.6％。
1HNMR d-DMSO 400Hz：1.29(9H,t,J＝8Hz),2.07(6H,s),3.51(6H,q,J＝8Hz),4.33(2H,s),6.49(2H,s),9.32(1H,s),10.21(1H,s).
实施例2
Figure PCTCN2021090726-appb-000018
将15.7克4-氨基-3-氯-5-甲基苯酚和40克三乙胺溶于150mL二氯甲烷中，冰浴下缓慢滴加11.3克氯乙酰氯。滴毕后搅拌反应2小时，减压蒸干溶剂，加入150mL乙酸乙酯，用50mL稀盐酸洗涤有机层，分出有机层。减压蒸干乙酸乙酯，得棕黑色油状物，柱层析纯化产物(石油醚/乙酸乙酯＝3/1)，得黄色固体粉末3.22克(IM-2)。产率13.8％。
将300mg IM-2溶解在3mL无水乙醇中，加入2mL三乙胺，外温95℃封管搅拌反应3小时，析出白色固体，冷却后加入5mL乙醇，用2滴浓盐酸调pH值至3以下，减压蒸干乙醇，得灰白色固体粉末，柱层析纯化(二氯甲烷/甲醇＝10/1)得109mg白色粉末，即化合物2，产率：25.4％。
1HNMR d-DMSO 400Hz：1.26(9H,t,J＝8Hz),2.14(3H,s),3.48(6H,q,J＝8Hz),4.31(2H,s),6.52(1H,s),7.18(1H,s),9.21(1H,s),10.18(1H,s).
实施例3
Figure PCTCN2021090726-appb-000019
将600mg化合物1与1克醋酐混合，加入3mL吡啶。外温90℃封管加热搅拌18小时。加入硅胶拌样，减压蒸干，残余物经柱层析(二氯甲烷/甲醇＝20/1)得黄色油状物，用乙酸乙酯重结晶，析出白色固体，过滤，50℃烘干，得白色固体粉末350mg，即化合物3，产率：51.5％。
1HNMR d-DMSO 400Hz：1.31(9H,t,J＝8Hz),2.17(6H,s),2.25(3H,s),3.53(6H,q,J＝8Hz),4.42(2H,s),6.88(2H,s),10.66(1H,s).
实施例4
Figure PCTCN2021090726-appb-000020
将500mg化合物1溶解在30mL二氯甲烷中，加入200mg三光气，冷却至0～5℃，缓慢滴加3mL吡啶，撤去冰浴，搅拌2小时后再降温至0～5℃，缓慢滴加50％乙胺的乙醇溶液1.5mL，搅拌1小时后撤去冰浴，室温搅拌2小时,滴入稀盐酸调pH至3。反应液减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝10/1)得白色粉末389mg，即化合物4，产率63.5％。
1HNMR d-DMSO 400Hz：1.06(3H,t,J＝8Hz),1.29(9H,t,J＝8Hz),2.07(6H,s),3.05(2H,m),3.51(6H,q,J＝8Hz),4.33(2H,s),6.49(2H,s),6.78(1H,s),10.21(1H,s).
实施例5
Figure PCTCN2021090726-appb-000021
将600mg化合物1与3mL吡啶混合，加入丙酰氯1mL。外温40℃加热搅拌5小时。加入硅胶拌样，减压蒸干，残余物经柱层析(二氯甲烷/甲醇＝20/1)得黄色油状物，用乙酸乙酯重结晶，析出白色固体，过滤，50℃烘干，得白色固体粉末110mg，即化合物5，产率：15.6％。
1HNMR d-DMSO 400Hz：1.13(3H,t,J＝8Hz),1.29(9H,t,J＝8Hz),2.17(6H,s),2.51～2.61(2H,m),3.53(6H,q,J＝8Hz),4.44(2H,s),6.88(2H,s),10.72(1H,s).
实施例6
Figure PCTCN2021090726-appb-000022
将600mg化合物1与3mL吡啶混合，加入1克正丁酸酐。外温90℃封管加热搅拌18小时，用0.5mol/L的硫酸乙醇溶液调pH至3以下，减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得黄色油状物，用乙酸乙酯重结晶，析出灰白色固体，过滤，50℃烘干，得白色固体粉末378mg，即化合物6，产率：44.5％。
1HNMR d-DMSO 400Hz：0.97(3H,t,J＝8Hz),1.31(9H,t,J＝8Hz),1.61～1.70(2H,m),2.17(6H,s),2.49～2.56(2H,m),3.53(6H,q,J＝8Hz),4.41(2H,s),6.87(2H,s),10.62(1H,s).
实施例7
Figure PCTCN2021090726-appb-000023
将2.36克N-boc-3，5-二甲基-4-氨基苯胺(CAS:1392273-50-5)溶解在30mL二氯甲烷中，加入5克吡啶，冰浴下缓慢滴加1.3克氯乙酰氯。滴毕后撤去冰浴，室温搅拌2小时。减压蒸干溶剂，加入100mL乙酸乙酯溶解残余物，每次用3N盐酸50mL洗涤乙酸乙酯层2次，水洗乙酸乙酯层1次，分出有机层，减压蒸干乙酸乙酯，残余物加入50mL乙腈，加入4克三乙胺，加热至65℃反应过夜。减压蒸干乙腈，加入50mL二氯甲烷溶解残余物，通入干燥氯化氢气体30分钟，之后室温搅拌反应液3小时，减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色粉末0.79克，即化合物7，产率22.6％。
1HNMR d-DMSO 400Hz：1.27(9H,t,J＝8Hz),2.05(6H,s),3.50(6H,q,J＝8Hz),4.32(2H,s),6.78(2H,s),8.32(3H,s),10.20(1H,s).
实施例8
Figure PCTCN2021090726-appb-000024
将3.5克化合物7溶解在50mL乙腈中，加入1.5克无水碳酸钠室温搅拌2小时，随后加入1.2克溴丙烷，氮气保护下封管，于75℃搅拌过夜。冷却后过滤，向滤液中通入氯化氢气体10分钟，减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色粉末1.39克，即化合物8，产率35.5％。
1HNMR d-DMSO 400Hz：0.89(3H,t,J＝8Hz),1.26(9H,t,J＝8Hz),1.53～1.58(2H,m),2.07(6H,s),3.32(2H,m),3.51(6H,q,J＝8Hz),4.31(2H,s),6.72(2H,s),8.32(2H,s),10.13(1H,s).
实施例9
Figure PCTCN2021090726-appb-000025
将3.5克化合物7溶解在50mL乙腈中，加入1.5克无水碳酸钠室温搅拌2小时，滴入氯甲酸丁酯(CAS:592-34-7)1.5克，室温反应过夜。过滤，滤液减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色粉末2.7克，即化合物9，产率65.2％。
1HNMR d-DMSO 400Hz：0.91(3H,t,J＝8Hz),1.24～1.28(11H,m),1.43～1.48(2H,m),2.09(6H,s),3.50(6H,q,J＝8Hz),3.89～3.93(2H,m),4.30(2H,s),6.75(2H,s),8.37(2H,s),10.43(1H,s).
实施例10
Figure PCTCN2021090726-appb-000026
将315mg化合物1与1mL正戊酸酐混合，加入3mL吡啶，封管后于90℃搅拌8小时，减压蒸干吡啶，加入乙酸乙酯析出粉末状固体。过滤，得白色固体粉末，用乙酸乙酯/乙醇重结晶两次，得白色固体粉末198mg，即化合物10，产率49.6％。
1HNMR d-DMSO 400Hz：0.92(3H,t,J＝8Hz),1.29～1.39(11H,m),1.60～1.62(2H,m),2.17(6H,s),2.5～2.57(4H,m),3.53(6H,q,J＝8Hz),4.4(2H,s),6.87(2H,s),10.59(1H,s).
