CN112851599B - Compound with biscationic quaternary ammonium salt structure, and preparation method and application thereof - Google Patents

Compound with biscationic quaternary ammonium salt structure, and preparation method and application thereof Download PDF

Info

Publication number
CN112851599B
CN112851599B CN201911184468.XA CN201911184468A CN112851599B CN 112851599 B CN112851599 B CN 112851599B CN 201911184468 A CN201911184468 A CN 201911184468A CN 112851599 B CN112851599 B CN 112851599B
Authority
CN
China
Prior art keywords
compound
substituting
yield
referring
procedure
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.)
Active
Application number
CN201911184468.XA
Other languages
Chinese (zh)
Other versions
CN112851599A (en
Inventor
杨俊�
刘进
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.)
West China Hospital of Sichuan University
Original Assignee
West China Hospital of Sichuan University
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 West China Hospital of Sichuan University filed Critical West China Hospital of Sichuan University
Priority to CN201911184468.XA priority Critical patent/CN112851599B/en
Publication of CN112851599A publication Critical patent/CN112851599A/en
Application granted granted Critical
Publication of CN112851599B publication Critical patent/CN112851599B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D295/08—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 singly bound oxygen or sulfur atoms
    • C07D295/084—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 singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—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 singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • C07D211/08—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
    • C07D211/10—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • 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
    • C07D211/38—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D295/08—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 singly bound oxygen or sulfur atoms
    • C07D295/084—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 singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D295/155—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 separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a double quaternary ammonium compound, or a crystal form, or a solvate, or a stereoisomer, or an isotope label or a salt thereof, wherein the structure of the double quaternary ammonium compound is shown as a formula (I). Experiments prove that the compound provided by the invention has a quick effect after single administration, can provide thorough muscle relaxation effect for 2-10 minutes, can realize ultra-short effect non-depolarized muscle relaxation effect only by depending on metabolism of an organism, and still shows quick fading of the muscle relaxation effect after large-dose and continuous administration. Compared with the control agent cisatracurium, the compound of the invention has smaller dosage, quicker onset of action and complete recovery of muscle Tone (TOF)>90 percent) is shorter, and has very good application prospect in preparing skeletal muscle relaxation drugs with quick effect, quick recovery and small toxic and side effects.

