[go: up one dir, main page]

WO2024222788A1 - Composé de sel d'ammonium quaternaire, forme de sel et utilisation de celui-ci - Google Patents

Composé de sel d'ammonium quaternaire, forme de sel et utilisation de celui-ci Download PDF

Info

Publication number
WO2024222788A1
WO2024222788A1 PCT/CN2024/089769 CN2024089769W WO2024222788A1 WO 2024222788 A1 WO2024222788 A1 WO 2024222788A1 CN 2024089769 W CN2024089769 W CN 2024089769W WO 2024222788 A1 WO2024222788 A1 WO 2024222788A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
formula
compound
pharmaceutically acceptable
compound according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/089769
Other languages
English (en)
Chinese (zh)
Inventor
李莉娥
柯博文
田峦鸢
刘进
陈雷
张文胜
梁大力
杨俊�
刘蓉
张宇豪
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yichang Humanwell Pharmaceutical Co Ltd
Original Assignee
Yichang Humanwell Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yichang Humanwell Pharmaceutical Co Ltd filed Critical Yichang Humanwell Pharmaceutical Co Ltd
Publication of WO2024222788A1 publication Critical patent/WO2024222788A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D211/36—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/22—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/16—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
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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

Definitions

  • the present application relates to but is not limited to the field of medical technology, and in particular, to a quaternary ammonium salt compound, a salt form and applications thereof.
  • Local anesthetics also known as local anesthetics
  • local anesthetics are a type of drug that is applied topically around nerve trunks or nerve endings and can temporarily, completely and reversibly block the generation and conduction of nerve impulses, causing the local pain to temporarily disappear.
  • the mechanism of action of local anesthetics is to achieve an anesthetic effect by binding to the binding sites of sodium channels located on the nerve cell membrane, reducing the influx of Na + in the cell membrane, changing the membrane potential, and thus blocking the conduction of nerve impulses. Due to its advantages of precise effect, low risk of hyperalgesia, convenient local application, low blood drug concentration and few systemic side effects, local anesthetics are still a more commonly used pain treatment method in clinical practice.
  • the local anesthetics currently used in clinical practice are mainly a class of compounds formed by aromatic groups and amine groups connected by ester bonds or amide bonds, such as procaine, tetracaine, lidocaine, bupivacaine and ropivacaine.
  • bupivacaine and ropivacaine are considered to be new long-acting local anesthetics, their analgesic time for a single dose usually does not exceed 8 hours (“Local anesthetics: review of pharmacological considerations", Becker DE et al., Anesth Prog. 2012, 59 (2): 90-102.), although they can meet the needs of most surgeries or invasive operations, they are far from fully meeting the needs of postoperative pain, chronic pain, etc.
  • QX-314 a quaternary ammonium derivative of lidocaine
  • QX-314 can effectively block sodium ion currents after passing through the cell membrane and produce a more lasting anesthetic effect.
  • the present application provides a compound represented by formula (I), or a stereoisomer, a mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate or a solvate thereof:
  • X - represents a pharmaceutically acceptable anion
  • the present application also provides a method for preparing the compound of formula (I).
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of the compound as described above, and a pharmaceutically acceptable carrier or excipient.
  • the present application provides use of the compound as described above, or the pharmaceutical composition as described above, in the preparation of a local anesthetic drug.
  • the present application provides the compound as described above, or the pharmaceutical composition as described above, for use as a local anesthesia.
  • the present application provides a method of local anesthesia, which comprises administering a therapeutically effective amount of the compound as described above, or the pharmaceutical composition as described above, to an individual in need thereof.
  • the present application provides a compound represented by formula (I), or a stereoisomer, a mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate or a solvate thereof:
  • X - represents a pharmaceutically acceptable anion
