CN112851599A - Compound with dication quaternary ammonium salt structure and preparation method and application thereof - Google Patents

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

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CN112851599A
CN112851599A CN201911184468.XA CN201911184468A CN112851599A CN 112851599 A CN112851599 A CN 112851599A CN 201911184468 A CN201911184468 A CN 201911184468A CN 112851599 A CN112851599 A CN 112851599A
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halogen
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杨俊�
刘进
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West China Hospital of Sichuan University
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    • 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
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
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    • 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

Abstract

The invention provides a quaternary ammonium compound, or a crystal form, a solvate, a stereoisomer, an isotope marker or a salt thereof, wherein the structure of the quaternary ammonium compound is shown as a formula (I). Experiments prove that the compound has quick response after single administration, can provide thorough muscle relaxation effect for 2-10 minutes, can realize ultra-short-effect non-depolarizing muscle relaxation effect only by depending on the metabolism of an organism, and still shows quick regression of the muscle relaxation effect after large-dose and continuous administration. Compared with the control muscle relaxant namely cisatracurium and succinylcholine, the compound of the invention has the advantages of smaller dosage, faster effect and complete muscle tension recovery (TOF)>90 percent), and has very good application prospect in preparing skeletal muscle relaxation medicaments with quick response, quick recovery and small toxic and side effects.

Description

Compound with dication quaternary ammonium salt structure and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a compound with a dication quaternary ammonium salt structure, a preparation method thereof and application of the compound as a skeletal muscle relaxation medicine.
Background
The N2 choline receptor blocker is also called skeletal muscle relaxant (abbreviated as muscle relaxant), and is an important anesthetic drug for surgical operations. The muscle relaxant can selectively act on N2 receptors on the motor nerve terminal plate membrane, block nerve impulses from being transmitted to skeletal muscles, and cause the skeletal muscles to relax, and is mainly used for generating muscle relaxation during surgical operations and tracheal intubation. Muscle relaxants are divided into two major classes, i.e., depolarized (depolarizing) and non-depolarized (depolarizing) classes, according to their mechanisms of action. Muscle relaxants can be classified into ultra-short, intermediate and long-acting ones according to their duration of action (Anesthesiology,82(1),33a, 1995).
Depolarizing muscle relaxants bind to N2 receptors on the motor endplate membrane, causing a persistent depolarization of the muscle cell membrane, and a diminished or abolished response to ACh, resulting in skeletal muscle relaxation. Currently, succinylcholine (also known as scoline) is a depolarizing muscle relaxant in clinical use. After the application of the succinylcholine, because the time for depolarization of skeletal muscles at different parts under the action of the medicament is different, uncoordinated fasciculation firstly occurs, and then the fasciculation is rapidly converted into muscle relaxation, so that the muscle relaxation of neck, limbs and abdomen is most obvious, and the effect is fast and transient. The utility model can be used for short-time minor operations such as tracheal intubation, bronchoscope, esophagoscope, etc., and can also be used as auxiliary medicine in general anesthesia operation, so that skeletal muscle under shallow anesthesia is completely relaxed, the dosage of general anesthesia medicine is reduced, and the safety of surgical operation is improved. The succinylcholine has quick response and short action time, and the human body duration is about 10 minutes, so the succinylcholine is often used as an ultrashort-acting muscle relaxant in clinic and is particularly suitable for emergency patients, thereby avoiding serious brain injury and even death caused by the use of the muscle relaxant with longer action time under the emergency condition. Therefore, the currently depolarizing muscle relaxant, succincholine, is the most suitable muscle relaxant for emergency treatment. But due to the special action mechanism of depolarizing muscle relaxants, serious side effects such as elevated blood potassium, nausea, high fever, arrhythmia, increased intraocular pressure and gastric stress are generated when using them, thus greatly limiting their clinical application.