Description

Compound with biscationic quaternary ammonium salt structure, and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmacy, and in particular relates to a compound with a biscationic quaternary ammonium salt structure, a preparation method thereof and application of the compound serving as a skeletal muscle relaxing medicament.
Background
N2 cholinergic blocking drugs, also known as skeletal muscle relaxants (abbreviated as muscle relaxants, skeletal muscular relaxants), are important anesthetics. The muscle relaxant can selectively act on N2 receptor on the motor nerve endplate membrane to block transmission of nerve impulse to skeletal muscle, so that skeletal muscle is relaxed, and the muscle relaxant is mainly used for producing muscle relaxation in surgical operation and trachea cannula. Muscle relaxants are mainly classified into depolarizing type (depolarizing muscular relaxants) and non-depolarizing type (nondepolarizing muscular relaxants) according to their action mechanisms. Muscle relaxants can be classified into ultra-short, short-acting, medium-acting and long-acting muscle relaxants according to the length of time they act on muscle relaxants (analysis, 82 (1), 33a, 1995).
Depolarizing muscle relaxants bind to the N2 receptor on the motor endplate membrane, causing durable depolarization of the muscle cell membrane, weakening or eliminating the response to ACh, resulting in skeletal muscle relaxation. The depolarizing muscle relaxant currently in clinical use is succinylcholine (also known as scoline). After succinylcholine is used, because the skeletal muscles at different parts depolarize under the action of the medicine for different time, firstly uncoordinated muscular bundle tremors appear, then the skeletal muscles are quickly transformed into muscular relaxations, and the muscular relaxations of the neck, the limbs and the abdomen are most obvious, and the action is quick and short. Can be used for short-time minor operations such as trachea cannula, bronchoscope, esophagoscope, and the like, and can also be used as auxiliary medicine in general anesthesia operation, so that skeletal muscle under shallower anesthesia is completely relaxed, the dosage of general anesthesia medicine is reduced, and the safety of the surgical operation is improved. Because the succinylcholine has rapid effect and short action time, and the duration of human body is about 10 minutes, the succinylcholine is often used as an ultrashort-acting muscle-relaxing medicament in clinic, and is particularly suitable for emergency patients, thereby avoiding serious brain injury and even death caused by using the muscle-relaxing medicament with longer action time under emergency conditions. Thus, the depolarizing muscle relaxant succinylcholine is currently the most suitable muscle relaxant for emergency treatment. However, due to the special action mechanism of depolarizing muscle relaxants, serious side effects such as increased potassium, nausea and hyperthermia, arrhythmia, increased intraocular pressure and gastric tension can be generated during use, so that the clinical application of the depolarizing muscle relaxant is greatly limited.
Non-depolarizing muscle relaxants, also known as competitive muscle relaxants (competitive muscular relaxants), compete with ACh for the N2 choline receptor on the skeletal muscle motor endplate membrane, which is inherently inactive, but can be prevented from depolarizing by blocking ACh binding to the N2 choline receptor, resulting in skeletal muscle relaxation. Non-depolarizing muscle relaxants do not have many of the side effects of depolarizing muscle relaxants and are therefore recognized as clinically safer muscle relaxants, but too long a time to act on the muscle is also considered a major drawback. Anticholinesterase drugs such as neostigmine antagonize skeletal muscle relaxant action of non-depolarizing muscle relaxants and are useful in relief when used in excess. CN101588803a also discloses a non-depolarizing muscle relaxant which can be administered 200 times the dose of cysteine to reverse its muscle relaxing effect rapidly, which, although rapid resolution of muscle relaxation is achieved, must be achieved with a large number of sulfhydryl amino acids (e.g. cysteines), which obviously increases medical procedures, and a large number of sulfhydryl amino acids also increases safety uncertainties such as excessive cysteines causing bronchospasm, vomiting, etc.
All non-depolarizing muscle relaxants currently on the market do not meet the clinical need for rapid recovery with a single administration having a skeletal muscle relaxation duration of more than 10 minutes. For example: in the clinical muscle relaxant on the market, the duration of muscle relaxation after single administration of Miku ammonium chloride is about 15-20 minutes, the duration of muscle relaxation after single use of cis-atraku ammonium and rocuronium bromide is about 40-60 minutes, and the duration of muscle relaxation after single use of panturonium bromide is even more than 60 minutes, so that rapid recovery of muscle relaxation cannot be realized.
Therefore, the skeletal muscle relaxing medicament which does not need a reversing agent, has small dosage, quick response, quick recovery and small toxic and side effects is urgently needed in clinic at present.
Disclosure of Invention
In view of the above problems in the prior art, it is an object of the present invention to provide a biscationic quaternary ammonium salt structured compound, a preparation method thereof and use thereof as a skeletal muscle relaxant.
The invention provides a biscationic quaternary ammonium salt compound, or a stereoisomer, or a solvate, or a salt, or a crystal form or an isotope label thereof, wherein the structure of the biscationic quaternary ammonium salt compound is shown as a formula (I):
Figure BDA0002292072840000021
wherein:
R 1 ，R 2 ，R 3 ，R 4 each independently selected from substituted or unsubstituted, saturated or unsaturated C 1～20 Hydrocarbyl, or C 1～20 A group obtained by replacing a skeleton atom in a hydrocarbon group with a hetero atom; the C is 1～20 The substituents on the hydrocarbon radicals are selected from nitro, cyano, hydroxy, alkyl, alkoxy, halogen, aryl, heteroaryl, -OCOR 9 、-COR 9 、-COOR 9 ，R 9 Selected from C 1～8 An alkyl group;
R 5 selected from H, C 1～6 Alkyl, hydroxy, halogen, cycloalkyl;
m 1 selected from substituted or unsubstituted C 1～8 Alkylene, or C 1～8 1 to 3-CH in the alkylene skeleton of (C) 2 -groups substituted by heteroatoms, vinyl groups or cycloalkyl groups; the C is 1～8 The substituents on the alkylene groups of (2) are selected from C 1～6 Alkyl, C 1～6 Alkoxy, cycloalkyl, hydroxy, halogen;
m 2 selected from substituted or unsubstituted C 1～8 Alkylene, or C 1～8 1 to 3-CH in the alkylene skeleton of (C) 2 -groups substituted by heteroatoms, vinyl groups or cycloalkyl groups; the C is 1～8 The substituents on the alkylene groups of (2) are selected from C 1～6 Alkyl, C 1～6 Alkoxy, cycloalkyl, hydroxy, halogen;
e is O, S or CR 7 R 8 ，R 7 、R 8 Each independently selected from H, halogen, C 1～6 An alkyl group;
n=1 or 2;
g selectionFrom O or NR 6 Wherein R is 6 H, C of a shape of H, C 1～6 Alkyl, cycloalkyl;
a is O or S; b is O or S;
p=0 or 1; q=0 or 1; h=0 or 1;
Z 1 、Z 2 each independently selected from anions.
Further, the method comprises the steps of,
R 1 ，R 2 ，R 3 ，R 4 each independently selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl group,
Figure BDA0002292072840000031
Wherein a is an integer of 0 to 2, R 10 Selected from the following substituted or unsubstituted: aryl, heteroaryl, benzoheterocyclyl, saturated cycloalkyl, saturated heterocyclyl, said R 10 The substituents on the ring members being selected from nitro, cyano, hydroxy, halogenated or unhalogenated C 1-4 Alkyl, halogenated or non-halogenated C 1-4 Alkoxy, halogen, -OCOR 9 、-COR 9 、-COOR 9 ，R 9 Selected from C 1～4 An alkyl group;