  • the present application provides the above-mentioned compound of formula (I), wherein X- is a pharmaceutically acceptable anion of an inorganic acid (e.g., a mineral acid), such as a halogen anion (Br- or Cl-), an anion of a sulfuric acid (HSO4-) or an anion of a phosphoric acid (H2PO4- ) , or an anion of an organic acid, such as an aliphatic, aromatic or aromatic aliphatic carboxylic acid or sulfonic acid, such as an acetoxy anion, a trifluoroacetoxy anion, a methanesulfonyloxy anion, and the like.
  • an inorganic acid e.g., a mineral acid
  • a halogen anion Br- or Cl-
  • an anion of a sulfuric acid HSO4-
  • H2PO4- phosphoric acid
  • an organic acid such as an aliphatic, aromatic or aromatic alipha
  • the present application provides the above-mentioned compound of formula (I), wherein the compound is in the form of a stereoisomer, as shown in formula (II):
  • X - represents a pharmaceutically acceptable anion
  • the present application provides the compound of the above formula (I), wherein the compound is in the form of a stereoisomer, as shown in formula (III):
  • X - represents a pharmaceutically acceptable anion
  • the compound of formula (I) provided herein is in the form of a mixture of stereoisomers, that is, a mixture of a compound represented by formula (II) and a compound represented by formula (III), and the weight ratio of the compound represented by formula (II) to the compound represented by formula (III) is (0.01 to 99.99): (99.99 to 0.01):
  • X- in formula (II) and formula (III) represents a pharmaceutically acceptable anion.
  • the present application provides the above-mentioned compound of formula (I), wherein the compound is stereoisomerized
  • the weight ratio of the compound represented by formula (II) to the compound represented by formula (III) is 50:50, that is, the compound represented by formula (I) is a racemic mixture.
  • the present application provides the compound of the above formula (I), wherein the compound is in the form of a pharmaceutically acceptable salt thereof, as shown in formula (IV):
  • X - represents a pharmaceutically acceptable anion
  • n 0.3 to 2;
  • HY is hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, phosphoric acid, fumaric acid, L-tartaric acid, oxalic acid, succinic acid, citric acid, acetic acid, benzoic acid, ethanesulfonic acid, malonic acid, adipic acid, salicylic acid, nicotinic acid, L-glutamic acid, L-phenylalanine, L-lysine, L-aspartic acid or D-proline.
  • the present application provides the compound of the above formula (IV), wherein the compound is in the form of a stereoisomer, as shown in formula (V):
  • X - represents a pharmaceutically acceptable anion
  • n 0.3 to 2;
  • HY is hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, phosphoric acid, fumaric acid, L-tartaric acid, oxalic acid, succinic acid, citric acid, acetic acid, benzoic acid, ethanesulfonic acid, malonic acid, adipic acid, salicylic acid, nicotinic acid, L-glutamic acid, L-phenylalanine, L-lysine, L-aspartic acid or D-proline.
  • the present application provides the compound of the above formula (IV), wherein the compound is in the form of a stereoisomer, as shown in formula (VI):
  • X - represents a pharmaceutically acceptable anion
  • n 0.3 to 2;
  • HY is hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, phosphoric acid, fumaric acid, L-tartaric acid, oxalic acid, succinic acid, citric acid, acetic acid, benzoic acid, ethanesulfonic acid, malonic acid, adipic acid, salicylic acid, nicotinic acid, L-glutamic acid, L-phenylalanine, L-lysine, L-aspartic acid or D-proline.
  • the compound of formula (IV) provided herein is in the form of a mixture of stereoisomers, i.e., a mixture of a compound represented by formula (V) and a compound represented by formula (VI), and the weight ratio of the compound represented by formula (V) to the compound represented by formula (VI) is (0.01 to 99.99): (99.99 to 0.01):
  • X- represents a pharmaceutically acceptable anion
  • n 0.3 to 2;
  • HY is hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, phosphoric acid, fumaric acid, L-tartaric acid, oxalic acid, succinic acid, citric acid, acetic acid, benzoic acid, ethanesulfonic acid, malonic acid, adipic acid, salicylic acid, nicotinic acid, L-glutamic acid, L-phenylalanine, L-lysine, L-aspartic acid or D-proline.
  • the compound of formula (IV) provided herein is in the form of a mixture of stereoisomers, and the weight ratio of the compound represented by formula (V) to the compound represented by formula (VI) is 50:50, that is, the compound of formula (IV) is a racemic mixture.
  • the present application provides the above-mentioned formula (I), formula (II), formula (III), formula (IV), formula (V) or a compound of formula (VI), wherein X- is a halogen anion, preferably Br- or Cl- .