The non-depolarizing muscle relaxants, also called competitive muscle relaxants (competitive muscle relaxants), compete with ACh for N2 choline receptors on the skeletal muscle motor terminal plate membrane, and are not inherently active, but can block ACh from binding to N2 choline receptors, so that the terminal plate membrane cannot depolarize, resulting in skeletal muscle relaxation. The non-depolarizing muscle relaxant has no side effects of the depolarizing muscle relaxant, so it is recognized as a clinically safer muscle relaxant, but its long action time is also considered as a major disadvantage. Anticholinesterase drugs such as neostigmine antagonize skeletal muscle relaxation of non-depolarizing muscle relaxants, and neostigmine can be used in appropriate amounts for rescue when an excess of non-depolarizing muscle relaxants is used. CN101588803A also discloses a non-depolarizing muscle relaxant, which can be rapidly reversed by administering 200 times cysteine, and although the muscle relaxant is achieved, it must be achieved by using a large amount of sulfhydryl amino acid (e.g. cysteine), which obviously increases the medical procedure, and also increases the uncertainty of safety, such as excessive cysteine causing tracheal spasm, vomiting, etc.
All non-depolarizing muscle relaxants currently on the market, which have skeletal muscle relaxation duration of more than 10 minutes after single administration, cannot meet the clinical requirement for rapid recovery. For example: in clinical muscle relaxants on the market, the duration of muscle relaxation after single administration of microcuronium chloride is about 15-20 minutes, the duration of muscle relaxation after single use of cisatracurium and rocuronium bromide is about 40-60 minutes, and the duration of muscle relaxation after single use of pancuronium bromide even exceeds 60 minutes, so that rapid recovery of muscle relaxation cannot be realized.
Therefore, the prior art needs no reversal agent clinically, and has the advantages of small dosage, quick response, quick recovery and small toxic and side effects.
Disclosure of Invention
In view of the problems in the prior art, the present invention aims to provide a compound with a dicationic quaternary ammonium salt structure, a preparation method thereof and an application thereof as a skeletal muscle relaxation drug.
The invention provides a dication quaternary ammonium salt compound, or a stereoisomer, a solvate, a salt, a crystal form or an isotope label thereof, wherein the structure of the dication quaternary ammonium salt compound is shown as the formula (I):
Figure BDA0002292072840000021
wherein:
R1，R2，R3，R4each independently selected from substituted or unsubstituted, saturated or unsaturated C1～20A hydrocarbon radical, or C1～20A group in which a skeleton atom in the hydrocarbon group is replaced with a hetero atom; said C is1～20The substituents on the hydrocarbon radical are selected from the group consisting of nitro, cyano, hydroxy, halogenated or non-halogenated alkyl, halogenated or non-halogenated alkoxy, halogen, aryl, heteroaryl, -OCOR9、-COR9、-COOR9，R9Is selected from C1～8An alkyl group;
R5selected from H, C1～6Alkyl, hydroxy, halogen, cycloalkyl;
m1selected from substituted or unsubstituted C1～8Alkylene, or C1～81 to 3-CH in the alkylene skeleton of (A)2-substituted by heteroatoms, vinyl or cycloalkyl; said C is1～8The substituents on the alkylene group of (a) are selected from C1～6Alkyl radical, C1～6Alkoxy, cycloalkyl, hydroxy, halogen;
m2selected from substituted or unsubstituted C1～8Alkylene, or C1～81 to 3-CH in the alkylene skeleton of (A)2-substituted by heteroatoms, vinyl or cycloalkyl; said C is1～8The substituents on the alkylene group of (a) are selected from C1～6Alkyl radical, C1～6Alkoxy, cycloalkyl, hydroxy, halogen;
e is O, S or CR7R8，R7、R8Each independently selected from H, halogen, C1～6An alkyl group;
n is 1 or 2;
g is selected from O or NR6Wherein R is6Is H, C1～6Alkyl, cycloalkyl;
a is O or S; b is O or S;
p is 0 or 1; q is 0 or 1; h is 0 or 1;
Z1、Z2each independently selected from anions.