R 5 selected from H, C 1～4 Alkyl, hydroxy, halogen, cycloalkyl;
m 1 selected from substituted or unsubstituted C 1～6 Alkylene, or C 1～6 1-2-CH in the alkylene skeleton of (C) 2 -groups substituted by heteroatoms, vinyl groups or cycloalkyl groups; the C is 1～6 The substituents on the alkylene groups of (2) are selected from C 1～4 Alkyl, C 1～4 Alkoxy, cycloalkyl, hydroxy, halogen;
m 2 selected from substituted or unsubstituted C 1～6 Alkylene, or C 1～6 1-2-CH in the alkylene skeleton of (C) 2 -groups substituted by heteroatoms, vinyl groups or cycloalkyl groups; the C is 1～6 The substituents on the alkylene groups of (2) are selected from C 1～4 Alkyl, C 1～4 Alkoxy, cycloalkyl, hydroxy, halogen;
e is O, S or CR 7 R 8 ，R 7 、R 8 Each independently selected from H, halogen, C 1～4 An alkyl group;
n=1 or 2;
g is selected from O or NR 6 Wherein R is 6 Is H or C 1～4 An alkyl group;
a is O; b is O;
p=0 or 1; q=0 or 1; h=0 or 1;
Z 1 、Z 2 each independently selected from anions.
Further, the method comprises the steps of,
the structure of the biscationic quaternary ammonium salt compound is shown as a formula (II):
Figure BDA0002292072840000041
wherein R is 1 Selected from C 1-4 Alkyl, C 2-4 Alkenyl group,
Figure BDA0002292072840000042
R 10 ，R 11 Each independently selected from phenyl, heteroaryl, benzoheterocyclyl substituted with 0 to 3 substituents; the substituents are each independently selected from nitro, cyano, hydroxy, halogenated or non-halogenated C 1-3 Alkyl, halogenated or non-halogenated C 1-3 Alkoxy, halogen, -OCOR 9 、-COR 9 、-COOR 9 ，R 9 Is C 1～3 An alkyl group;
preferably, the heteroaryl group is
Figure BDA0002292072840000043
The benzoheterocyclyl is +.>
Figure BDA0002292072840000044
b is an integer of 0 to 3, R 12 Selected from nitro, cyano, hydroxy, halogenated or non-halogenated C 1-3 Alkyl, halogenated or non-halogenated C 1-3 Alkoxy, halogen, -OCOR 9 、-COR 9 、-COOR 9 ，R 9 Is C 1～3 An alkyl group;
R 5 selected from H, C 1～4 Alkyl, hydroxy, halogen;
m 1 selected from substituted or unsubstituted C 1～6 Alkylene, or C 1～6 1-2-CH in the alkylene skeleton of (C) 2 -a group substituted by a heteroatom selected from O or S, a vinyl group or a cycloalkyl group, said cycloalkyl group being a 3-membered cycloalkyl group; the C is 1～6 The substituents on the alkylene groups of (2) are selected from C 1～3 Alkyl, hydroxy, halogen;
m 2 selected from substituted or unsubstituted C 1～6 Alkylene, or C 1～6 1-2-CH in the alkylene skeleton of (C) 2 -a group obtained by substitution with a heteroatom selected from O or S; the C is 1～6 The substituents on the alkylene groups of (2) are selected from C 1～3 Alkyl, hydroxy, halogen;
e is O, S or CR 7 R 8 ，R 7 、R 8 Each independently selected from H, halogen, C 1～3 An alkyl group;
n=1 or 2;
g is selected from O or NR 6 Wherein R is 6 Is H or C 1～3 An alkyl group;
p=0 or 1; q=0 or 1; h=0 or 1;
Z 1 、Z 2 each independently selected from anions.
Further, the method comprises the steps of,
the structure of the biscationic quaternary ammonium salt compound is shown as a formula (III):
Figure BDA0002292072840000051
wherein R is 1 Selected from C 1-4 Alkyl, C 2-4 Alkenyl group,
Figure BDA0002292072840000052
b. c and d are each independently selected from integers from 0 to 2, R 12 、R 13 、R 14 Each independently selected from nitro, cyano, hydroxy, halogenated or unhalogenated C 1-3 Alkyl, halogenated or non-halogenated C 1-3 Alkoxy, halogen, -OCOR 9 、-COR 9 、-COOR 9 ，R 9 Is C 1～3 An alkyl group;
R 5 selected from H, C 1～4 Alkyl, hydroxy, halogen;
m 1 selected from substituted or unsubstituted C 1～5 Alkylene group, the C 1～5 The substituents on the alkylene groups of (2) are selected from C 1～3 Alkyl, hydroxy, halogen;
m 2 selected from substituted or unsubstituted C 1～5 Alkylene, or C 1～5 1-2-CH in the alkylene skeleton of (C) 2 -a group obtained by substitution with a heteroatom selected from O or S; the C is 1～5 The substituents on the alkylene groups of (2) are selected from C 1～3 Alkyl, hydroxy, halogen;
e is CR 7 R 8 ，R 7 、R 8 Each independently selected from H, halogen, C 1～3 An alkyl group;
n=1 or 2;
Z 1 、Z 2 each independently selected from pharmaceutically acceptable anions.
Further, the method comprises the steps of,
the structure of the biscationic quaternary ammonium salt compound is shown as a formula (IV):
Figure BDA0002292072840000061
wherein R is 1 Selected from C 1-4 Alkyl, C 2-4 Alkenyl group,
Figure BDA0002292072840000062
R 12 、R 13 、R 14 Each independently ofIn situ selected from nitro, cyano, hydroxy, halogenated or non-halogenated C 1-3 Alkyl, halogenated or non-halogenated C 1-3 Alkoxy, halogen, -OCOR 9 、-COR 9 、-COOR 9 ，R 9 Is C 1～3 An alkyl group;
R 5 selected from H, C 1～4 Alkyl, hydroxy, halogen;
m 1 selected from substituted or unsubstituted C 1～5 Alkylene group, the C 1～5 The substituents on the alkylene groups of (2) are selected from C 1～3 Alkyl, hydroxy, halogen;
m 2 selected from substituted or unsubstituted C 1～5 Alkylene, or C 1～5 1-2-CH in the alkylene skeleton of (C) 2 -a group obtained by substitution with a heteroatom selected from O or S; the C is 1～5 The substituents on the alkylene groups of (2) are selected from C 1～3 Alkyl, hydroxy, halogen;
e is CR 7 R 8 ，R 7 、R 8 Each independently selected from H, halogen, C 1～3 An alkyl group;
Z 1 、Z 2 each independently selected from bromide, chloride, acetate, sulfate, citrate, sulfonate.
Further, the method comprises the steps of,
R 1 is methyl;
R 12 、R 13 、R 14 each independently selected from nitro, methyl, halogen, halomethyl;
R 5 selected from H or methyl;
m 1 selected from substituted or unsubstituted C 1～5 Alkylene group, the C 1～5 The substituent on the alkylene of (a) is selected from methyl, halogen;
m 2 selected from substituted or unsubstituted C 1～5 Alkylene, or C 1～5 1-2-CH in the alkylene skeleton of (C) 2 -a group obtained by substitution with a heteroatom selected from O or S; the C is 1～5 The substituent on the alkylene of (a) is selected from methyl, halogen;
e is CR 7 R 8 ，R 7 、R 8 Each independently selected from H, halogen, C 1～2 An alkyl group.
Further, the method comprises the steps of,
the halogen is selected from F, cl or Br; the halomethyl group is selected from CF 3 。
Further, the method comprises the steps of,
the structure of the biscationic quaternary ammonium salt compound is selected from one of the following structures:
Figure BDA0002292072840000071
Figure BDA0002292072840000081
Figure BDA0002292072840000091
Figure BDA0002292072840000101
Figure BDA0002292072840000111
the invention also provides application of the biscationic quaternary ammonium salt compound, or a stereoisomer, or a solvate, or a salt, or a crystal form or an isotope label thereof in preparing skeletal muscle relaxing medicaments.
The invention also provides a pharmaceutical composition which is prepared by taking the biscationic quaternary ammonium salt compound, or a stereoisomer, or a solvate, or a salt, or a crystal form or an isotope label thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
In the present invention, "stereoisomers" refers to isomers produced by the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"solvate" refers to a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.
“C 1～20 The hydrocarbon group refers to all groups containing 1 to 20 carbon atoms and only containing two atoms of carbon and hydrogen; "C 1～20 The "group obtained by substituting a hetero atom for the skeleton atom in the hydrocarbon group" means C 1～20 And a group obtained by replacing 1 or more skeleton atoms in a hydrocarbon group with a group containing a hetero atom such as O, S, N.
“C 1～8 1 to 3-CH in the alkylene skeleton of (C) 2 The term "group substituted by a heteroatom, vinyl or cycloalkyl" means C 1～8 1 to 3-CH in the alkylene skeleton of (C) 2 -each independently replaced by a heteroatom group such as S, O, NH, or a vinyl group, or a cycloalkyl group.