  • the present application provides the above-mentioned compound of formula (IV), formula (V) or formula (VI), wherein HY is hydrochloric acid, hydrobromic acid, benzenesulfonic acid, maleic acid or citric acid, preferably, hydrobromic acid, citric acid or hydrochloric acid, and further preferably, hydrochloric acid.
  • the present application provides the above-mentioned compounds of formula (IV), formula (V) or formula (VI), wherein the numerical value of n ranges from 0.5 to 1.5, preferably, n is 0.8 to 1.3, more preferably, n is 1.0 to 1.3, and particularly preferably, n is 1.
  • the present application provides a compound selected from one of the following structures:
  • the present application provides a compound selected from one of the following structures:
  • the present application also provides a method for preparing the compound of formula (I), which comprises the following steps: step:
  • the compound of formula (VII) reacts with the compound of formula (VIII) under alkaline conditions and in the presence of an organic solvent to obtain a compound of formula (I);
  • the preparation method of the present application also includes providing a method for preparing various acid addition salts of the compound of formula (I).
  • the overall method is described as follows, comprising the following steps:
  • step (b) Cooling the mixture obtained in step (b), directly or after removing part of the solvent, mixing with an anti-solvent to obtain a second mixture;
  • step (b) the mixture obtained in step (b), directly or after removing part of the solvent, is mixed with an anti-solvent to precipitate the salt at room temperature, and the salt is dried in vacuo and then dissolved in a certain volume of water to obtain a second mixture;
  • step (b) the mixture obtained in step (b) is directly or partially treated with solvent, and the remaining solution is ion exchanged using an anion exchange resin to obtain a second mixture;
  • step (d) freeze-drying the second mixture obtained in step (c) to obtain a product.
  • the present application provides a method for preparing various acid addition salts of the compound of formula (I), wherein the solvent is a mixture of one or more of methanol, ethanol, butanone, dimethyl sulfoxide, isopropanol, acetone, tetrahydrofuran, acetonitrile, dichloromethane, methyl tert-butyl ether, ethyl acetate, n-heptane and water; preferably methanol or water; optionally, the anti-solvent is: ethyl acetate, methyl tert-butyl ether, n-heptane, isopropyl ether or methylcyclohexane; preferably methyl tert-butyl ether.
  • the solvent is a mixture of one or more of methanol, ethanol, butanone, dimethyl sulfoxide, isopropanol, acetone, tetrahydrofuran, acetonit
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of the compound as described above, and a pharmaceutically acceptable carrier or excipient.
  • the present application provides use of the compound as described above, or the pharmaceutical composition as described above, in the preparation of a local anesthetic drug.
  • the present application provides the compound as described above, or the pharmaceutical composition as described above, for use as a local anesthesia.
  • the present application provides a method of local anesthesia, which comprises administering a therapeutically effective amount of the compound as described above, or the pharmaceutical composition as described above, to an individual in need thereof.
  • the local anesthesia is long-acting local anesthesia and/or selective local anesthesia.
  • the present invention has one or more of the following beneficial effects:
  • the compounds provided in this application have excellent long-acting local anesthetic effects and can be used to prepare drugs with long-acting local anesthetic effects.
  • experimental studies have shown that the compounds of the present invention also have excellent pharmacokinetic effects and good Security.
  • halogen anion refers to F - , Cl - , Br - or I - .
  • “Pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt of an inorganic acid or base, including a salt formed with an inorganic acid or an inorganic base or a salt formed with an organic acid and an organic base.
  • “Pharmaceutical composition” means a mixture of one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components. Other components are, for example, physiologically/pharmaceutically acceptable carriers or excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS was determined using an Agilent 6230 TOF LC/MS mass spectrometer, the solvent was methanol/water (1:1), and the ionization mode was ESI (+).
  • HPLC determination used Dionex UltiMate 3000 high performance liquid chromatography (chromatographic column: Agilent Poroshell 120 Bonus-RP 4.6mm ⁇ 150mm 2.7 ⁇ m).