实施例11
Figure PCTCN2021090726-appb-000027
将315mg化合物1与1mL正己酸酐混合，加入3mL吡啶，封管后于90℃搅拌8小时，减压蒸干吡啶，加入乙酸乙酯析出粉末状固体。过滤，得白色固体粉末，用乙酸乙酯/乙醇重结晶两次，得白色固体粉末157mg，即化合物11，产率38％。
1HNMR d-DMSO 400Hz：0.88～0.91(3H,m),1.27～1.37(13H,m),1.60～1.67(2H,m),2.18(6H,s),2.49～2.57(2H,m),3.34～3.55(6H,m),4.46(2H,s),6.86(2H,s),10.82(1H,s).
实施例12
Figure PCTCN2021090726-appb-000028
将315mg化合物1与1mL正庚酸酐混合，加入3mL吡啶，封管后于90℃搅拌8小时，减压蒸干吡啶，加入乙酸乙酯析出粉末状固体。过滤，得白色固体粉末，用乙酸乙酯/乙醇重结晶两次，得白色固体粉末141mg，即化合物12，产率33％。
1HNMR d-DMSO 400Hz：086～0.90(3H,m),1.27～1.38(15H,m),1.49～1.64(2H,m),2.17(6H,s),2.55(2H,t,J＝8Hz),3.50～3.55(6H,m),4.42(2H,s),6.86(2H,s),10.65(1H,s).
实施例13
Figure PCTCN2021090726-appb-000029
将315mg化合物1与1mL正辛酸酐混合，加入3mL吡啶，封管后于90℃搅拌8小时，减压蒸干吡啶，加入乙酸乙酯析出粉末状固体。过滤，得白色固体粉末，用乙酸乙酯/乙醇重结晶两次，得白色固体粉末121mg，即化合物13，产率27.4％。
1HNMR d-DMSO 400Hz：0.86～0.89(3H,m),1.29～1.33(17H,m),1.59～1.65(2H,m),2.17(6H,s),2.50～2.56(2H,m),3.50～3.55(6H,m),4.43(2H,s),6.86(2H,s),10.68(1H,s).
实施例14
Figure PCTCN2021090726-appb-000030
将315mg化合物1与700mg锌粉用30mL甲苯混合搅拌，加入95mg氯代叔丁烷，室温搅拌2小时，减压蒸干溶剂，加入30mL无水乙醇，硅藻土过滤，滤液减压蒸干，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末109mg，即化合物14，产率：29.4％。
1HNMR d-DMSO 400Hz：1.27(9H,t,J＝8Hz),1.49(9H,s),2.05(6H,s),3.50(6H,q,J＝8Hz),4.31(2H,s),6.67(2H,s),10.21(1H,s).
实施例15
Figure PCTCN2021090726-appb-000031
将315mg化合物1与100mg 2-氯丙烷混合在3mL乙腈中，加入500mg无水碳酸钾和5mg碘化钾，封管后于70℃搅拌过夜。冷却后过滤，滤液减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色粉末95mg，即化合物15，产率26.6％。
1HNMR d-DMSO 400Hz：1.23～1.29(15H,m),2.04(6H,s),3.51(6H,q,J＝8Hz),4.30(2H,s),4.69～4.73(1H,m),6.65(2H,s),10.29(1H,s).
实施例16
Figure PCTCN2021090726-appb-000032
将315mg化合物1与110mg 1-氯丁烷混合在3mL乙腈中，加入500mg无水碳酸钾和5mg碘化钾，封管后于70℃搅拌过夜。冷却后过滤，滤液减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色粉末81mg，即化合物16，产率21.8％。
1HNMR d-DMSO 400Hz：0.91～0.94(3H,m),1.26(9H,t,J＝8Hz),1.43～1.46(2H,m),1.68～1.71(2H,m),2.06(6H,s),3.52(6H,q,J＝8Hz),4.01～4.04(2H,m),4.30(2H,s),6.63(2H,s),10.21(1H,s).
实施例17
Figure PCTCN2021090726-appb-000033
将315mg化合物1与125mg 1-氯己烷混合在3mL乙腈中，加入500mg无水碳酸钾和5mg碘化钾，封管后于70℃搅拌过夜。冷却后过滤，滤液减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色粉末53mg，即化合物17，产率13.3％。
1HNMR d-DMSO 400Hz：0.88～0.90(3H,m),1.27(9H,t,J＝8Hz),1.35～1.45(4H,m),1.79～1.82(2H,m),2.09(6H,s),3.51(6H,q,J＝8Hz),4.02～4.05(2H,m),4.28(2H,s),6.61(2H,s),10.29(1H,s).
实施例18
Figure PCTCN2021090726-appb-000034
将315mg化合物1与130mg甲磺酸乙酯混合在10mL乙腈中，加入800mg三乙胺，封管后于70℃搅拌过夜。冷却后过滤，滤液减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色粉末213mg，即化合物17，产率62.1％。
1HNMR d-DMSO 400Hz：1.25～1.35(12H,m),2.06(6H,s),3.50(6H,q,J＝8Hz),4.01～4.05(2H,m),4.29(2H,s),6.60(2H,s),10.23(1H,s).
实施例19
Figure PCTCN2021090726-appb-000035
将315mg化合物1与1mL特戊酸酐混合，加入3mL吡啶，封管后于90℃搅拌8小时，减压蒸干吡啶，加入乙酸乙酯析出粉末状固体。过滤，得白色固体粉末，用乙酸乙酯/乙醇重结晶两次，得白色固体粉末78mg，即化合物19，产率19.5％。
1HNMR d-DMSO 400Hz：1.29～1.32(18H,m),2.17(6H,s),3.51(6H,q,J＝8Hz),4.37(2H,s),6.86(2H,s),10.46(1H,s).
实施例20
Figure PCTCN2021090726-appb-000036
向30mL二氯甲烷中加入315mg化合物1和220mg 5,5,5-三氟正戊酰氯，冰浴下滴入500mg吡啶，撤去冰浴室温搅拌8小时。减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色粉末状固体211mg，即化合物20，产率46.6％。
1HNMR d-DMSO 400Hz：1.27(9H,t,J＝8Hz),1.63～1.66(2H,m),2.16(6H,s),2.45～2.51(4H,m),3.50(6H,q,J＝8Hz),4.35(2H,s),6.83(2H,s),10.41(1H,s).
实施例21
Figure PCTCN2021090726-appb-000037
将2.13克IM-1与3克2-二乙氨基乙醇溶于20mL乙腈中，封管90℃搅拌过夜。冷却后减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末2.09克，即化合物21，产率63.2％。
1HNMR d-DMSO 400Hz：1.28(9H,t,J＝8Hz),2.17(6H,s),3.50～3.52(4H,m),3.64～3.66(2H,m),3.98～4.02(2H,m),4.36(2H,s),5.11(1H,s),6.81(2H,s),9.10(1H,s),10.31(1H,s).
实施例22
Figure PCTCN2021090726-appb-000038
将2.13克IM-1与3克二羟乙基乙基胺溶于20mL乙腈中，封管90℃搅拌过夜。冷却后减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末2.18克，即化合物22，产率62.9％。
1HNMR d-DMSO 400Hz：1.25(3H,t,J＝8Hz),2.13(6H,s),3.43～3.51(6H,m),3.94～3.99(4H,m),4.32(2H,s),5.67(2H,s),6.80(2H,s),9.03(1H,s),10.11(1H,s).
实施例23
Figure PCTCN2021090726-appb-000039
将2.13克IM-1与3克甲氧乙基二乙基胺溶于20mL乙腈中，封管90℃搅拌过夜。冷却后减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末1.68克，即化合物23，产率48.7％。
1HNMR d-DMSO 400Hz：1.27(6H,t,J＝8Hz),2.16(6H,s),3.25(3H,s),3.50～3.53(6H,m),3.82～3.85(2H,m),4.30(2H,s),6.81(2H,s),9.01(1H,s),10.41(1H,s).