"isotopic label" refers to a compound obtained by substituting one or more atoms in the compound with their corresponding isotopes, for example, hydrogen in the compound is substituted with protium, deuterium or tritium.
The compound shown in the formula (I) has quick response after single administration, can provide thorough muscle relaxation effect for 2-10 minutes, can realize ultra-short effect non-depolarized muscle relaxation effect only by depending on the metabolism of the organism, and still shows quick fading of the muscle relaxation effect after large-dose and continuous administration. Compared with the contrast agent cisatracurium and succinylcholine, the compound has smaller dosage, quicker onset of action and shorter time required for complete recovery of the muscular tension (TOF > 90%), and has good application prospect in preparing skeletal muscle relaxation drugs with quick onset of action, quick recovery and small toxic and side effects.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
The compound shown in the formula (I) is prepared by connecting two molecules with positive charges through a linker, wherein the synthesis route is that quaternary ammonium salt molecules at one end of a target compound are prepared, quaternary ammonium salt molecules at the other end are synthesized, and the two quaternary ammonium salt molecules are coupled through the linker, so that the target compound is prepared.
The following are specific examples of preparation of each specific compound:
example 1 preparation of Compound 1
Compound 1 (i.e., compound 1) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000131
1.25 g of bromoethanol was dissolved in 30 ml of acetonitrile, 0.85 g of piperidine and 1.38 g of anhydrous potassium carbonate were added, followed by stirring at 50℃for 10 hours, then 2.16 g of p-nitrobenzyl bromide were added, stirring at 55℃for 6 hours, filtration and evaporation of the solvent under reduced pressure were carried out to obtain 3.5 g of yellow solid. 1.6 g of yellow solid and 0.66 g of chloromethyl chloroformate were dissolved in 30 ml of anhydrous methylene chloride, and 0.8 g of pyridine was added dropwise thereto under cooling with cold water, followed by stirring for 5 hours. The solvent was evaporated under reduced pressure and the residue was subjected to column chromatography to give 0.98 g of intermediate 1-1.
1.21 g of N-methylbenzylamine and 1.8 g of methyl 4-bromobutyrate are dissolved in 30 ml of acetonitrile, 1.4 g of anhydrous potassium carbonate is added, stirring is carried out at 55 ℃ for 8 hours, then 2.16 g of p-nitrobenzyl bromide is added, stirring is carried out at 55 ℃ for 6 hours, filtering is carried out, the solvent is evaporated to dryness under reduced pressure, 40 ml of 2N aqueous sodium hydroxide solution is added to the residue, stirring is carried out at room temperature for 2 hours, the pH value is regulated to 9 by aqueous hydrobromic acid solution, the solvent is evaporated to dryness under reduced pressure, 50 ml of dichloromethane is added to the residue, heating is carried out to slight boiling, filtering is carried out while the mixture is still hot, and 1.68 g of bright yellow intermediate 1-2 is obtained after the filtrate is evaporated to dryness.
0.98 g of intermediate 1-1 and 1.05 g of intermediate 1-2 were dissolved in 50 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.39 g of compound 1 as a white powder in 21.1% yield.
1 HNMR(DMSO-d6,400MHz)δ:1.42～1.45(1H,m),1.59～1.62(1H,m),1.77～1.89(4H,m),2.09～2.11(2H,m),2.53～2.57(2H,m),3.01(3H,m),3.15～3.25(4H,m),3.41～3.43(2H,m),3.65～3.73(2H,m),4.49(1H,d,J＝12.8Hz),4.65～4.76(5H,m),4.83(1H,d,J＝12.8Hz),4.95(1H,d,J＝12.8Hz),5.73(2H,s),7.48～7.60(5H,m),7.83(2H,d,J＝8.8Hz),7.93(2H,d,J＝8.8Hz),8.30～8.35(4H,m).
ESI,M 2+ :332.1
Example 2 preparation of Compound 2
Compound 2 (i.e., compound 2) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000141
intermediate 1-1 was prepared by the method of reference example 1; referring to the procedure of example 1, benzyl bromide was replaced with p-nitrobenzyl bromide to prepare intermediate 2-2 (yield 56%). In the intermediate preparation process, the molar ratio, the solvent amount and the reaction conditions of each reagent were the same as those in example 1, and the same as described below.
0.43 g of intermediate 1-1 and 0.49 g of intermediate 2-2 are dissolved in 10 ml of acetonitrile, stirred for 12 hours at 50 ℃, the solvent is evaporated to dryness under reduced pressure, and the residue is separated by reversed phase preparative chromatography to obtain 0.21 g of compound 2 as a white powder with a yield of 24.1%.
1 HNMR(DMSO-d6,400MHz)δ:1.40～1.43(1H,m),1.57～1.60(1H,m),1.74～1.86(4H,m),2.08～2.10(2H,m),2.52～2.56(2H,m),3.02(3H,m),3.14～3.24(4H,m),3.40～3.42(2H,m),3.66～3.74(2H,m),4.46(1H,d,J＝12.8Hz),4.64～4.75(5H,m),4.84(1H,d,J＝12.8Hz),4.96(1H,d,J＝12.8Hz),5.74(2H,s),7.82～7.92(6H,m),8.31～8.36(6H,m).
ESI,M 2+ :354.6
EXAMPLE 3 preparation of Compound 3
Compound 3 of the present invention (i.e., compound 3) was prepared according to the following synthetic route:
Figure BDA0002292072840000151
intermediate 1-1 was prepared by the method of reference example 1; referring to the procedure of example 1, benzyl bromide was replaced with p-fluorobenzyl bromide to prepare intermediate 3-2 (yield 46%). 0.43 g of intermediate 1-1 and 0.46 g of intermediate 3-2 are dissolved in 10 ml of acetonitrile, stirred for 12 hours at 50 ℃, the solvent is evaporated to dryness under reduced pressure, and the residue is separated by reversed phase preparative chromatography to obtain 0.23 g of white powder, namely compound 3, with a yield of 27.4%.
1 HNMR(DMSO-d6,400MHz)δ:1.41～1.43(1H,m),1.58～1.61(1H,m),1.78～1.90(4H,m),2.10～2.12(2H,m),2.52～2.56(2H,m),3.01(3H,m),3.14～3.24(4H,m),3.42～3.44(2H,m),3.64～3.73(2H,m),4.47(1H,d,J＝12.8Hz),4.64～4.75(5H,m),4.82(1H,d,J＝12.8Hz),4.93(1H,d,J＝12.8Hz),5.77(2H,s),7.38～7.40(4H,m),7.82(2H,d,J＝8.8Hz),7.92(2H,d,J＝8.8Hz),8.31～8.36(4H,m).
ESI,M 2+ :341.1
EXAMPLE 4 preparation of Compound 4
Compound 4 (i.e., compound 4) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000152
intermediate 1-1 was prepared by the method of reference example 1; referring to the procedure of example 1, benzyl bromide was replaced with p-cyanobenzyl bromide to prepare intermediate 4-2 (yield 66%). 0.43 g of intermediate 1-1 and 0.47 g of intermediate 4-2 are dissolved in 10 ml of acetonitrile, stirred for 12 hours at 50 ℃, the solvent is evaporated to dryness under reduced pressure, and the residue is separated by reversed phase preparative chromatography to obtain 0.20 g of compound 4 as a white powder with a yield of 23.5%.
1 HNMR(DMSO-d6,400MHz)δ:1.42～1.44(1H,m),1.59～1.62(1H,m),1.79～1.91(4H,m),2.11～2.13(2H,m),2.51～2.55(2H,m),3.03(3H,m),3.13～3.23(4H,m),3.41～3.43(2H,m),3.63～3.72(2H,m),4.48(1H,d,J＝12.8Hz),4.63～4.74(5H,m),4.81(1H,d,J＝12.8Hz),4.92(1H,d,J＝12.8Hz),5.75(2H,s),7.82～7.92(8H,m),8.29～8.34(4H,m).
ESI,M 2+ :344.6
EXAMPLE 5 preparation of Compound 5
Compound 5 (i.e., compound 5) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000161
intermediate 1-1 was prepared by the method of reference example 1; referring to the procedure of example 1, benzyl bromide was replaced with p-chlorobenzyl bromide to prepare intermediate 5-2 (yield 51%). 0.43 g of intermediate 1-1 and 0.48 g of intermediate 5-2 are dissolved in 10 ml of acetonitrile, stirred for 12 hours at 50 ℃, the solvent is evaporated to dryness under reduced pressure, and the residue is separated by reversed phase preparative chromatography to obtain 0.25 g of compound 5 as a white powder with a yield of 29.1%.
1 HNMR(DMSO-d6,400MHz)δ:1.43～1.45(1H,m),1.61～1.63(1H,m),1.78～1.91(4H,m),2.10～2.12(2H,m),2.53～2.57(2H,m),3.02(3H,m),3.15～3.26(4H,m),3.41～3.43(2H,m),3.63～3.72(2H,m),4.46(1H,d,J＝12.8Hz),4.63～4.74(5H,m),4.81(1H,d,J＝12.8Hz),4.92(1H,d,J＝12.8Hz),5.79(2H,s),7.34～7.37(4H,m),7.81(2H,d,J＝8.8Hz),7.91(2H,d,J＝8.8Hz),8.32～8.37(4H,m).