  • the thin layer chromatography silica gel plate used was West Asia Reagent GF254 silica gel plate.
  • the known starting materials of the present application can be synthesized by methods known in the art, or can be purchased from Chengdu Cologne Chemical Co., Ltd., Binhai Zhanhua District Ruian Chemical Co., Ltd., Anhui Dexinjia Biopharmaceutical Co., Ltd. and other companies.
  • DIPEA N,N-diisopropylethylamine
  • N-methylpyrrolidone (3.3g) to dissolve compound 1-1 (2-bromo-N-(2,6-xylyl)acetamide) (1.6g, 1.0eq) under stirring until it is clear, then add anhydrous potassium carbonate (1.4g) to the reaction system, cool to 0-10°C, add dropwise N-methylpyrrolidone solution (0.8g) of N-ethylpropylamine 1a (0.7g, 1.2eq), and keep warm for 0.5h after the addition is complete. Stir the system and heat it to 15-25°C, keep warm for 4h, and take samples for HPLC detection until the endpoint requirements are met.
  • Filter collect the filtrate, drop the filtrate into water cooled to 0-10°C, stir and crystallize, and keep warm for 6h. Filter, collect the filter cake, and dry the filter cake under nitrogen purge at room temperature to obtain the target compound 1-2 as an off-white solid with a yield of 1.38g, a yield of 84.03%, and a purity of 96.7%.
  • Step 2 5-Bromo-N-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-N-ethyl-N-propylpentane-1-ammonium bromide (1-3)
  • 1,5-dibromopentane 2a (7.2 g, 6.0 eq) and compound 1-2 (1.3 g, 1.0 eq) were added to the reaction bottle in sequence, stirred and mixed, and then heated to 95-105°C, kept warm for at least 16 hours, and sampled for HPLC detection until the endpoint requirements were met. The temperature was lowered to 55-65°C, and n-heptane (4.5 g) was added to the system three times, stirred and washed, and allowed to stand for separation. The upper n-heptane layer was discarded.
  • ethylene glycol dimethyl ether (DME, 5.6 g) was added to the lower system, and the temperature was maintained at 55-65°C and stirred for 6 hours, then cooled to room temperature, filtered, and the filtrate was collected.
  • Step 3 N-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-5-((S)-2-((2,6-dimethylphenyl)carbamoyl)piperidin-1-yl)-N-ethyl-N-propylpentan-1-ammonium bromide (Compound 1)
  • compound 1 150 mg was dissolved in 0.45 mL of methanol, and 0.03 mL (concentration of 12.1 mol/L) of hydrochloric acid was added. After stirring at room temperature for 1 h, 0.6 mL of water was added to the mixed solution. The methanol was then concentrated under reduced pressure. The remaining solution was ion exchanged with 1.5 g of chloroform 717 anion exchange resin and freeze-dried for 22 h to obtain compound 1 hydrochloride, i.e., compound 1 dichloride (152.0 mg, 95.5%, HPLC purity 99.91%).
  • compound 1 hydrochloride i.e., compound 1 dichloride (152.0 mg, 95.5%, HPLC purity 99.91%).
  • Test Example 1 Subcutaneous infiltration anesthetic effect and skin irritation test of the compound of the present invention
  • SD rats, female, were purchased from Hunan Slake Jingda Experimental Animal Co., Ltd.
  • the ambient temperature was maintained at 22 ⁇ 1°C, the humidity was 40-70%, sufficient water and feed were provided during the entire experiment, and a 12-hour day and night cycle (8:00AM-8:00PM) was maintained.
  • the comparative example compound 3 and the compound 1 of the present invention were prepared into 6 mmol/L solution with DMSO and normal saline for use; the double salt of levobupivacaine hydrochloride and the compound 1 of the present invention was prepared into 6 mmol/L solution with normal saline for use.
  • Rats weighing 200-300 g were selected and randomly divided into groups according to the number of specific test compounds. Each group had 6 rats and was housed in separate cages. The backs of the rats were shaved and disinfected before the experiment, and the drugs were subcutaneously injected into the exposed skin at the center of the back by subcutaneous infiltration anesthesia.
  • each rat was acupunctured three times at each time point in the central area of the skin on the side of the drug administration to determine whether the compound has a peripheral nerve blocking effect.
  • the drug is considered to be ineffective or ineffective on the rat (n ⁇ 1); if more than half of the rats show skin contraction, avoidance, and screaming phenomena, the drug is considered to be ineffective or ineffective at this time point in the group of rats (N>3, 6 rats/group).
  • a second test is required with an interval of 10 minutes to confirm the result.
  • the measurement fails to work twice in a row, the compound to be tested is considered to be ineffective or ineffective. Its local anesthetic effect is summarized in Table 1 below.
  • Test Example 3 Stability study of different salt forms of compound 1