Further, the air conditioner is provided with a fan,
R1，R2，R3，R4each independently selected from C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, alkynyl,
Figure BDA0002292072840000031
Wherein a is an integer of 0-2, R10Selected from the following substituted or unsubstituted groups: aryl, heteroaryl, benzoheterocyclyl, saturated cycloalkyl, saturated heterocyclyl, said R10The substituent on (A) is selected from nitro, cyano, hydroxy, halogenated or non-halogenated C1-4Alkyl, halogenated or non-halogenated C1-4Alkoxy, halogen, -OCOR9、-COR9、-COOR9，R9Is selected from C1～4An alkyl group;
R5selected from H, C1～4Alkyl, hydroxy, halogen, cycloalkyl;
m1selected from substituted or unsubstituted C1～6Alkylene, or C1～61 to 2-CH in the alkylene skeleton of (A)2-substituted by heteroatoms, vinyl or cycloalkyl; said C is1～6The substituents on the alkylene group of (a) are selected from C1～4Alkyl radical, C1～4Alkoxy, cycloalkyl, hydroxy, halogen;
m2selected from substituted or unsubstituted C1～6Alkylene, or C1～61 to 2-CH in the alkylene skeleton of (A)2-substituted by heteroatoms, vinyl or cycloalkyl; said C is1～6The substituents on the alkylene group of (a) are selected from C1～4Alkyl radical, C1～4Alkoxy, cycloalkyl, hydroxy, halogen;
e is O, S or CR7R8，R7、R8Each independently selected from H, halogen, C1～4An alkyl group;
n is 1 or 2;
g is selected from O or NR6Wherein R is6Is H or C1～4An alkyl group;
a is O; b is O;
p is 0 or 1; q is 0 or 1; h is 0 or 1;
Z1、Z2each independently selected from anions.
Further, the air conditioner is provided with a fan,
the structure of the dicationic quaternary ammonium salt compound is shown as the formula (II):
Figure BDA0002292072840000041
wherein R is1Is selected from C1-4Alkyl radical, C2-4An alkenyl group,
Figure BDA0002292072840000042
R10，R11Each independently selected from phenyl, heteroaryl, benzoheterocyclyl substituted with 0-3 substituents; each of said substituents being independently selected from nitro, cyano, hydroxy, halogenated or non-halogenated C1-3Alkyl, halogenated or non-halogenated C1-3Alkoxy, halogen, -OCOR9、-COR9、-COOR9，R9Is C1～3An alkyl group;
preferably, the heteroaryl is
Figure BDA0002292072840000043
Said benzoheterocyclyl is
Figure BDA0002292072840000044
b is an integer of 0 to 3, R12Selected from nitro, cyano, hydroxy, halogenated or non-halogenated C1-3Alkyl, halogenated or non-halogenated C1-3Alkoxy, halogen, -OCOR9、-COR9、-COOR9，R9Is C1～3An alkyl group;
R5selected from H, C1～4Alkyl, hydroxy, halogen;
m1selected from substituted or unsubstituted C1～6Alkylene, or C1～61 to 2-CH in the alkylene skeleton of (A)2-substituted by a heteroatom selected from O or S, vinyl or cycloalkyl, said cycloalkyl being a 3-membered cycloalkyl; said C is1～6The substituents on the alkylene group of (a) are selected from C1～3Alkyl, hydroxy, halogen;
m2selected from substituted or unsubstituted C1～6Alkylene, or C1～61 to 2-CH in the alkylene skeleton of (A)2-a group substituted by a heteroatom selected from O or S; said C is1～6The substituents on the alkylene group of (a) are selected from C1～3Alkyl, hydroxy, halogen;
e isO, S or CR7R8，R7、R8Each independently selected from H, halogen, C1～3An alkyl group;
n is 1 or 2;
g is selected from O or NR6Wherein R is6Is H or C1～3An alkyl group;
p is 0 or 1; q is 0 or 1; h is 0 or 1;
Z1、Z2each independently selected from anions.