ESI,M 2+ :344.6
EXAMPLE 5 preparation of Compound 6
Compound 6 of the present invention (i.e., compound 6) was prepared according to the following synthetic route:
Figure BDA0002292072840000162
referring to the procedure of example 1, substituting bromoethanol for 4-bromobutanol produced intermediate 6-1 (43% yield); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl bromoacetate produced intermediate 6-2 (yield 58%).
Equimolar (1 mmol) of the intermediates 6-1 and 6-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 15 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.21 g of compound 6 as a white powder. ESI, M 2+ ：332.1。
EXAMPLE 7 preparation of Compound 7
Compound 7 of the present invention (i.e., compound 7) was prepared according to the following synthetic route:
Figure BDA0002292072840000171
referring to the procedure of example 1, substituting bromoethanol for 3-bromopropanol produced intermediate 7-1 (yield 53%); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl 3-bromopropionate produced intermediate 7-2 (yield 53%).
Equimolar (1 mmol) of intermediate 7-1 and 7-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.23 g of compound 7 as a white powder. ESI, M 2+ ：332.1。
EXAMPLE 8 preparation of Compounds
Compound 8 (i.e., compound 8) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000172
referring to the procedure of example 1, substituting bromoethanol for 3-bromopropanol and substituting chloromethyl chloroformate for chloroethyl chloroformate, intermediate 8-1 was prepared (yield 39%); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl 3-bromopropionate produced intermediate 7-2 (yield 52%).
Equimolar (1 mmol) of intermediate 8-1 and 7-2 were dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.28 g of compound 8 as a white powder. ESI, M 2+ ：339.1。
EXAMPLE 9 preparation of Compound 9
Compound 9 of the present invention (i.e., compound 9) was prepared according to the following synthetic route:
Figure BDA0002292072840000173
referring to the procedure of example 1, substituting bromoethanol for 2-methyl-4-bromobutanol produced intermediate 9-1 (yield 49%); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl bromoacetate produced intermediate 6-2 (yield 42%).
Equimolar (1 mmol) of the intermediates 9-1 and 4-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.23 g of compound 9 as a white powder. ESI, M 2+ ：339.1。
Example 10 preparation of Compound 10
Compound 10 of the present invention (i.e., compound 10) was prepared according to the following synthetic route:
Figure BDA0002292072840000181
referring to the procedure of example 1, substituting bromoethanol for 1-methyl-4-bromobutanol produced intermediate 10-1 (yield 45%); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl bromoacetate produced intermediate 6-2 (yield 42%).
Dissolving equimolar (1 mmol) of the intermediates 10-1 and 6-2 in 10 ml of acetonitrile, stirring at 50deg.C for 12 hours, evaporating the solvent under reduced pressure, and separating the residue by reversed phase preparative chromatography to obtain white powder0.22 g, compound 10.ESI, M 2+ ：339.1。
EXAMPLE 11 preparation of Compound 11
Compound 11 (i.e., compound 11) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000182
referring to the procedure of example 1, substituting bromoethanol for 2- (2-bromoethoxy) -ethanol, intermediate 11-1 was prepared (yield 35%); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl bromoacetate produced intermediate 6-2 (yield 41%).
Equimolar (1 mmol) of the intermediates 11-1 and 6-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.27 g of compound 11 as a white powder. ESI, M 2+ ：340.1。
EXAMPLE 12 preparation of Compound 12
Compound 12 of the present invention (i.e., compound 12) was prepared according to the following synthetic route:
Figure BDA0002292072840000191
referring to the procedure of example 1, substituting bromoethanol for 2- (2-bromoethylthio) -ethanol, intermediate 12-1 was prepared (yield 33%); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl bromoacetate produced intermediate 6-2 (yield 41%).
Equimolar (1 mmol) of the intermediates 12-1 and 6-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.31 g of compound 12 as a white powder. ESI, M 2+ ：346.9。
EXAMPLE 13 preparation of Compound 13
Compound 13 (i.e., compound 13) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000192
referring to the procedure of example 1, substituting bromoethanol for 3-bromopropanol produced intermediate 7-1 (yield 51%); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl 2- (2-bromoethyloxy) -acetate produced intermediate 13-2 (yield 33%).
Equimolar (1 mmol) of intermediate 7-1 and 13-2 were dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.29 g of compound 13 as a white powder. ESI, M 2+ ：347.1。
EXAMPLE 14 preparation of Compound 14
Compound 14 of the present invention (i.e., compound 14) was prepared according to the following synthetic route:
Figure BDA0002292072840000193
reference example 1, intermediate 1-1 (56% yield) was prepared; referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl 3-bromopropionate produced intermediate 7-2 (yield 50%).
Equimolar (1 mmol) of intermediates 1-1 and 7-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.22 g of compound 14 as a white powder. ESI, M 2+ ：325.1。
EXAMPLE 15 preparation of Compound 15
Compound 15 of the present invention (i.e., compound 15) was prepared according to the following synthetic route:
Figure BDA0002292072840000201
referring to the procedure of example 1, substituting bromoethanol for 3-bromopropanol produced intermediate 7-1 (yield 51%); referring to the procedure of example 1, methyl 4-bromobutyrate was replaced with methyl 3-propionate and benzyl bromide was replaced with p-bromobenzyl bromide to prepare intermediate 15-2 (yield 45%).
Equimolar (1 mmol) of intermediate 7-1 and 15-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.21 g of compound 15 as a white powder. ESI, M 2+ ：378.6。
EXAMPLE 16 preparation of Compound 16
Compound 16 of the present invention (i.e., compound 16) was prepared according to the following synthetic route:
Figure BDA0002292072840000202
referring to the procedure of example 1, substituting bromoethanol for 3-bromopropanol produced intermediate 7-1 (yield 46%); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl 3-propionate and substituting benzyl bromide with p-fluorobenzyl bromide produced intermediate 16-2 (yield 41%).
Equimolar (1 mmol) of intermediate 7-1 and 16-2 were dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.20 g of compound 16 as a white powder. ESI, M 2+ ：341.1。
EXAMPLE 17 preparation of Compound 17
Compound 17 of the present invention (i.e., compound 17) was prepared according to the following synthetic route:
Figure BDA0002292072840000211
referring to the procedure of example 1, substituting bromoethanol for 3-bromopropanol produced intermediate 7-1 (yield 47%); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl 3-propionate and substituting benzyl bromide with p-chlorobenzyl bromide produced intermediate 16-2 (yield 53%).
Equimolar (1 mmol) of the intermediates 7-1 and 17-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure and the residue was prepared in reverse phaseChromatography gave 0.28 g of white powder, compound 17.ESI, M 2+ ：349.1。
EXAMPLE 18 preparation of Compound 18
Compound 18 of the present invention (i.e., compound 18) was prepared according to the following synthetic route:
Figure BDA0002292072840000212
referring to the procedure of example 1, substituting bromoethanol for 3-bromopropanol produced intermediate 7-1 (yield 45%); referring to the procedure of example 1, methyl 4-bromobutyrate was replaced with methyl 3-propionate and benzyl bromide was replaced with p-2, 4-difluorobenzyl bromide to prepare intermediate 18-2 (yield 43%).