  • compound 1 has poor stability under the experimental conditions of high temperature 7 days.
  • the stability of compound 1 salt was significantly more stable under the experimental conditions of high temperature 7 days, among which the chemical purity of citrate, hydrobromide and dichloride salt of compound 1 remained basically unchanged, and had excellent chemical stability.
  • Test Example 4 Sprague-Dawley rat pharmacokinetic test
  • dichlorobenzene salt of compound 1 of the present invention was prepared into 0.5 mg/mL and 1.2 mg/mL with normal saline for use.
  • Experimental plan A total of 24 SD rats were used in this experiment and randomly divided into 4 groups (3 rats of each sex in each group). The animals were given the test samples by single intravenous injection and subcutaneous injection. Blood samples were collected from the animals in the intravenous administration group before the drug and at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h and 24h after the drug administration, and plasma was separated. Blood samples were collected from the animals in the subcutaneous administration group before the drug and at 15min, 30min, 45min, 1h, 2h, 4h, 8h, 12h, 24h and 48h after the drug administration, and plasma was separated.
  • the concentration of the sample to be tested in the sample was detected by LC-MS/MS method, and the pharmacokinetic parameters were calculated using the metabolic kinetic data analysis software WinNonlin.
  • the pharmacokinetic data were described by descriptive statistics such as mean value, standard deviation and sample size. Microsoft Excel was used for calculation. The results are recorded in Table 5 below.
  • Test Example 5 Test on the effect of hERG potassium channel on human embryonic kidney cells (HEK293)
  • Test samples stable cell line HEK-hERG; negative control (extracellular solution containing 0.1% DMSO) and positive control (0.1 ⁇ M cisapride); dichlorobenzene salt of the compound 1 of the present invention was prepared at 0.3, 1, 3, 10, 30 ⁇ M.
  • the hERG channel current was recorded from a single cell at room temperature using the whole-cell recording mode.
  • the cell membrane potential was clamped at -80 mV, and the membrane potential was depolarized to +30 mV for 3 seconds to activate the hERG current, followed by a repolarization potential of -50 mV for 4 seconds to remove channel inactivation.
  • This voltage mode was run approximately once every 10 seconds, and the data acquisition frequency was 200 Hz.
  • the maximum current (peak tail current) during the repolarization period was measured.
  • the cells are continuously perfused, first with extracellular solution, and then with the drug preparation (negative control, test substance, or positive control preparation). Each cell is given one or two concentrations of the test preparation, and 2 cells are given the positive control preparation after the test preparation.
  • the tail current peak should reach a stable state for at least 1 minute before the preparation is given. The tail current is measured again after the new stable state is achieved for at least 1 minute after the addition of the drug or when the exposure reaches 12 minutes.
  • the data acceptance criteria are as follows:
  • the absolute value of the stable leakage current at the holding potential is ⁇ 100pA or ⁇ 10% of the peak value of the tail current
  • the initial stable tail current peak value is greater than the current size during the depolarization period of +30mV
  • the peak value of the tail current of each current was obtained using online analysis using PatchMaster Pro software.
  • test substance and negative control were subjected to one-way analysis of variance (ANOVA) between groups. If there was a statistical difference, Dunnett's method was used to perform a pairwise analysis between each test substance administration group and the negative control group. The test results are shown in Table 6 below.
  • Test method A total of 64 SD rats were used in this test and randomly divided into 4 groups (8 rats per sex in each group). The animals were given a single subcutaneous injection of a vehicle (0.9% sodium chloride injection) and the compound of the present invention (2.5, 5.0, 15.0 mg/kg). All rats were observed by cage observation, detailed clinical observation, body weight, body weight change and respiratory system indicators (respiratory rate, tidal volume and minute ventilation) were evaluated. All animals in this test were euthanized after the completion of the data collection in the body stage.
  • Test results A single subcutaneous injection of the compound of the present invention, such as compound 1 dichloride salt, to 15 mg/kg to SD rats had no effect on the respiratory parameters evaluated in the rats, including tidal volume, minute ventilation and respiratory rate.