实施例24
Figure PCTCN2021090726-appb-000040
将500mg化合物12溶解在100mL二氯甲烷中，加入含有5％甲烷磺酸钠水溶液100mL，充分振摇10分钟，分出有机层，减压蒸干溶剂得315mg白色固体粉末，即化合物24。
1HNMR d-DMSO 400Hz：：088～0.92(3H,m),1.26～1.37(15H,m),1.48～1.64(2H,m),2.15(6H,s),2.52(2H,t,J＝8Hz),2.78(3H,s),3.51～3.55(6H,m),4.41(2H,s),6.80(2H,s),10.11(1H,s).
实施例25
Figure PCTCN2021090726-appb-000041
将2.13克化合物IM-1溶解在30mL乙腈中，加入N,N-二正丙基乙胺3.6克，回流搅拌过夜。冷却后减压蒸干溶剂，经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末1.07克，即化合物IM-5。
1HNMR d-DMSO 400Hz：：0.92(6H,t,J＝8Hz),1.23(3H,t,J＝8Hz),1.68～1.73(4H,m),2.16(6H,s),3.48～3.52(6H,m),4.40(2H,s),6.38(2H,s),9.24(1H,s),10.82(1H,s).
将343mg IM-5与1ml丙酸酐混合，加入3mL吡啶，封管于90℃搅拌过夜。冷却后减压蒸干溶剂， 加入乙酸乙酯析出粉末状固体。过滤，得白色固体粉末，用乙酸乙酯/乙醇重结晶两次，得白色固体粉末168mg，即化合物25，产率42.1％。
1HNMR d-DMSO 400Hz：0.91(6H,t,J＝8Hz),1.23～1.27(6H,m),1.65～1.72(4H,m),2.16(6H,s),2.50～2.53(2H,m),3.45～3.51(6H,m),4.42(2H,s),6.84(2H,s),9.01(1H,s),10.42(1H,s).
实施例26
Figure PCTCN2021090726-appb-000042
将2.13克IM-1溶于20mL乙腈中，加入0.9克哌啶和2克无水碳酸钾，加热至50℃搅拌5小时，随后加入丙烯溴继续反应1.5小时，冷却后过滤，滤液减压蒸干，经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末0.98克，即IM-7。
1HNMR d-DMSO 400Hz：1.58～1.74(6H,m),2.14(6H,s),3.16～3.21(4H,m),3.95(2H,m),4.40(2H,s),5.01～5.06(2H,m),5.83～5.85(1H,m),6.35(2H,s),9.09(1H,s),10.22(1H,s).
将383mg IM-7与1mL正丁酸酐混合，加入3mL吡啶，封管90℃搅拌过夜。冷却后减压蒸干溶剂，加入乙酸乙酯析出粉末状固体。过滤，得白色固体粉末，用乙酸乙酯/乙醇重结晶两次，得白色固体粉末217mg，即化合物26，产率47.9％。
1HNMR d-DMSO 400Hz：0.91(3H,t,J＝8Hz),1.54～1.73(8H,m),2.13(6H,s),2.52～2.56(2H,m),3.15～3.22(4H,m),3.96(2H,m),4.42(2H,s),5.02～5.08(2H,m),5.82～5.85(1H,m),6.83(2H,s),10.42(1H,s).
实施例27
Figure PCTCN2021090726-appb-000043
将3.14克化合物1溶解在50mL乙腈中，加入1.5克无水碳酸钠室温搅拌2小时，滴入氯甲酸戊酯(CAS:638-41-5)1.55克，室温反应过夜。过滤，滤液减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色粉末1.32克，即化合物27，产率30.8％。
1HNMR d-DMSO 400Hz：0.88(3H,t,J＝8Hz),1.26～1.35(13H,m),1.58～1.63(2H,m),2.14(6H,s),3.50～3.55(6H,m),4.32～4.33(4H,m),6.88(2H,s),10.31(1H,s).
实施例28
Figure PCTCN2021090726-appb-000044
将315mg化合物1溶解在50mL二氯甲烷中，加入160mg N-甲基-N-正戊基-氨基乙酸，加入200mg1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)，室温搅拌过夜。用水洗涤反应液2次，分出有机层，减压蒸干溶剂，残余物经柱层析得浅黄色粉末87mg，即化合物28，产率11.5％。
1HNMR d-DMSO 400Hz：0.89(3H,t,J＝8Hz),1.24～1.33(15H,m),2.15(6H,s),2.27(3H,s),2.39～2.42(2H,m),3.51(6H,q,J＝8Hz),3.55(2H,s),4.42(2H,s),6.82(2H,s),10.37(1H,s).
实施例29
Figure PCTCN2021090726-appb-000045
将315mg化合物1溶解在50mL二氯甲烷中，加入210mg 7-二乙氨基庚酸，加入200mg 1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)，室温搅拌过夜。用水洗涤反应液2次，分出有机层，减压蒸干溶剂，残余物经柱层析得浅黄色粉末106mg，即化合物29，产率21.3％。
1HNMR d-DMSO 400Hz：1.13(6H,t,J＝8Hz),1.22～1.31(15H,m),1.62～1.64(2H,m),2.12(6H,s),2.50～2.52(2H,m),2.99～3.04(6H,m),3.52(6H,q,J＝8Hz),4.39(2H,s),6.78(2H,s),10.81(1H,s).
实施例30
Figure PCTCN2021090726-appb-000046
将315mg化合物1溶解在50mL二氯甲烷中，加入140mg 4-氟苯甲酸，加入200mg 1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)，室温搅拌过夜。用水洗涤反应液2次，分出有机层，减压蒸干溶剂，残余物经柱层析得白色粉末251mg，即化合物30，产率57.4％。
1HNMR d-DMSO 400Hz：1.26(9H,t,J＝8Hz),2.05(6H,s),3.50(6H,q,J＝8Hz),4.32(2H,s),6.77(2H,s),7.41～7.45(2H,m),8.10～8.14(2H,m),10.57(1H,s).
实施例31
Figure PCTCN2021090726-appb-000047
将315mg化合物1溶解在50mL二氯甲烷中，加入200mg 4-对氯苯基丁酸，加入200mg 1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)，室温搅拌过夜。用水洗涤反应液2次，分出有机层，减压蒸干溶剂，残余物经柱层析得白色粉末201mg，即化合物31，产率39.3％。
1HNMR d-DMSO 400Hz：1.28(6H,t,J＝8Hz),1.78～1.80(2H,m),2.08(6H,s),2.50～2.59(4H,m),3.48～3.55(6H,m),3.94～3.97(2H,m)，4.31(2H,s),5.67(1H,s),6.75(2H,s),7.23～7.27(2H,m),7.43～7.46(2H,m),10.51(1H,s).
实施例32
Figure PCTCN2021090726-appb-000048
将500mg化合物1溶解在30mL二氯甲烷中，加入200mg三光气，冷却至0～5℃，缓慢滴加3mL吡啶，撤去冰浴，搅拌2小时后再降温至0～5℃，加入300mg对三氟甲基苯乙醇，搅拌1小时后撤去冰浴，室温搅拌过夜,滴入稀盐酸调pH至3。反应液减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝10/1)得白色粉末179mg，即化合物32，产率33.7％。
1HNMR d-DMSO 400Hz：1.27(9H,t,J＝8Hz),2.08(6H,s),3.01～3.05(2H,m),3.48(6H,q,J＝8Hz),4.30(2H,s),4.51～4.54(2H,m),6.89～7.01(4H,m),7.49～7.55(2H,m),10.31(1H,s).
实施例33
Figure PCTCN2021090726-appb-000049
将1.43克N-甲基哌啶-2-甲酸与10mL二氯亚砜混合，加热至40℃搅拌1小时，减压蒸除未反应的二氯亚砜，加入50mL二氯甲烷溶解残余物，作备用溶液。将1.37克4-氨基-3,5-二甲基苯酚混合在50mL二氯甲烷中，加入4克三乙胺，冰浴冷却，向反应液中缓慢滴入备用溶液并搅拌，滴毕后撤去冰浴，室温搅拌反应2小时。减压蒸干溶剂，残余物用石油醚/乙酸乙酯重结晶，得黄色固体0.98克，即IM-8。
1HNMR d-DMSO 400Hz：1.27～1.33(1H,m),1.55～1.81(4H,m),2.09～2.17(8H,m),2.41(3H,s),2.65(1H,dd,J＝15Hz),2.98～3.06(1H,m),6.47(2H,s),9.03(1H,s),10.52(1H,s).