Equimolar (1 mmol) of intermediate 7-1 and 18-2 were dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.25 g of compound 18 as a white powder. ESI, M 2+ ：350.1。
EXAMPLE 19 preparation of Compound 19
Compound 19 of the present invention (i.e., compound 19) was prepared according to the following synthetic route:
Figure BDA0002292072840000213
referring to the procedure of example 1, substituting bromoethanol for 3-bromopropanol and substituting p-nitrobenzyl bromide for p-chlorobenzyl bromide to afford intermediate 19-1 (yield 55%); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl 3-propionate and substituting benzyl bromide with p-nitrobenzyl bromide produced intermediate 19-2 (yield 63%).
Equimolar (1 mmol) of the intermediates 19-1 and 19-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.23 g of compound 19 as a white powder. ESI, M 2+ ：349.1。
EXAMPLE 20 preparation of Compound 20
Compound 20 of the present invention (i.e., compound 20) was prepared according to the following synthetic route:
Figure BDA0002292072840000221
referring to the procedure of example 1, substituting bromoethanol for 3-bromopropanol and substituting p-nitrobenzyl bromide for benzyl bromide produced intermediate 20-1 (39% yield); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl 3-propionate and substituting p-nitrobenzyl bromide with benzyl bromide produced intermediate 20-2 (yield 43%).
Equimolar (1 mmol) of the intermediates 20-1 and 20-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.29 g of compound 20 as a white powder. ESI, M 2+ ：287.1。
EXAMPLE 21 preparation of Compound 21
Compound 21 (i.e., compound 21) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000222
referring to the procedure of example 1, substituting bromoethanol for 3-bromopropanol produced intermediate 7-1 (yield 49%); referring to the procedure of example 1, methyl 4-bromobutyrate was replaced with methyl 3-propionate and benzyl bromide was replaced with 3, 4-dimethoxybenzyl bromide to prepare intermediate 21-2 (yield 39%).
Equimolar (1 mmol) of intermediate 7-1 and 21-2 were dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.23 g of compound 21 as a white powder. ESI, M 2+ ：362.1。
EXAMPLE 22 preparation of Compound 22
Compound 22 of the present invention (i.e., compound 22) was prepared according to the following synthetic route:
Figure BDA0002292072840000231
referring to the procedure of example 1, substituting bromoethanol for 4-bromobutanol and substituting p-nitrobenzyl bromide for 4-trifluoromethyl benzyl bromide produced intermediate 22-1 (39% yield); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl bromoacetate produced intermediate 6-2 (yield 49%).
Equimolar (1 mmol) of intermediate 22-1 and 6-2 were dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.28 g of compound 22 as a white powder. ESI, M 2+ ：343.6。
EXAMPLE 23 preparation of Compound 23
Compound 23 of the present invention (i.e., compound 23) was prepared according to the following synthetic route:
Figure BDA0002292072840000232
referring to the procedure of example 1, substituting bromoethanol for 4-bromobutanol and substituting p-nitrobenzyl bromide for p-fluorobenzyl bromide produced intermediate 23-1 (yield 35%); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl bromoacetate and substituting benzyl bromide with p-fluorobenzyl bromide produced intermediate 23-2 (yield 43%).
Equimolar (1 mmol) of the intermediates 23-1 and 23-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.31 g of compound 23 as a white powder. ESI, M 2+ ：327.6。
EXAMPLE 24 preparation of Compound 24
Compound 24 of the present invention (i.e., compound 24) was prepared according to the following synthetic route:
Figure BDA0002292072840000241
referring to the procedure of example 1, substituting bromoethanol for 4-bromobutanol and substituting p-nitrobenzyl bromide for 4-trifluoromethyl benzyl bromide produced intermediate 22-1 (yield 37%); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl bromoacetate and substituting p-nitrobenzyl bromide with 4-trifluoromethyl benzyl bromide produced intermediate 24-2 (yield 48%).
Equimolar (1 mmol) of intermediate 22-1 and 24-2 were dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.32 g of compound 24 as a white powder. ESI, M 2+ ：355.1。
EXAMPLE 25 preparation of Compound 25
Compound 25 of the present invention (i.e., compound 25) was prepared according to the following synthetic route:
Figure BDA0002292072840000242
referring to the procedure of example 1, substituting bromoethanol for 4-bromobutanol and substituting p-nitrobenzyl bromide for p-fluorobenzyl bromide produced intermediate 23-1 (39% yield); referring to the procedure of example 1, substituting methyl 4-bromobutyrate with methyl bromoacetate, substituting benzyl bromide with p-fluorobenzyl bromide, substituting benzyl bromide with p-chlorobenzyl bromide produced intermediate 25-2 (yield 53%).
Equimolar (1 mmol) of the intermediates 23-1 and 25-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.26 g of compound 25 as a white powder. ESI, M 2+ ：322.1。
EXAMPLE 26 preparation of Compound 26
Compound 26 of the present invention (i.e., compound 26) was prepared according to the following synthetic route:
Figure BDA0002292072840000251
referring to the procedure of example 1, substituting bromoethanol for 3-bromopropanol and substituting p-nitrobenzyl bromide for 4-ethoxycarbonylbenzyl bromide produced intermediate 26-1 (yield 51%); referring to the procedure of example 1, methyl 4-bromobutyrate was replaced with methyl 3-bromopropionate to prepare intermediate 7-2 (yield 43%).
Equimolar (1 mmol) of intermediate 26-1 and 7-2 were dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.26 g of compound 25 as a white powder. ESI, M 2+ ：345.6。
EXAMPLE 27 preparation of Compound 27
Compound 27 of the present invention (i.e., compound 27) was prepared according to the following synthetic route:
Figure BDA0002292072840000252
referring to the procedure of example 1, substituting bromoethanol for 3-bromopropanol and substituting p-nitrobenzyl bromide for 3, 4-dimethylbenzyl bromide produced intermediate 27-1 (yield 64%); referring to the procedure of example 1, methyl 4-bromobutyrate was replaced with methyl 3-bromopropionate to prepare intermediate 7-2 (yield 40%).
Equimolar (1 mmol) of intermediate 27-1 and 7-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.23 g of compound 27 as a white powder. ESI, M 2+ ：323.6。
EXAMPLE 28 preparation of Compound 28
Compound 28 of the present invention (i.e., compound 28) was prepared according to the following synthetic route:
Figure BDA0002292072840000253
referring to example 1, substituting bromoethanol for 4-bromobutanol and piperidine for 4-methylpiperidine produced intermediate 28-1 (44% yield); referring to the procedure of example 1, methyl 4-bromobutyrate was substituted for methyl bromoacetate to prepare intermediate 6-2 (yield 50%).
Equimolar (1 mmol) of the intermediates 28-1 and 6-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, and evaporated to dryness under reduced pressureThe residue was chromatographed on reverse phase to give 0.25 g of compound 28 as a white powder. ESI, M 2+ ：339.1。
EXAMPLE 29 preparation of Compound 29
Compound 29 of the present invention (i.e., compound 29) was prepared according to the following synthetic route:
Figure BDA0002292072840000261
referring to example 1, substituting bromoethanol for 3-bromopropanol, substituting p-nitrobenzyl bromide for p-fluorobenzyl bromide, substituting piperidine for 4, 4-difluoropiperidine gave intermediate 29-1 (34% yield); referring to the procedure of example 1, methyl 4-bromobutyrate was substituted for methyl 3-bromopropionate, benzyl bromide was substituted for p-fluorobenzyl bromide, and p-nitrobenzyl bromide was substituted for p-fluorobenzyl bromide to prepare intermediate 29-2 (yield 42%).
Equimolar (1 mmol) of intermediate 29-1 and 29-2 were dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.28 g of compound 29 as a white powder. ESI, M 2+ ：332.1。