Further, the air conditioner is provided with a fan,
the structure of the dicationic quaternary ammonium salt compound is shown as the formula (III):
Figure BDA0002292072840000051
wherein R is1Is selected from C1-4Alkyl radical, C2-4An alkenyl group,
Figure BDA0002292072840000052
b. c and d are each independently an integer of 0 to 2, R12、R13、R14Each independently selected from nitro, cyano, hydroxy, halogenated or non-halogenated C1-3Alkyl, halogenated or non-halogenated C1-3Alkoxy, halogen, -OCOR9、-COR9、-COOR9，R9Is C1～3An alkyl group;
R5selected from H, C1～4Alkyl, hydroxy, halogen;
m1selected from substituted or unsubstituted C1～5Alkylene radical of the formula C1～5The substituents on the alkylene group of (a) are selected from C1～3Alkyl, hydroxy, halogen;
m2selected from substituted or unsubstituted C1～5Alkylene, or C1～51 to 2-CH in the alkylene skeleton of (A)2-a group substituted by a heteroatom selected from O or S; said C is1～5The substituents on the alkylene group of (a) are selected from C1～3Alkyl, hydroxy, halogen;
e is CR7R8，R7、R8Each independently selected from H, halogen, C1～3An alkyl group;
n is 1 or 2;
Z1、Z2each independently selected from pharmaceutically acceptable anions.
Further, the air conditioner is provided with a fan,
the structure of the dicationic quaternary ammonium salt compound is shown as a formula (IV):
Figure BDA0002292072840000061
wherein R is1Is selected from C1-4Alkyl radical, C2-4An alkenyl group,
Figure BDA0002292072840000062
R12、R13、R14Each independently selected from nitro, cyano, hydroxy, halogenated or non-halogenated C1-3Alkyl, halogenated or non-halogenated C1-3Alkoxy, halogen, -OCOR9、-COR9、-COOR9，R9Is C1～3An alkyl group;
R5selected from H, C1～4Alkyl, hydroxy, halogen;
m1selected from substituted or unsubstituted C1～5Alkylene radical of the formula C1～5The substituents on the alkylene group of (a) are selected from C1～3Alkyl, hydroxy, halogen;
m2selected from substituted or unsubstituted C1～5Alkylene, or C1～51 to 2-CH in the alkylene skeleton of (A)2-a group substituted by a heteroatom selected from O or S; said C is1～5The substituents on the alkylene group of (a) are selected from C1～3Alkyl, hydroxy, halogen;
e is CR7R8，R7、R8Each independently selected from H,Halogen, C1～3An alkyl group;
Z1、Z2each independently selected from bromide, chloride, acetate, sulfate, citrate, sulfonate.
Further, the air conditioner is provided with a fan,
R1is methyl;
R12、R13、R14each independently selected from nitro, methyl, halogen, halomethyl;
R5selected from H or methyl;
m1selected from substituted or unsubstituted C1～5Alkylene radical of the formula C1～5The substituents on the alkylene group of (a) are selected from methyl, halogen;
m2selected from substituted or unsubstituted C1～5Alkylene, or C1～51 to 2-CH in the alkylene skeleton of (A)2-a group substituted by a heteroatom selected from O or S; said C is1～5The substituents on the alkylene group of (a) are selected from methyl, halogen;
e is CR7R8，R7、R8Each independently selected from H, halogen, C1～2An alkyl group.
Further, the air conditioner is provided with a fan,
the halogen is selected from F, Cl or Br; the halomethyl group is selected from CF3。
Further, the air conditioner is provided with a fan,
the dicationic quaternary ammonium salt compound has a structure selected from one of the following structures:
Figure BDA0002292072840000071
Figure BDA0002292072840000081
Figure BDA0002292072840000091
Figure BDA0002292072840000101
Figure BDA0002292072840000111
the invention also provides application of the dicationic quaternary ammonium salt compound, or a stereoisomer, a solvate, a salt, a crystal form or an isotope marker of the dicationic quaternary ammonium salt compound in preparation of skeletal muscle relaxation medicines.