将500mg IM-8溶解在10mL乙腈中，加入500mg无水碳酸钾，加入300mg溴丙烷，封管80℃搅拌过夜。冷却后过滤，减压蒸干溶剂，经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末411mg，即IM-9。
1HNMR d-DMSO 400Hz：0.89(3H,t,J＝8Hz),1.24～1.32(2H,m),1.78～1.91(4H,m),2.07～2.16(8H,m),3.19～3.31(7H,m),4.49～4.52(1H,m),6.45(2H,s),9.01(1H,s),10.12(1H,s).
将385mg IM-9与1mL正丁酸酐混合，加入3mL吡啶，封管于90℃反应过夜。冷却后减压蒸干溶剂，加入乙酸乙酯析出粉末状固体。过滤，得白色固体粉末，用乙酸乙酯/乙醇重结晶两次，得白色固体粉末209mg，即化合物33，产率45.9％。
1HNMR d-DMSO 400Hz：0.89～0.92(6H,m),1.25～1.34(2H,m),1.78～1.91(6H,m),2.05～2.14(8H,m),2.51～2.59(2H,m),3.16～3.29(7H,m),4.45～4.48(1H,m),6.80(2H,s),10.72(1H,s).
实施例34
Figure PCTCN2021090726-appb-000050
将1.43克(-)-(2S)-1-甲基哌啶-2-羧酸溶于50mL二氯甲烷，加入2.06克二环己基碳二亚胺(DCC)， 搅拌半小时后，加入1.37克4-氨基-3,5-二甲基苯酚，室温搅拌5小时后过滤，滤液减压蒸干，经柱层析得黄色固体粉末，用石油醚/乙酸乙酯重结晶，得白色固体0.85克，即IM-10。
1HNMR d-DMSO 400Hz：1.25～1.31(1H,m),1.56～1.86(4H,m),2.05～2.12(8H,m),2.49(3H,s),2.69～2.93(1H,m),2.95～3.03(1H,m),6.44(2H,s),9.01(1H,s),10.12(1H,s).
将500mg IM-10溶解在10mL乙腈中，加入500mg无水碳酸钾，加入300mg溴丙烷，封管80℃搅拌过夜。冷却后过滤，减压蒸干溶剂，经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末367mg，即IM-11。
1HNMR d-DMSO 400Hz：0.92(3H,t,J＝8Hz),1.22～1.32(2H,m),1.74～1.90(4H,m),2.05～2.16(8H,m),3.14～3.31(7H,m),4.52(1H,m),6.41(2H,s),9.00(1H,s),10.32(1H,s).
将385mg IM-11与1mL正庚酸酐混合，加入3mL吡啶，封管于90℃反应过夜。冷却后减压蒸干溶剂，加入乙酸乙酯析出粉末状固体。过滤，得白色固体粉末，用乙酸乙酯/乙醇重结晶两次，得白色固体粉末168mg，即化合物34，产率33.8％。
1HNMR d-DMSO 400Hz：0.87～0.93(6H,m),1.24～1.31(8H,m),1.75～1.92(7H,m),2.04～2.18(7H,m),2.53～2.62(2H,m),3.14～3.28(7H,m),4.43～4.47(1H,m),6.83(2H,s),10.22(1H,s).
实施例35
Figure PCTCN2021090726-appb-000051
将500mg IM-10溶解在10mL乙腈中，加入500mg无水碳酸钾，加入300mg烯丙基氯，封管65℃搅拌过夜。冷却后过滤，减压蒸干溶剂，经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末269mg，即IM-12。
1HNMR d-DMSO 400Hz：1.21～1.28(2H,m),1.72～1.76(2H,m),2.03～2.14(8H,m),2.93～3.04(1H,m),3.14～3.31(5H,m),4.55～4.58(1H,m),5.02～5.05(2H,m),5.78～5.82(1H,m),6.40(2H,s),9.01(1H,s),10.12(1H,s).
将338mg IM-12与1mL正辛酸酐混合，加入3mL吡啶，封管于80℃反应过夜。冷却后减压蒸干溶剂，加入乙酸乙酯析出粉末状固体。过滤，得白色固体粉末，用乙酸乙酯/乙醇重结晶两次，得白色固体粉末129mg，即化合物35，产率27.7％。
1HNMR d-DMSO 400Hz：0.91(3H,t,J＝8Hz),1.23～1.35(10H,m),1.67～1.73(4H,m),1.95～2.14(8H,m),2.49～2.51(2H,m),3.16～3.41(5H,m),4.53～4.59(1H,m),5.01～5.04(2H,m),5.75～5.81(1H,m),6.84(2H,s),9.09(1H,s),10.52(1H,s).
实施例36
Figure PCTCN2021090726-appb-000052
将1.45克4-甲基-3-吗啉酸溶于50mL二氯甲烷，加入2.06克二环己基碳二亚胺(DCC)，搅拌半小时后，加入1.37克4-氨基-3,5-二甲基苯酚，室温搅拌5小时后过滤，滤液减压蒸干，经柱层析得白色固体粉末，用石油醚/乙酸乙酯重结晶，得白色固体0.69克，即IM-13。
1HNMR d-DMSO 400Hz：2.15(6H,s),2.43(3H,s),2.63～2.71(2H,m),3.67～3.73(3H,m),3.88～4.04(2H,m),6.41(2H,s),9.05(1H,s),10.72(1H,s).
将500mg IM-14溶解在10mL乙腈中，加入500mg无水碳酸钾，加入200mg烯丙氯，封管65℃搅拌过夜。冷却后过滤，减压蒸干溶剂，经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末391mg，即IM-14。
1HNMR d-DMSO 400Hz:2.13(6H,s),3.34～3.51(5H,m),3.77～4.01(5H,m),4.25～4.28(1H,m),4.87～5.11(3H,m),5.74～5.79(1H,m),6.38(2H,s),9.11(1H,s),10.32(1H,s).
将340mg IM-14与1mL正壬酸酐混合，加入3mL吡啶，封管于90℃反应过夜。冷却后减压蒸干溶剂，加入乙酸乙酯析出粉末状固体。过滤，得白色固体粉末，用乙酸乙酯/乙醇重结晶两次，得白色固体粉末98mg，即化合物36，产率20.4％。
1HNMR d-DMSO 400Hz：0.87～0.91(3H,t,J＝8Hz),1.23～1.35(10H,m),1.63～1.66(2H,m),2.17(6H,s),2.53～2.58(2H,m),3.34～3.58(5H,m),3.75～4.00(5H,m),4.23～4.28(1H,m),,4.85～5.09(3H,m),5.72～5.75(1H,m),6.85(2H,s),10.71(1H,s).
实施例37
Figure PCTCN2021090726-appb-000053
将315mg化合物1溶于30mL二氯甲烷，加入156mg环己基丙酸，搅拌。将210mg DCC溶解在10mL二氯甲烷中，搅拌下滴入上述反应液中，滴毕后室温反应过夜。过滤，滤液减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末266mg，即化合物37，产率60.6％。
1HNMR d-DMSO 400Hz：1.23(9H,t,J＝8Hz),1.53～1.66(13H,m),2.14(6H,s),2.53～2.56(2H,m), 3.58(6H,q,J＝8Hz),4.36(2H,s),6.75(2H,s),10.31(1H,s).