EXAMPLE 30 preparation of Compound 30
Compound 30 of the present invention (i.e., compound 30) was prepared according to the following synthetic route:
Figure BDA0002292072840000262
referring to example 1, substituting bromoethanol for 4-bromobutanol, substituting p-nitrobenzyl bromide for p-fluorobenzyl chloride, substituting piperidine for 4, 4-difluoropiperidine produced intermediate 30-1 (29% yield); referring to the procedure of example 1, methyl 4-bromobutyrate was substituted for methyl 3-bromopropionate, benzyl bromide was substituted for p-fluorobenzyl chloride, and p-nitrobenzyl bromide was substituted for p-chlorobenzyl chloride to prepare intermediate 30-2 (yield 39%).
Equimolar (1 mmol) of the intermediates 30-2 and 30-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, and the solvent was evaporated under reduced pressureThe residue was chromatographed on reverse phase preparative chromatography to give 0.33 g of compound 30 as a white powder. ESI, M 2+ ：347.1。
EXAMPLE 31 preparation of Compound 31
Compound 31 of the present invention (i.e., compound 31) was prepared according to the following synthetic route:
Figure BDA0002292072840000271
referring to the procedure of example 1, substituting p-nitrobenzyl bromide for p-cyanobenzyl chloride produced intermediate 31-1 (59% yield); referring to the procedure of example 1, substitution of benzyl bromide for p-cyanobenzyl chloride and substitution of p-nitrobenzyl bromide for p-cyanobenzyl chloride produced intermediate 31-2 (yield 49%).
Equimolar (1 mmol) of the intermediates 31-1 and 31-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.31 g of compound 31 as a white powder. ESI, M 2+ ：324.6。
EXAMPLE 32 preparation of Compound 32
Compound 32 of the present invention (i.e., compound 32) was prepared according to the following synthetic route:
Figure BDA0002292072840000272
referring to the procedure of example 1, substituting bromoethanol for 4-bromo-2-en-butanol and substituting p-nitrobenzyl bromide for p-fluorobenzyl chloride, intermediate 32-1 was prepared (yield 59%); referring to the procedure of example 1, methyl 4-bromobutyrate was substituted for methyl 3-bromopropionate, benzyl bromide was substituted for p-fluorobenzyl chloride, and p-nitrobenzyl bromide was substituted for p-chlorobenzyl chloride to prepare intermediate 30-2 (yield 43%).
Equimolar (1 mmol) of the intermediates 32-1 and 30-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.32 g of compound 32 as a white powder. ESI, M 2+ ：328.1。
EXAMPLE 33 preparation of Compound 33
Compound 33 of the present invention (i.e., compound 33) was prepared according to the following synthetic route:
Figure BDA0002292072840000273
referring to the procedure of example 1, substituting p-nitrobenzyl bromide for p-cyanobenzyl chloride produced intermediate 31-1 (yield 41%); referring to the procedure of example 1, substitution of p-nitrobenzyl bromide for p-cyanobenzyl chloride produced intermediate 33-2 (yield 38%).
Equimolar (1 mmol) of intermediate 31-1 and 33-2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was separated by reverse phase preparative chromatography to give 0.22 g of compound 33 as a white powder. ESI, M 2+ ：312.1。
EXAMPLE 34 preparation of Compound 34
200mg of Compound 2 was dissolved in 20mL of water, 130mg of silver p-toluenesulfonate was added, stirred for 30 minutes, the precipitate was removed by filtration, and the filtrate was lyophilized to give p-toluenesulfonate of Compound 2, compound 34.
Figure BDA0002292072840000281
EXAMPLE 35 preparation of Compounds 35-50
Referring to the procedure of example 1, as in examples 2 to 33, the starting material used was replaced with a starting material containing the target molecule fragment to prepare the corresponding new intermediate 1 (yield 25 to 68%) and intermediate 2 (yield 21 to 71%), then equimolar (1 mmol) of intermediate 1 and intermediate 2 were dissolved in 10 ml of acetonitrile, stirred at 50℃for 12 hours, the solvent was evaporated under reduced pressure, and the residue was isolated by reverse phase preparative chromatography to give the target compound in 11 to 32%.
If it is desired to change anions in the target compound, this can be achieved in the usual manner by ion exchange. The structure of compounds 35-50 and mass spectrum data are shown in Table 1:
mass spectral data for compounds 35-50 of table 1
Figure BDA0002292072840000282
Figure BDA0002292072840000291
Figure BDA0002292072840000301
Figure BDA0002292072840000311
The following experiments prove the beneficial effects of the invention.
Experimental example 1 muscle relaxation experiment of the Compound of the invention
1. Experimental method
Adult male white rabbits weighing 2-3 kg are subjected to anesthesia induction by using a general Li Ma intravenous injection at a dosage of 5mg/kg, trachea cannula is implemented, a respirator supplies oxygen, and the general Li Ma maintains anesthesia at an intravenous infusion speed of 0.6 mg/kg/min. Subsequently, physiological saline solution containing a certain dose of the compound of the present invention was intravenously administered in groups, and the change in muscle strength was detected by using TOF muscle relaxation monitor, and the time required for onset (T1.ltoreq.5%) and complete recovery of muscle tone were recorded (TOF)>90%) for the time required, 6 animals per group. The compound of the invention and the control drug succinylcholine and cis-atracurium use two times of ED respectively 95 As the administered dose (specific doses are shown in table 2).
2. Experimental results
Table 1 Rabbit muscle relaxation due to each drug
Figure BDA0002292072840000312
Figure BDA0002292072840000321
The experimental results show that the compound provided by the invention has small dosage and quick response, can quickly generate muscle relaxation effect (< 1 min) in animals, and the time required for complete recovery of the muscle tension (TOF > 90%) is far shorter than that of the control drug cisatracurium and obviously shorter than that of depolarizing muscle relaxant succinylcholine. The compound, in particular the compounds 1, 2, 3, 5, 13 and 22, have remarkably better rapid onset and rapid recovery effects when the dosage of the compound is equal to or lower than that of the control muscle relaxant cis-atracurium and succinylcholine.
Furthermore, following administration of the compounds of the invention, the ratio of T1 to T4 is gradually decreased at the onset of action, rather than the equivalent ratio, in the animals tested, and the ratio of T1 to T4 is gradually restored at the recovery, the variation characteristic of TOF being characteristic of non-depolarizing muscle relaxants. Therefore, the experiment proves that the compound disclosed by the patent has the activity of non-depolarizing muscle relaxant molecules with rapid effect and ultra-short effect, and belongs to typical non-depolarizing muscle relaxants.
In summary, the invention provides the double quaternary ammonium compound shown in the formula (I), the single dosage of the double quaternary ammonium compound is small, the effect is quick, the thorough muscle relaxation effect can be provided for 2-10 minutes, the compound can realize the ultra-short effect non-depolarized muscle relaxation effect only by depending on the metabolism of the organism, and the rapid regression of the muscle relaxation effect can be still shown after the large dosage and continuous administration. Compared with the contrast agent cisatracurium and succinylcholine, the compound disclosed by the invention has the advantages of smaller dosage, quicker onset of action, shorter time required for complete recovery of muscular tension (TOF > 90%), and very good application prospect in preparing skeletal muscle relaxation drugs with quick onset of action, quick recovery and small toxic and side effects.