The invention also provides a pharmaceutical composition, which is prepared by taking the dicationic quaternary ammonium salt compound, or the stereoisomer, or the solvate, or the salt, or the crystal form, or the isotope marker thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
In the present invention, "stereoisomer" refers to an isomer produced by spatially different arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers and conformational isomers.
"solvates" refers to compounds of the invention or salts thereof, which also include stoichiometric or non-stoichiometric amounts of solvents bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.
“C1～20The hydrocarbyl group refers to all groups containing 1-20 carbon atoms and only containing two atoms of carbon and hydrogen; "C1～20The "group obtained by replacing a skeleton atom in a hydrocarbon group with a hetero atom" means C1～20A group obtained by substituting 1 or two or more skeleton atoms in the hydrocarbon group with a group containing a hetero atom such as O, S, N.
“C1～81 to 3-CH in the alkylene skeleton of (A)2The radical "substituted by a heteroatom, vinyl or cycloalkyl" means C1～81 to 3-CH in the alkylene skeleton of (A)2Independently of one another by a heteroatom group such as S, O, NH, orVinyl, or cycloalkyl.
An "isotopic label" is a compound in which one or more atoms in the compound have been replaced by their corresponding isotopes, for example, hydrogen in the compound has been replaced by protium, deuterium or tritium.
The compound of the formula (I) has quick response after single administration, can provide thorough muscle relaxation effect for 2-10 minutes, can realize ultra-short-acting non-depolarized muscle relaxation effect only by relying on the metabolism of an organism, and still shows the quick regression of the muscle relaxation effect after large-dose and continuous administration. Compared with contrast muscle relaxants such as cisatracurium and succincholine, the compound disclosed by the invention is smaller in dosage, faster in effect, shorter in time required for complete recovery of muscle tension (TOF > 90%), and has a very good application prospect in preparation of skeletal muscle relaxants which are fast in effect, fast in recovery and small in toxic and side effects.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the invention are 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 comprises the steps of firstly preparing a quaternary ammonium salt molecule at one end of a target compound, then synthesizing a quaternary ammonium salt molecule at the other end, and then coupling the two quaternary ammonium salt molecules through the linker to prepare the target compound.
The following are specific preparation examples 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
dissolving 1.25 g of bromoethanol in 30 ml of acetonitrile, adding 0.85 g of piperidine and 1.38 g of anhydrous potassium carbonate, stirring at 50 ℃ for 10 hours, then adding 2.16 g of p-nitrobenzyl bromide, stirring at 55 ℃ for 6 hours, filtering, and evaporating the solvent to dryness under reduced pressure to obtain 3.5 g of yellow solid. 1.6 g of a 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 with cooling in 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.
Dissolving 1.21 g of N-methylbenzylamine and 1.8 g of methyl 4-bromobutyrate in 30 ml of acetonitrile, adding 1.4 g of anhydrous potassium carbonate, stirring at 55 ℃ for 8 hours, then adding 2.16 g of p-nitrobenzyl bromide, stirring at 55 ℃ for 6 hours, filtering, evaporating the solvent under reduced pressure, adding 40 ml of 2N aqueous sodium hydroxide solution to the residue, stirring at room temperature for 2 hours, adjusting the pH value to 9 with aqueous hydrobromic acid, evaporating the solvent under reduced pressure, adding 50 ml of dichloromethane to the residue, heating to a slight boiling point, filtering while hot, and evaporating the filtrate to dryness to obtain 1.68 g of bright yellow intermediate 1-2.
0.98 g of intermediate 1-1 and 1.05 g of intermediate 1-2 are dissolved in 50 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.39 g of white powder, namely compound 1, with a yield of 21.1%.
1HNMR(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,M2+: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; intermediate 2-2 was prepared by substituting benzyl bromide for p-nitrobenzyl bromide according to the procedure of example 1 (yield 56%). In the intermediate preparation process, the molar ratio, solvent amount and reaction conditions of the reagents were the same as in example 1, and the following were the same.