实施例38
Figure PCTCN2021090726-appb-000054
将13.7克4-氨基-3,5-二甲基苯酚和40克三乙胺溶于150mL二氯甲烷中，冰浴下缓慢滴加12.7克2-氯丙酰氯。滴毕后搅拌反应2小时，减压蒸干溶剂，加入150mL乙酸乙酯，用50mL稀盐酸洗涤有机层，分出有机层。减压蒸干乙酸乙酯，得棕黑色油状物，柱层析纯化产物(石油醚/乙酸乙酯＝3/1)，得黄色固体粉末4.11克(IM-15)。产率18％。
将600mg IM-15溶解在5mL无水乙醇中，加入2mL三乙胺，外温95℃封管搅拌反应8小时，析出白色固体，冷却后加入5mL乙醇，用2滴浓盐酸调pH值至3以下，减压蒸干乙醇，得白色固体粉末，柱层析纯化(二氯甲烷/甲醇＝10/1)得311mg白色粉末，即IM-16，产率：35.9％。
1HNMR d-DMSO 400Hz：1.26(9H,t,J＝8Hz),1.53(3H,d,J＝Hz),2.09(6H,s),3.50(6H,q,J＝8Hz),4.58～4.61(1H,m),6.45(2H,s),9.02(1H,s),10.11(1H,s).
将329mg IM-16与1mL正丁酸酐混合，加入3mL吡啶，封管于90℃反应过夜。冷却后减压蒸干溶剂，加入乙酸乙酯析出粉末状固体。过滤，得白色固体粉末，用乙酸乙酯/乙醇重结晶两次，得白色固体粉末105mg，即化合物38，产率26.3％。
1HNMR d-DMSO 400Hz：1.02(3H,t,J＝8Hz),1.24(9H,t,J＝8Hz),1.50(3H,d,J＝Hz),1.65～1.69(2H,m),2.04(6H,s),2.52～2.58(2H,m),3.51(6H,q,J＝8Hz),4.55～4.61(1H,m),6.87(2H,s),10.61(1H,s).
实施例39
Figure PCTCN2021090726-appb-000055
将315mg化合物1溶于30mL二氯甲烷，加入157mg 1-哌啶丙酸，搅拌。将210mg DCC溶解在10mL二氯甲烷中，搅拌下滴入上述反应液中，滴毕后室温反应过夜。过滤，滤液减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末241mg，即化合物39，产率53.1％。
1HNMR d-DMSO 400Hz：1.25(9H,t,J＝8Hz),1.41～1.51(6H,m),2.12(6H,s),2.43～2.47(4H,m), 2.61～2.65(2H,m),3.51(6H,q,J＝8Hz),3.75～3.79(2H,m),4.34(2H,s),6.81(2H,s),10.11(1H,s).
实施例40
Figure PCTCN2021090726-appb-000056
将315mg化合物1溶于30mL二氯甲烷，加入159mg 3-(4-吗啉基)丙酸，搅拌。将210mg DCC溶解在10mL二氯甲烷中，搅拌下滴入上述反应液中，滴毕后室温反应过夜。过滤，滤液减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末257mg，即化合物40，产率56.4％。
1HNMR d-DMSO 400Hz：1.26(9H,t,J＝8Hz),2.14(6H,s),2.23～2.28(4H,m),2.60～2.67(2H,m),3.53(6H,q,J＝8Hz),3.55～3.61(4H,m),3.74～3.77(2H,m),4.36(2H,s),6.83(2H,s),10.62(1H,s).
实施例41
Figure PCTCN2021090726-appb-000057
将315mg化合物1溶于30mL二氯甲烷，加入186mg 3-(4-乙基哌嗪-1-基)-丙酸(CAS:799262-18-3)，搅拌。将210mg DCC溶解在10mL二氯甲烷中，搅拌下滴入上述反应液中，滴毕后室温反应过夜。过滤，滤液减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得浅黄色固体粉末187mg，即化合物41，产率38.7％。
1HNMR d-DMSO 400Hz：1.01(3H,t,J＝8Hz),1.24(9H,t,J＝8Hz),2.13(6H,s),2.29～2.38(10H,m),2.61～2.66(2H,m),3.55(6H,q,J＝8Hz),3.73～3.78(2H,m),4.35(2H,s),6.80(2H,s),10.18(1H,s).
实施例42
Figure PCTCN2021090726-appb-000058
将2.13克IM-1溶于20mL乙腈中，加入0.88克吗啉和2克无水碳酸钾，加热至50℃搅拌5小时，随后加入丙烯基氯继续反应6小时，冷却后过滤，滤液减压蒸干，经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末1.05克，即IM-17。
1HNMR d-DMSO 400Hz：2.16(6H,s),3.39～3.45(4H,m),3.96～4.03(6H,m),4.32(2H,s),5.03～5.07(2H,m),5.72～5.77(1H,m),6.35(2H,s),9.09(1H,s),10.22(1H,s).
将340mg IM-17与1mL乙酸酐混合，加入3mL吡啶，封管90℃搅拌过夜。冷却后减压蒸干溶剂，加入乙酸乙酯析出粉末状固体。过滤，得白色固体粉末，用乙酸乙酯/乙醇重结晶两次，得白色固体粉末208mg，即化合物42，产率54.3％。
1HNMR d-DMSO 400Hz：2.14(6H,s),2.37(3H,s),3.37～3.44(4H,m),3.95～4.01(6H,m),4.35(2H,s),5.04～5.09(2H,m),5.71～5.77(1H,m),6.85(2H,s),9.01(1H,s),10.82(1H,s).
实施例43
Figure PCTCN2021090726-appb-000059
315mg化合物1溶于20mL二氯甲烷，加入146mg 6-甲氧基己酸,搅拌。将210mg DCC溶解在10mL二氯甲烷中，搅拌下滴入上述反应液中，滴毕后室温反应过夜。过滤，减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末155mg，即化合物43，产率:35.0％。
1HNMR d-DMSO 400Hz：1.24～1.29(11H,m),1.54～1.57(2H,m),1.64～1.68(2H,m),2.14(6H,s),2.51～2.55(2H,m),3.21～3.38(11H,m),4.33(2H,s),6.83(2H,s),10.17(1H,s).
实施例44
Figure PCTCN2021090726-appb-000060
将2.06克N-(2，6-二甲基苯胺)-2-乙氨基乙酸酰胺溶于100mL乙腈，加入1.95克4-溴丁酸乙酯，加入2克无水碳酸钾，40℃搅拌2小时，冷却过滤，滤液减压蒸干，加入甲醇50mL，滴入10％氢氧化钠水溶液5mL室温搅拌2小时，用6N盐酸调节pH至3，减压蒸除溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体1.27克，即IM-21，产率：38.6％。
1HNMR d-DMSO 400Hz：1.54(3H,t,J＝8Hz),1.97～2.32(10H,m),3.38～3.95(4H,m),4.28(2H,s),7.09～7.18(3H,m),10.12(1H,s),10.49(1H，s),12.9(1H,s,broad).
将329mg IM-21溶于20mL二氯甲烷，加入315mg化合物1，搅拌。将210mg DCC溶解在10mL二氯甲烷中，搅拌下滴入上述反应液中，滴毕后室温反应过夜。过滤，减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体粉末103mg，即化合物44，产率:16.5％。
1HNMR d-DMSO 400Hz：1.23(9H,t,J＝8Hz),1.56(3H,t,J＝8Hz),2.09～2.18(14H,m),2.53～2.58(2H,m),3.41～3.51(10H,m),4.28(2H,s),4.31(2H,m),6.82(2H,s),7.12～7.19(3H,m),10.12(1H,s),10.67(1H,s).
实施例45
Figure PCTCN2021090726-appb-000061
将2.06克N-(2，6-二甲基苯胺)-2-乙氨基乙酸酰胺溶于100mL乙腈，加入2.3克1,5-二溴戊烷，加入3克无水碳酸钾，40℃搅拌2小时，再加入3.15克化合物1，继续搅拌过夜。冷却过滤，滤液减压蒸干，加入甲醇50mL，滴入10％氢氧化钠水溶液5mL室温搅拌2小时，用6N盐酸调节pH至3，减压蒸除溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体0.93克，即化合物45，产率：14.8％。
1HNMR d-DMSO 400Hz：1.23～1.28(11H,m),1.59～1.81(7H,m),2.17(6H,s),3.31～3.41(10H,m), 3.99～4.07(2H,m),4.24(2H,s),6.81(2H,s),7.16～7.18(3H,m),10.02(1H,s),10.45(1H，s).