Claims (3)

1. A biscationic quaternary ammonium salt compound or salt thereof, characterized in that: the structure of the biscationic quaternary ammonium salt compound is selected from one of the following structures:
Figure QLYQS_1
。
2. use of a biscationic quaternary ammonium salt compound according to claim 1, or a salt thereof, in the preparation of a skeletal muscle relaxing medicament.
3. A pharmaceutical composition characterized by: the pharmaceutical composition is prepared by taking the biscationic quaternary ammonium salt compound or salt thereof according to claim 1 as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
CN201911184468.XA 2019-11-27 2019-11-27 Compound with biscationic quaternary ammonium salt structure, and preparation method and application thereof Active CN112851599B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201911184468.XA CN112851599B (en) 2019-11-27 2019-11-27 Compound with biscationic quaternary ammonium salt structure, and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201911184468.XA CN112851599B (en) 2019-11-27 2019-11-27 Compound with biscationic quaternary ammonium salt structure, and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN112851599A CN112851599A (en) 2021-05-28
CN112851599B true CN112851599B (en) 2023-06-09

Family

ID=75985868

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201911184468.XA Active CN112851599B (en) 2019-11-27 2019-11-27 Compound with biscationic quaternary ammonium salt structure, and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN112851599B (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110156665A (en) * 2018-02-11 2019-08-23 四川大学华西医院 A kind of quaternary ammonium compound and preparation method thereof and purposes

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2934538A (en) * 1954-09-03 1960-04-26 Ciba Pharm Prod Inc Bis quaternary ammonium compounds of beta amino ethyl beta'-amino-alpha-methylpropionates
US2980673A (en) * 1954-10-14 1961-04-18 Cutter Lab Bis-quaternary ammonium esters of amino-carboxylic acids and aminoalcohols
CN110776481B (en) * 2018-07-24 2023-06-16 四川大学华西医院 Biscationic compound, preparation method and application thereof
CN108727248B (en) * 2018-07-25 2021-05-25 四川大学华西医院 Biquaternary ammonium compound and preparation method and application thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110156665A (en) * 2018-02-11 2019-08-23 四川大学华西医院 A kind of quaternary ammonium compound and preparation method thereof and purposes

Also Published As

Publication number Publication date
CN112851599A (en) 2021-05-28

Similar Documents

Publication Publication Date Title
DE69830157T2 (en) SUBSTITUTED ISOCHINOLINE AS ULTRA SHORT ACTING NEUROMUSCULAR BLOCKER
CN108727248B (en) Biquaternary ammonium compound and preparation method and application thereof
DE2316881A1 (en) BIOLOGICALLY ACTIVE COMPOUNDS, THE PROCESS FOR THEIR PRODUCTION AND MEDICINAL PREPARATIONS CONTAINING THESE COMPOUNDS
EP0171728B1 (en) Tryptamine derivatives, method for their preparation and their use
CN110776481B (en) Biscationic compound, preparation method and application thereof
EP0204269B1 (en) Pyridine derivatives, their preparation and use
CN113698345B (en) Compounds as potassium channel modulators, their preparation and use
DE2362754C2 (en) Oxazoline compounds containing cyclopropylalkylamino radicals, processes for their preparation and medicaments containing these compounds
DE69411616T2 (en) Triazolopyridazine derivatives, their preparation and use
CN112939896B (en) Biquaternary ammonium compound and preparation method and application thereof
CN112851599B (en) Compound with biscationic quaternary ammonium salt structure, and preparation method and application thereof
CN116925087A (en) Diaryl tetraglycoluril carboxylate and application thereof
DE69113505T2 (en) Spiro derivatives of dibenzosuberan.
EP1317430A1 (en) (2-azabicyclo 2.2.1]hept-7-yl)methanol derivatives as nicotinic acetylcholine receptor agonists
CN112876408B (en) Short-acting bis-quaternary ammonium compound and preparation method and application thereof
DE69707080T2 (en) Pyrrolidinone derivatives and their use as antipsychotic drugs
CN111662230A (en) Benzyl isoquinoline compound, preparation method and application
CN115785094B (en) Benzyl substituted alpha-carboline compound or medicinal salt thereof, pharmaceutical composition thereof, preparation method and application thereof
CN113087686B (en) Cyano-containing biquaternary ammonium compound and preparation method and application thereof
CN115215790B (en) Cyclic quaternary ammonium salt derivative and preparation method and application thereof
CN112876373A (en) Biquaternary ammonium compound and preparation method and application thereof
DE2629877C2 (en)
DE3316155C2 (en)
Johnson et al. Synthesis of substituted 2-aminopyrrole analogs of lidocaine I
DE3907512C2 (en) Aryloxy-alkylamines, their preparation and medicaments containing them

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
EE01 Entry into force of recordation of patent licensing contract

Application publication date: 20210528

Assignee: YICHANG HUMANWELL PHARMACEUTICAL Co.,Ltd.

Assignor: WEST CHINA HOSPITAL OF SICHUAN University

Contract record no.: X2022990000253

Denomination of invention: Compound with double cation quaternary ammonium salt structure and its preparation method and Application

License type: Exclusive License

Record date: 20220610

EE01 Entry into force of recordation of patent licensing contract
GR01 Patent grant
GR01 Patent grant