0.43 g of intermediate 1-1 and 0.49 g of intermediate 2-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.21 g of white powder, namely compound 2, with a yield of 24.1%.
1HNMR(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,M2+:354.6
EXAMPLE 3 preparation of Compound 3
Compound 3 (i.e., compound 3) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000151
intermediate 1-1 was prepared by the method of reference example 1; intermediate 3-2 was prepared by substituting benzyl bromide for p-fluorobenzyl bromide according to the procedure of example 1 (yield 46%). 0.43 g of intermediate 1-1 and 0.46 g of intermediate 3-2 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 white powder, compound 3, in 27.4% yield.
1HNMR(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,M2+: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; intermediate 4-2 was prepared by substituting benzyl bromide for p-cyanobenzyl bromide according to the procedure of example 1 (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 at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.20 g of white powder, i.e. compound 4, with a yield of 23.5%.
1HNMR(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,M2+: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; intermediate 5-2 was prepared by substituting benzyl bromide for p-chlorobenzyl bromide according to the procedure of example 1 (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 at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.25 g of white powder, i.e. compound 5, with a yield of 29.1%.
1HNMR(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,M2+:344.6
EXAMPLE 5 preparation of Compound 6
Compound 6 (i.e., compound 6) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000162
intermediate 6-1 was prepared by substituting bromoethanol for 4-bromobutanol with reference to the procedure of example 1 (yield 43%); intermediate 6-2 was prepared by substituting methyl 4-bromobutyrate for methyl bromoacetate according to the procedure of example 1 (yield 58%).
Equimolar (1mmol) of the intermediates 6-1 and 6-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 15 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.21 g of white powder, i.e. the compound 6. ESI, M2+：332.1。
EXAMPLE 7 preparation of Compound 7
Compound 7 (i.e., compound 7) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000171
intermediate 7-1 was prepared by substituting bromoethanol for 3-bromopropanol with reference to the procedure of example 1 (yield 53%); intermediate 7-2 was prepared by substituting methyl 4-bromobutyrate for methyl 3-bromopropionate according to the procedure of example 1 (yield 53%).
Equimolar (1mmol) of the intermediates 7-1 and 7-2 were dissolved in 10 ml 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 white powder, compound 7. ESI, M2+：332.1。
Preparation of the Compound of example 8
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, intermediate 8-1 was prepared by substituting bromoethanol for 3-bromopropanol and chloromethyl chloroformate for chloroethyl chloroformate (yield 39%); intermediate 7-2 was prepared by substituting methyl 4-bromobutyrate for methyl 3-bromopropionate according to the procedure of example 1 (yield 52%).
Equimolar (1mmol) of the intermediates 8-1 and 7-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.28 g of white powder, i.e. the compound 8. ESI, M2+：339.1。
EXAMPLE 9 preparation of Compound 9
Compound 9 (i.e., compound 9) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000173
intermediate 9-1 was prepared by substituting bromoethanol for 2-methyl-4-bromobutanol according to the procedure of example 1 (yield 49%); intermediate 6-2 was prepared by substituting methyl 4-bromobutyrate for methyl bromoacetate according to the procedure of example 1 (yield 42%).
Equimolar (1mmol) of the intermediates 9-1 and 4-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.23 g of white powder, i.e. the compound 9. ESI, M2+：339.1。
EXAMPLE 10 preparation of Compound 10
Compound 10 (i.e., compound 10) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000181
intermediate 10-1 was prepared (yield 45%) by substituting bromoethanol for 1-methyl-4-bromobutanol with reference to the procedure of example 1; intermediate 6-2 was prepared by substituting methyl 4-bromobutyrate for methyl bromoacetate according to the procedure of example 1 (yield 42%).
Equimolar (1mmol) of the intermediates 10-1 and 6-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.22 g of white powder, i.e. the compound 10. ESI, M2+：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
intermediate 11-1 was prepared (35% yield) by substituting bromoethanol for 2- (2-bromoethoxy) -ethanol with reference to the procedure of example 1; intermediate 6-2 was prepared by substituting methyl 4-bromobutyrate for methyl bromoacetate according to the procedure of example 1 (yield 41%).