实施例46
Figure PCTCN2021090726-appb-000062
将2.06克N-(2，6-二甲基苯胺)-2-乙氨基乙酸酰胺溶于100mL乙腈，加入1.87克6-溴-1-己醇，加入3克无水碳酸钾，70℃搅拌5小时，冷却后过滤，滤液蒸干得粗品备用。
将3.77克化合物1溶解在100mL二氯甲烷中，加入1.4克三光气，冷却至0～5℃，缓慢滴加30mL吡啶，撤去冰浴，搅拌2小时后再降温至0～5℃，加入上述备用粗品，搅拌1小时后撤去冰浴，室温搅拌过夜,滴入稀盐酸调pH至3。减压蒸干溶剂，粗品经柱层析柱层析(二氯甲烷/甲醇＝20/1)得白色固体1.12克，即化合物46，产率：16.4％。
1HNMR d-DMSO 400Hz：1.24～1.31(11H,m),1.41～1.46(2H,m),1.59～1.62(3H,m),1.69～1.73(4H,m),2.14(6H,s),2.17(6H,s),3.29～3.40(10H,m),4.21～4.28(4H,m),6.80(2H,s),7.13～7.18(3H,m),10.31(1H,s),10.45(1H，s).
实施例47
Figure PCTCN2021090726-appb-000063
将2.06克N-(2，6-二甲基苯胺)-2-乙氨基乙酸酰胺溶于100mL乙腈，加入2.80克N-BOC-6-溴代己胺(142356-33-0)，加入3克无水碳酸钾，70℃搅拌5小时，冷却后过滤，滤液蒸干,残余物用50mL乙酸乙酯溶解，通入干燥氯化氢气体10分钟，室温搅拌2小时，减压蒸干溶剂得粗品备用。
将3.77克化合物1溶解在100mL二氯甲烷中，加入1.4克三光气，冷却至0～5℃，缓慢滴加30mL吡啶，撤去冰浴，搅拌2小时后再降温至0～5℃，加入上述备用粗品，搅拌1小时后撤去冰浴，室温搅拌过夜,滴入稀盐酸调pH至3。减压蒸干溶剂，粗品经柱层析柱(二氯甲烷/甲醇＝20/1)得白色固体1.98 克，即化合物47，产率：29.0％。
1HNMR d-DMSO 400Hz：1.23～1.33(13H,m),1.45～1.53(5H,m),1.69～1.72(2H,m),2.16(6H,s),2.19(6H,s),3.27～3.39(12H,m),4.19～4.25(4H,m),6.58(1H,s),6.80(2H,s),7.11～7.15(3H,m),10.28(1H,s),10.44(1H，s).
实施例48
Figure PCTCN2021090726-appb-000064
将2.32克N-(2,6-二甲基苯基)哌啶-2-甲酰胺(CAS:15883-20-2)溶于100mL乙腈，加入1.39克3-溴-1-丙醇，加入3克无水碳酸钾，70℃搅拌5小时，冷却后过滤，滤液蒸干,得粗品备用。
将3.77克化合物1溶解在100mL二氯甲烷中，加入1.4克三光气，冷却至0～5℃，缓慢滴加30mL吡啶，撤去冰浴，搅拌2小时后再降温至0～5℃，加入上述备用粗品，搅拌1小时后撤去冰浴，室温搅拌过夜,滴入稀盐酸调pH至3。减压蒸干溶剂，粗品经柱层析柱(二氯甲烷/甲醇＝20/1)得白色固体1.31克，即化合物48，产率：19.61％。
1HNMR d-DMSO 400Hz：1.27～1.54(11H,m),1.69～1.73(2H,m),1.93～2.21(16,m),3.25～3.37(10H,m),4.23～4.29(4H,m),4.55～4.59(1H,m),6.81(2H,s),7.08～7.15(3H,m),10.12(1H,s),10.47(1H，s).
实施例49
Figure PCTCN2021090726-appb-000065
将2.32克N-(2,6-二甲基苯基)哌啶-2-甲酰胺(CAS:15883-20-2)溶于100mL乙腈，加入2.94 克N-BOC-7-溴代庚胺(142356-34-1)，加入3克无水碳酸钾，70℃搅拌5小时，冷却后过滤，滤液蒸干,残余物用50mL乙酸乙酯溶解，通入干燥氯化氢气体10分钟，室温搅拌2小时，减压蒸干溶剂得粗品备用。
将3.77克化合物1溶解在100mL二氯甲烷中，加入1.4克三光气，冷却至0～5℃，缓慢滴加30mL吡啶，撤去冰浴，搅拌2小时后再降温至0～5℃，加入上述备用粗品，搅拌1小时后撤去冰浴，室温搅拌过夜,滴入稀盐酸调pH至3。减压蒸干溶剂，粗品经柱层析柱(二氯甲烷/甲醇＝20/1)得白色固体2.11克，即化合物49，产率：29.2％。
1HNMR d-DMSO 400Hz：1.27～1.37(17H,m),1.59～1.74(4H,m),1.91～2.23(14,m),3.25～3.39(12H,m),4.29(2H,s),4.52～4.56(1H,m),6.80(2H,s),7.01(1H,s),7.08～7.15(3H,m),10.01(1H,s),10.36(1H，s).
实施例50
Figure PCTCN2021090726-appb-000066
将2.32克N-(2,6-二甲基苯基)哌啶-2-甲酰胺(CAS:15883-20-2)溶于100mL乙腈，加入2.23克8-溴-辛酸(17696-11-6)，加入3克无水碳酸钾，70℃搅拌5小时，冷却后过滤，滤液用稀盐酸调pH至3，蒸干溶剂得粗品备用。
将3.77克化合物1溶解在100mL二氯甲烷中，加入上述备用粗品，加入2.1克二环己基碳二亚胺(DCC)，搅拌过夜。次日过滤，滤液减压蒸干溶剂，粗品经柱层析柱(二氯甲烷/甲醇＝20/1)得白色固体1.58克，即化合物50，产率：22.3％。
1HNMR d-DMSO 400Hz：1.25～1.38(17H,m),1.61～1.75(6H,m),1.88～2.17(14,m),2.43～2.49(2H,m),3.21～3.33(10H,m),4.21(2H,s),4.51～4.55(1H,m),6.82(2H,s),7.05～7.13(3H,m),10.09(1H,s),10.32(1H，s).
实施例51
Figure PCTCN2021090726-appb-000067
将2.32克N-(2,6-二甲基苯基)哌啶-2-甲酰胺(CAS:15883-20-2)溶于100mL乙腈，加入2.23克6-溴-己酸(4224-70-8)，加入3克无水碳酸钾，70℃搅拌5小时，冷却后过滤，滤液用稀盐酸调pH至3，蒸干溶剂得粗品备用。
将3.77克化合物1溶解在100mL二氯甲烷中，加入上述备用粗品，加入2.1克二环己基碳二亚胺(DCC)，搅拌过夜。次日过滤，滤液减压蒸干溶剂，粗品经柱层析柱(二氯甲烷/甲醇＝20/1)得白色固体1.66克，即化合物51，产率：24.4％。
1HNMR d-DMSO 400Hz：1.22～1.39(13H,m),1.65～1.76(6H,m),1.89～2.21(14,m),2.49～2.54(2H,m),3.25～3.36(10H,m),4.23(2H,s),4.50～4.57(1H,m),6.81(2H,s),7.07～7.14(3H,m),10.19(1H,s),10.42(1H，s).
实施例52
Figure PCTCN2021090726-appb-000068
将3.15克化合物1溶于20mL DMF中，加入3克DBU(CAS:6674-22-2),加入2.16克1,4-二溴丁烷，于70℃搅拌6小时，加入1.23克2-哌啶甲酸(CAS:4043-87-2),继续搅拌反应6小时。加入6N盐酸将反应液pH调至3，减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体0.78克，即化合物52，产率：12.2％。
1HNMR d-DMSO 400Hz：1.24～1.33(11H,m),1.69～1.74(6H,m),1.92～2.23(14,m),3.21～3.32(10H,m),4.01～4.07(2H，m),4.21(2H,s),4.52～4.56(1H,m),6.80(2H,s),7.08～7.19(3H,m),10.21(1H, s),10.82(1H，s).