  • Experimental animals 10 beagle dogs, half male and half female, from Beijing Mars Biotechnology Co., Ltd.
  • Test method Four male and four female beagles with implants were selected for the test.
  • the test animals were subcutaneously injected with a vehicle (0.9% sodium chloride injection) or three different doses (1, 2 and 5 mg/kg) of the compound of the present invention by Latin prescription, and a 7-day washout period was performed between each dose.
  • the evaluation indicators of the animals included cage-side observation and detailed clinical observation, electrocardiogram, body temperature and blood pressure. All animals survived until the end of the experiment and were transferred out of the experiment on the 23rd day.
  • Test conclusion A single subcutaneous injection of the compound of the present invention at a dose of 5 mg/kg to beagle dogs did not reveal any test substance-related effects on the evaluated electrocardiographic parameters (including heart rate, RR interval, PR interval, QRS duration, QT and corrected QT interval) and body temperature.
  • Test method TA98, TA100, TA1535, TA1537 and WP2uvrA were selected as standard test strains. The test was carried out using the plate incorporation method, with and without the addition of the in vitro metabolic activation system (-S9). Based on the results of the preliminary test, this test used 0.9% sodium chloride injection as the solvent. The solvent control group and the positive control group were set in parallel.
  • the compound of the present invention was set in 5 concentration groups in each test strain of TA98, TA1535 and WP2uvrA, which were 200 ⁇ g/dish, 500 ⁇ g/dish, 1000 ⁇ g/dish, 2000 ⁇ g/dish, and 5000 ⁇ g/dish, and the compound of the present invention was set in 7 concentration groups in each test strain of TA100 and TA1537, which were 200 ⁇ g/dish, 500 ⁇ g/dish, 1000 ⁇ g/dish, 2000 ⁇ g/dish, 3000 ⁇ g/dish, 4000 ⁇ g/dish and 5000 ⁇ g/dish, and the solvent control group and the positive control group were set in parallel. Each concentration group (including the solvent control and the positive control) was set in parallel with 3 parallel plates.
  • Evaluation index For at least one strain among the test strains, when the in vitro metabolic activation system is added or not, the number of reverted mutant colonies in the test group exceeds a certain range compared with the number of reverted mutant colonies in the corresponding solvent control group (i.e., the mean number of reverted mutant colonies in the test group of the test strain TA1535 is equal to or greater than 3 times the average value of the solvent control group, and the mean number of reverted mutant colonies in the test group of other test strains is equal to or greater than 2 times the average value of the solvent control group), and there is a concentration-response relationship, or there is a reproducible and obvious increase in the number of reverted mutant colonies at a certain test point (strain or concentration), the test result can be judged as positive.
  • the increase in the number of reverted mutant colonies does not reach the threshold value (2 or 3 times), but there is a concentration-response relationship. Or the increase in the number of reverted mutant colonies is equal to or greater than the respective threshold value (2 or 3 times), but there is no concentration-response relationship.
  • the test results can all be judged as suspicious results.
  • the test results were input into Excel (2010 version), and the mean, standard deviation and ratio (mean of reverse mutations in treatment group/positive control group/mean of reverse mutations in solvent control group) of the number of reverse mutation colonies in three plates of each treatment group, solvent control group and positive control group were calculated.
  • the compounds of the present invention such as the dichloro salt of Example Compound 1, have no mutagenicity to all tested strains, that is, the Ames test result is negative.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Anesthesiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne un composé de sel d'ammonium quaternaire, une forme de sel et son utilisation. Le composé de sel d'ammonium quaternaire a la caractéristique structurale de formule (I). L'invention concerne en outre un sel du composé de formule (I), qui peut être utilisé en tant qu'anesthésique local.
PCT/CN2024/089769 2023-04-27 2024-04-25 Composé de sel d'ammonium quaternaire, forme de sel et utilisation de celui-ci Pending WO2024222788A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202310471682.3 2023-04-27
CN202310471682 2023-04-27