Equimolar (1mmol) of the intermediates 11-1 and 6-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to give 0.27 g of white powder, compound 11. ESI, M2+：340.1。
EXAMPLE 12 preparation of Compound 12
Compound 12 (i.e., compound 12) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000191
intermediate 12-1 was prepared by substituting bromoethanol for 2- (2-bromoethylthio) -ethanol according to the procedure of example 1 (yield 33%); intermediate 6-2 was prepared by substituting methyl 4-bromobutyrate for methyl bromoacetate according to the procedure of example 1 (yield 41%).
Equimolar (1mmol) of the intermediates 12-1 and 6-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.31 g of white powder, i.e. the compound 12. ESI, M2+：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
intermediate 7-1 was prepared by substituting bromoethanol for 3-bromopropanol with reference to the procedure of example 1 (yield 51%); intermediate 13-2 was prepared by substituting methyl 4-bromobutyrate with methyl 2- (2-bromoethyloxy) -acetate according to the procedure of example 1 (yield 33%).
Equimolar (1mmol) of the intermediates 7-1 and 13-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.29 g of white powder, i.e. the compound 13. ESI, M2+：347.1。
EXAMPLE 14 preparation of Compound 14
Compound 14 (i.e., compound 14) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000193
referring to example 1, intermediate 1-1 was prepared (56% yield); intermediate 7-2 was prepared by substituting methyl 4-bromobutyrate for methyl 3-bromopropionate according to the procedure of example 1 (yield 50%).
Equimolar (1mmol) of the intermediates 1-1 and 7-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to give 0.22 g of white powder, i.e. compound 14. ESI, M2+：325.1。
EXAMPLE 15 preparation of Compound 15
Compound 15 (i.e., compound 15) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000201
intermediate 7-1 was prepared by substituting bromoethanol for 3-bromopropanol with reference to the procedure of example 1 (yield 51%); intermediate 15-2 was prepared (yield 45%) by substituting methyl 4-bromobutyrate for methyl 3-propionate and benzyl bromide for p-bromobenzyl bromide, according to the procedure of example 1.
Equimolar (1mmol) of the intermediates 7-1 and 15-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to give 0.21 g of white powder, compound 15. ESI, M2+：378.6。
EXAMPLE 16 preparation of Compound 16
Compound 16 (i.e., compound 16) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000202
intermediate 7-1 was prepared by substituting bromoethanol for 3-bromopropanol with reference to the procedure of example 1 (yield 46%); intermediate 16-2 was prepared by substituting methyl 4-bromobutyrate with methyl 3-propionate and benzyl bromide with p-fluorobenzyl bromide according to the procedure of example 1 (yield 41%).
Equimolar (1mmol) of the intermediates 7-1 and 16-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.20 g of white powder, i.e. compound 16. ESI, M2+：341.1。
EXAMPLE 17 preparation of Compound 17
Compound 17 (i.e., compound 17) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000211
intermediate 7-1 was prepared by substituting bromoethanol for 3-bromopropanol with reference to the procedure of example 1 (yield 47%); intermediate 16-2 was prepared by substituting methyl 4-bromobutyrate with methyl 3-propionate and benzyl bromide with p-chlorobenzyl bromide according to the procedure of example 1 (yield 53%).
Equimolar (1mmol) of the intermediates 7-1 and 17-2 were dissolved in 10 ml 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 white powder, compound 17. ESI, M2+：349.1。
EXAMPLE 18 preparation of Compound 18
Compound 18 (i.e., compound 18) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000212
intermediate 7-1 was prepared by substituting bromoethanol for 3-bromopropanol with reference to the procedure of example 1 (yield 45%); intermediate 18-2 was prepared (43% yield) by substituting methyl 4-bromobutyrate for methyl 3-propionate and benzyl bromide for p-2, 4-difluorobenzyl bromide, according to the procedure of example 1.