实施例53
Figure PCTCN2021090726-appb-000069
将3.30克化合物21溶于20mL DMF中，加入3克DBU(CAS:6674-22-2),加入2.16克1,4-二溴丁烷，于70℃搅拌6小时，加入1.23克2-哌啶甲酸(CAS:4043-87-2),继续搅拌反应6小时。加入6N盐酸将反应液pH调至3，减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体0.93克，即化合物53，产率：14.2％。
1HNMR d-DMSO 400Hz：1.21～1.31(8H,m),1.67～1.73(6H,m),1.90～2.24(14,m),3.20～3.42(10H,m),3.95～4.24(7H，m),4.49～4.53(1H,m),6.76(2H,s),7.05～7.15(3H,m),10.11(1H,s),10.52(1H，s).
实施例54
Figure PCTCN2021090726-appb-000070
将3.15克化合物1溶于20mL DMF中，加入3克DBU(CAS:6674-22-2),加入2.58克1,7-二溴庚烷，于80℃搅拌6小时，加入1.23克2-哌啶甲酸(CAS:4043-87-2),继续搅拌反应6小时。加入6N盐酸将反应液pH调至3，减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体0.93克，即化合物54，产率：13.7％。
1HNMR d-DMSO 400Hz：1.20～1.24(10H,m),1.25～1.29(5H,m),1.41～1.44(2H,m),1.70～1.74(6,m),1.91～2.14(14H,m),3.15～3.29(10H,m),4.01～4.09(2H，m),4.19(2H,s),4.52～4.57(1H,m),6.75(2H,s),7.05～7.11(3H,m),10.21(1H,s),10.62(1H，s).
实施例55
Figure PCTCN2021090726-appb-000071
将3.30克化合物21溶于20mL DMF中，加入3克DBU(CAS:6674-22-2),加入2.44克1,6-二溴已烷，于80℃搅拌6小时，加入1.23克2-哌啶甲酸(CAS:4043-87-2),继续搅拌反应6小时。加入6N盐酸将反应液pH调至3，减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体0.95克，即化合物55，产率：13.9％。
1HNMR d-DMSO 400Hz：1.21～1.42(12H,m),1.69～1.75(6H,m),1.93～2.23(14,m),3.21～3.41(10H,m),3.96～4.04(4H，m),4.21(2H,s),4.49～4.52(1H,m),6.73(2H,s),7.03～7.14(3H,m),10.32(1H,s),10.72(1H，s).
实施例56
Figure PCTCN2021090726-appb-000072
将3.15克化合物1溶于20mL DMF中，加入3克DBU(CAS:6674-22-2),加入2.44克1,6-二溴已烷，于80℃搅拌6小时，加入1.23克2-哌啶甲酸(CAS:4043-87-2),继续搅拌反应6小时。加入6N盐酸将反应液pH调至3，减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体0.75克，即化合物56，产率：9.7％。
1HNMR d-DMSO 400Hz：1.22～1.32(13H,m),1.40～1.45(2H,m),1.69～1.72(6H,m),1.92～2.23(14,m),3.21～3.43(10H,m),3.99～4.09(2H，m),4.17(2H,s),4.52～4.56(1H,m),6.73(2H,s),7.03～7.13(3H,m),10.24(1H,s),10.67(1H，s).
实施例57
Figure PCTCN2021090726-appb-000073
将3.15克化合物1溶于20mL DMF中，加入3克DBU(CAS:6674-22-2),加入2.71克1,8-二溴辛烷，于80℃搅拌6小时，加入1.23克2-哌啶甲酸(CAS:4043-87-2),继续搅拌反应6小时。加入6N盐酸将反应液pH调至3，减压蒸干溶剂，残余物经柱层析(二氯甲烷/甲醇＝20/1)得白色固体0.67克，即化合物57，产率：11.3％。
1HNMR d-DMSO 400Hz：1.20～1.32(17H,m),1.41～1.46(2H,m),1.71～1.76(6H,m),1.91～2.21(14,m),3.19～3.37(10H,m),4.03～4.10(2H，m),4.19(2H,s),4.51～4.54(1H,m),6.75(2H,s),7.05～7.14(3H,m),10.11(1H,s),10.62(1H，s).
实施例58
将实施例化合物溶于注射用水，浓度为0.2～0.5g/100mL(0.2～0.5％)，或与市售临床常见局部麻醉药物配置成特定比例的混合溶液，以0.75％左布比卡因为阳性对照化合物。实验方法为：180～300克体重的雄性SD大鼠，在实验前1天剃除其背部毛，并裸露直径为4厘米的圆形皮肤区域。使用1mL注射器在背部裸露的圆形中心处皮下注射0.4mL药液，形成皮丘。1分钟后进行第一次测定：使用26G针头给予15g力度针刺刺激注射部位中心周围随机8个部位各1次(刺激部位距离注射中心不超过1厘米)，若大鼠出现躲避、缩背或嘶叫等行为，则视为局麻效果消退，若无上述行为视为局麻效果存在，8次刺激中有4次或多于4次表现出局麻效果存在时，视为局麻效果继续维持。除第一次测定外，给药后12小时内每2小时测定1次，12小时之后每6小时测定1次。每种药物使用8只大鼠进行实验。测试结果见表1。
表1药物皮下浸润麻醉结果
Figure PCTCN2021090726-appb-000074
Figure PCTCN2021090726-appb-000075
Figure PCTCN2021090726-appb-000076
0.2％和0.5％的化合物7注射后在第一次测定时并未起效。其余待测化合物或组合物均在第一次测试时产生局部麻醉作用。0.75％的布比卡因仅能产生4～6小时的局部麻醉作用，而本发明所述的绝大多数化合物在0.2％～0.5％浓度范围普遍可产生局麻效果，最高产生长达96小时的局部麻醉作用，且这种局部麻醉作用可抵抗针刺刺激，局麻作用时间长，强度大。低浓度的本发明所述化合物与低浓度的利多卡因、布比卡因、左布比卡因和丁卡因形成的混合溶液，可产生的局部麻醉时间显著延长，表现出较强的协同效应。
实验结束后7天取实验动物给药部位的皮肤和肌肉，HE染色制备病理切片后观察组织的炎症评分，评分标准为：0分(无炎症)；1分(局部轻微炎症)；2分(中度水肿，中度炎症)；3分(弥散性水肿，重度炎症)。病理结果显示，本发明所述的分子在0.2％、0.5％以及与常见局部麻醉药物形成混合物溶液给 药情况下，皮肤、肌肉组织的炎症评分与0.75％左布比卡因对照组无统计学差异，损伤评分均为0～1分，显示出本发明发明所述化合物局部安全性与临床浓度的布比卡因等同，具有良好的局部安全性。
实施例59
将实施例化合物溶于注射用水，浓度为0.5～2.0g/100mL(0.5％～2％)，或与市售临床常见局部麻醉药物配置成特定比例的混合溶液，以0.75％左布比卡因注射液为阳性对照化合物。实验方法为：180～300克体重的雄性SD大鼠，经异氟烷麻醉后，在左侧坐骨神经附近注射含药溶液0.2mL，每种药物使用8只大鼠进行实验。大鼠苏醒后开始测第一次测定，之后每2小时测定一次，测定六次之后若仍有麻醉作用，则每隔6小测定一次，直至麻醉作用消失。麻醉作用是否存在的判断方法为：使用Von Frey纤维丝(60g)刺激大鼠注射药物一侧后肢足底和足侧面皮肤，若大鼠出现抬脚，躲避等行为，视为局部麻醉作用消失，若无上述行为，视为局部麻醉效果存在。测试结果见表2。