Publications (1)

Publication Number Publication Date
WO2024222788A1 true WO2024222788A1 (fr) 2024-10-31

Family

ID=93159010

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/089769 Pending WO2024222788A1 (fr) 2023-04-27 2024-04-25 Composé de sel d'ammonium quaternaire, forme de sel et utilisation de celui-ci

Country Status (3)

Country Link
CN (1) CN118851987A (fr)
TW (1) TW202442634A (fr)
WO (1) WO2024222788A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1295558A (zh) * 1998-04-03 2001-05-16 先进医药公司 新的局部麻醉化合物及用途
CN103601650A (zh) * 2013-01-16 2014-02-26 四川大学华西医院 N-二乙氨基乙酰-2,6-二甲基苯胺衍生物、制备方法及用途
CN110156665A (zh) * 2018-02-11 2019-08-23 四川大学华西医院 一种季铵盐类化合物及其制备方法与用途
CN111153851A (zh) * 2019-02-01 2020-05-15 四川大学华西医院 一种季铵盐类化合物及其制备方法与用途
CN115215760A (zh) * 2021-04-19 2022-10-21 四川大学华西医院 一种含芳基的季铵盐衍生物及其在制备局部麻醉药物中的用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1295558A (zh) * 1998-04-03 2001-05-16 先进医药公司 新的局部麻醉化合物及用途
CN103601650A (zh) * 2013-01-16 2014-02-26 四川大学华西医院 N-二乙氨基乙酰-2,6-二甲基苯胺衍生物、制备方法及用途
CN110156665A (zh) * 2018-02-11 2019-08-23 四川大学华西医院 一种季铵盐类化合物及其制备方法与用途
CN111153851A (zh) * 2019-02-01 2020-05-15 四川大学华西医院 一种季铵盐类化合物及其制备方法与用途
CN115215760A (zh) * 2021-04-19 2022-10-21 四川大学华西医院 一种含芳基的季铵盐衍生物及其在制备局部麻醉药物中的用途

Also Published As

Publication number Publication date
CN118851987A (zh) 2024-10-29
TW202442634A (zh) 2024-11-01

Similar Documents

Publication Publication Date Title
CN110156665B (zh) 一种季铵盐类化合物及其制备方法与用途
US6242460B1 (en) Zolpidem salt forms
KR100578443B1 (ko) 초단기 작용성 신경근 차단제인 치환된 이소퀴놀린
TW201213329A (en) Pyrazine derivatives as ENaC blockers
JP2002500214A (ja) 置換２−ベンジルアミノ−２−フェニル−アセトアミド化合物
WO2022037590A1 (fr) Composé de sel d'ammonium quaternaire pour anesthésie, son procédé de préparation et son utilisation
UA114295C2 (uk) Сполука бензотіазолону
JP2003501469A (ja) 皮膚麻酔薬
EP3470402B1 (fr) Formes cristallines de composés mimétiques de la neurotrophine et leurs sels
CN115215760B (zh) 一种含芳基的季铵盐衍生物及其在制备局部麻醉药物中的用途
WO2024222788A1 (fr) Composé de sel d'ammonium quaternaire, forme de sel et utilisation de celui-ci
CN111315758B (zh) 短肽季铵盐化合物及其用途
CN115215759B (zh) 一种兼具长效局部麻醉和选择性局部麻醉作用的酰胺类季铵盐衍生物
EP1163241B1 (fr) Sels de zolpidem
CN115215790B (zh) 一种环状季铵盐衍生物及其制备方法和用途
CN115073518A (zh) 磷酸双依达拉奉酯类化合物、及其制备方法和用途
CN114685292A (zh) 反式金刚烷氨衍生物或其盐的用途
BR122014004640B1 (pt) Forma cristalina iii de [cloridrato de 4-metilbenzoato de 4-[2-dimetilamino-1-(1-hidroxiciclohexil)etil]fenila], sua utilização e seu método de preparação, e composição farmacêutica
WO2025237335A1 (fr) Sel pharmaceutiquement acceptable de dérivé de cucurbiturile, forme cristalline de celui-ci et son utilisation
EP4527833A1 (fr) Composé de sel d'ammonium quaternaire cyclique, son procédé de préparation et son utilisation
CN121021402A (zh) 一种杂环化合物及其药物组合物和用途
CN116023322A (zh) 一种n-乙酰苯胺类阳离子化合物及其制备方法和应用
CN119409607A (zh) 一种基于季胺利多卡因衍生物的活性氧响应型局部麻醉药物及其制备和应用
KR20120013378A (ko) Ｎ-［(7-아자-비시클로［2.2.1］헵트-1-일)-아릴-메틸］-벤즈아미드의 유도체, 그의 제조법, 및 그의 치료 용도
HUT55753A (en) Process for producing bis(benylpyrrolidine) derivatives and pharmaceutical compositions comprising such compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24796164

Country of ref document: EP

Kind code of ref document: A1