表2大鼠坐骨神经阻滞实验结果
Figure PCTCN2021090726-appb-000077
Figure PCTCN2021090726-appb-000078
Figure PCTCN2021090726-appb-000079
待测药物均在第一次测试时产生局部麻醉作用。0.75％的布比卡因仅能产生2～6小时的坐骨神经麻醉作用，而本发明所述的绝大多数化合物在0.5％～2.0％浓度范围可产生最高长达160小时的坐骨神经麻醉作用。低浓度的本发明所述化合物与低浓度的利多卡因、布比卡因、左布比卡因和丁卡因形成的混合溶液， 可产生的坐骨神经麻醉时间显著延长，表现出较强的协同效应。此外，0.75％的左布比卡因盐酸盐对大鼠药物注射一侧的后肢不仅产生了感觉阻滞，也显著阻滞了大鼠该侧后肢的运动功能，这种对运动的阻滞与感觉阻滞的时长基本一致。而本发明所披露的化合物，均未发现对大鼠后肢运动能力的阻滞，这说明本发明所述化合物具有选择性感觉阻滞的优势。
实验结束后7天取实验动物给药一侧的坐骨神经，HE染色制备病理切片后观察神经损伤情况，评分标准为：0分(神经外膜血管轻微充血，扩张，无炎细胞浸润)；1分(外膜血管轻微充血，扩张，伴少量炎细胞浸润)；2分(外膜血管明显充血，扩张，伴炎细胞浸润)；3分(外膜血管充血，扩张，脊髓实质有炎细胞浸润)。病理结果显示，本发明所述的分子在0.5％、1.0％以及与常见局部麻醉药物形成低浓度混合物溶液给药情况下，神经外膜的炎症情况与0.75％左布比卡因对照组无统计学差异，损伤评分均为0分。此外，所有大鼠的坐骨神经样本在电镜观察下均未发现脱髓鞘现象。上述结果显示出本发明发明所述化合物局部安全性与临床浓度的布比卡因等同，即具有良好的局部安全性。
实施例60
将0.2％的本发明所述的化合物水溶液，以及0.75％左布比卡因溶液经尾静脉注射0.4mL至大鼠体内，观察死亡率，每种药物注射10只大鼠(雌雄各半，体重290～310)。结果见表3
表3尾静脉注射药物后的死亡率
药物 死亡率％
盐酸左布比卡因 70
化合物1 0
化合物3 0
化合物10 0
化合物12 0
化合物13 0
化合物15 0
化合物17 0
化合物24 0
化合物26 0
化合物27 0
化合物28 0
化合物31 0
化合物33 0
化合物45 0
化合物48 0
化合物50 0
化合物53 0
在实施例51中，本发明所述的化合物在0.2％浓度下，0.4mL注射量即可产生24～66小时的局部浸润麻醉效果，这一剂量的化合物如果全部误注入血，由本实验可知将不会引起大鼠的死亡。而0.4mL 0.75％的左布比卡因仅能产生4～6小时的局部浸润麻醉效果，这一剂量的左布比卡因若全部误注入血，将导致70％的大鼠死亡。可见，本发明所述的化合物效价高，安全性好，在有效剂量下的整体安全性远高于对照药物左布比卡因。
本发明不局限于上述可选实施方式，任何人在本发明的启示下都可得出其他各种形式的产品，但不论在其形状或结构上作任何变化，凡是落入本发明权利要求界定范围内的技术方案，均落在本发明的保护范围之内。

Claims (10)

  1. 一种具备如式(Ⅰ)通式所述的化合物、立体异构体、溶剂化物、药学上可接受的盐或共晶：
    Figure PCTCN2021090726-appb-100001
    其中，R 1任意选自C1～5的烃基、烷氧基、羟基、氨基或取代氨基、羧基、卤素、氰基、烷氧羰基；
    R 2选自C1～8的烃基；
    R 3选自C1～8的烃基或亚烃基；
    R 4选自C1～8的烃基或亚烃基；
    R 5选自H或C1～8的烃基或亚烃基；
    R 3和R 4还可以由化学键直接相连，与季铵N原子形成环；
    R 4和R 5还可以由化学键直接相连，与季铵N原子形成环；
    X为O或HN或烷基取代N；
    Y为O或OH或NH 2或烷基取代N；
    L为羰基或不存在；
    m＝0或1；
    n＝0～4的整数；
    R 6为C1～18的烃基或如下指定结构：
    Figure PCTCN2021090726-appb-100002
    上述指定结构中p＝1～16的整数，R 7为C1～7的烃基，R 8为H或C1～8的烃基，Z为亚甲基或O；
    R 1～R 7的骨架中任一碳原子可被O，S，砜基，亚砜基，N原子替换；
    R1～R7的骨架上可具有1个或多个取代基，包括：卤素，硝基，氰基，羧基，酯基，羟基。
    M为药学上可以接受的阴离子，若分子(Ⅰ)具备内盐结构，M可以不存在。
  2. 如权利要求1所述的化合物，其特征是：
    R 1选自C1～5的烷基、卤素；
    R 2选自C1～4的烷基；
    R 3选自C1～4的烷基；
    R 4选自C1～4的烷基；
    R 5为H；
    X为HN；
    Y为O；
    L为羰基；
    m＝1；
    R 6为C1～12的烷基；
    R 1～R 7的骨架中任一碳原子可被N原子或O原子替换；
    R 1～R 7的骨架上可具有1个或多个羟基取代；
    M为药学上可以接受的阴离子，如氯离子、溴离子、硫酸根、醋酸根、磺酸根。
  3. 如权利利要求1所述的化合物，其特征是：
    R 1选自C1～2的烷基；
    R 2选自C1～3的烷基；
    R 3选自C1～3的烷基；
    R 4选自C1～3的烷基；
    R 5为H；
    X为HN；
    Y为O；
    L为羰基；
    m＝1；
    R 6为如下指定结构：
    Figure PCTCN2021090726-appb-100003
    上述指定结构中p＝1～10的整数，R7为C1～4的烷基，R8为H或C1～2的烷基，Z为亚甲基或O；
    R 1～R 7的骨架中任一碳原子可被O原子或N原子替换；
    R 1～R 7的骨架上可具有1个或多个羟基取代；
    M为药学上可以接受的阴离子，如氯离子、溴离子、硫酸根、醋酸根、磺酸根。
  4. 如权利要求1和2所述的化合物，包括但不限于如下具体化合物：
    Figure PCTCN2021090726-appb-100004
    Figure PCTCN2021090726-appb-100005
  5. 如权利要求1和3所述的化合物，包括但不限于如下具体化合物：
    Figure PCTCN2021090726-appb-100006
  6. 如权利要求1～5所述的化合物、同位素化合物、药物组合物、光学异构体、溶剂化物、药学上可接受的盐或共晶，可在局部产生快速、持久而安全的神经阻滞效果，可在制备局部麻醉、镇痛和止痒药物中应用。
  7. 如权利要求6所述的药物组合物，是指权利要求1～5所述的化合物与利多卡因或利多卡因盐形成的组合物，可在局部产生长效的局部神经阻滞作用，可在制备局部麻醉、镇痛和止痒药物中应用。
  8. 如权利要求6所述的药物组合物，是指权利要求1～5所述的化合物与布比卡因、左旋布比卡因、丁卡因或它们的盐形成的组合物，可在局部注射产生长效的局部神经阻滞作用，可在制备局部麻醉、镇痛和止痒药物中应用。。
  9. 如权利要求6所述的药物组合物，是指权利要求1～5所述的化合物与河豚毒素、辣椒素等离子通道激动剂形成的组合物，可在局部注射产生长效的局部神经阻滞作用，可在制备局部麻醉、镇痛和止痒药物中应用。
  10. 如权利要求1～5所述的化合物、同位素化合物、药物组合物、光学异构体、溶剂化物、药学上可接受的盐或共晶、与缓释材料制备成缓释制剂，在长时间局部麻醉、镇痛和止痒药物中的应用。
PCT/CN2021/090726 2020-05-11 2021-04-28 一种芳香类化合物、制备方法及在药物中的应用 WO2021227882A1 (zh)

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