Equimolar (1mmol) of the intermediates 7-1 and 18-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to give 0.25 g of white powder, i.e. compound 18. ESI, M2+：350.1。
EXAMPLE 19 preparation of Compound 19
Compound 19 (i.e., compound 19) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000213
intermediate 19-1 was prepared (55% yield) by substituting bromoethanol for 3-bromopropanol and p-nitrobenzyl bromide for p-chlorobenzyl bromide, according to the procedure of example 1; intermediate 19-2 was prepared by substituting methyl 4-bromobutyrate for methyl 3-propionate and benzyl bromide for p-nitrobenzyl bromide, according to the procedure of example 1 (yield 63%).
Equimolar (1mmol) of the intermediates 19-1 and 19-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to give 0.23 g of white powder, compound 19. ESI, M2+：349.1。
EXAMPLE 20 preparation of Compound 20
Compound 20 (i.e., compound 20) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000221
intermediate 20-1 was prepared by substituting bromoethanol for 3-bromopropanol and p-nitrobenzyl bromide for benzyl bromide, according to the procedure of example 1 (yield 39%); intermediate 20-2 was prepared by substituting methyl 4-bromobutyrate for methyl 3-propionate and p-nitrobenzyl bromide for benzyl bromide according to the procedure of example 1 (yield 43%).
Equimolar (1mmol) of the intermediates 20-1 and 20-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.29 g of white powder, i.e. the compound 20. ESI, M2+：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
intermediate 7-1 was prepared by substituting bromoethanol for 3-bromopropanol with reference to the procedure of example 1 (yield 49%); intermediate 21-2 was prepared by substituting methyl 4-bromobutyrate for methyl 3-propionate and benzyl bromide for 3, 4-dimethoxybenzyl bromide, according to the procedure of example 1 (yield 39%).
Equimolar (1mmol) of the intermediates 7-1 and 21-2 were dissolved in 10 ml 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 white powder, compound 21. ESI, M2+：362.1。
EXAMPLE 22 preparation of Compound 22
Compound 22 (i.e., compound 22) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000231
intermediate 22-1 was prepared by substituting bromoethanol for 4-bromobutanol and p-nitrobenzyl bromide for 4-trifluoromethylbenzyl bromide, according to the procedure of example 1 (yield 39%); intermediate 6-2 was prepared by substituting methyl 4-bromobutyrate for methyl bromoacetate according to the procedure of example 1 (yield 49%).
Equimolar (1mmol) of the intermediates 22-1 and 6-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to give 0.28 g of white powder, compound 22. ESI, M2+：343.6。
EXAMPLE 23 preparation of Compound 23
Compound 23 (i.e., compound 23) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000232
preparation of intermediate 23-1 (yield 35%) by substituting bromoethanol for 4-bromobutanol and p-nitrobenzyl bromide for p-fluorobenzyl bromide with reference to the procedure of example 1; intermediate 23-2 was prepared by substituting methyl 4-bromobutyrate with methyl bromoacetate and benzyl bromide with p-fluorobenzyl bromide according to the procedure of example 1 (yield 43%).
Equimolar (1mmol) 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 white powder, compound 23. ESI, M2+：327.6。
EXAMPLE 24 preparation of Compound 24
Compound 24 (i.e., compound 24) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000241
intermediate 22-1 was prepared by substituting bromoethanol for 4-bromobutanol and p-nitrobenzyl bromide for 4-trifluoromethylbenzyl bromide according to the procedure of example 1 (yield 37%); intermediate 24-2 was prepared in 48% yield by substituting methyl 4-bromobutyrate with methyl bromoacetate and p-nitrobenzyl bromide with 4-trifluoromethylbenzyl bromide according to the procedure of example 1.
Equimolar (1mmol) of the intermediates 22-1 and 24-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.32 g of white powder, i.e. the compound 24. ESI, M2+：355.1。
EXAMPLE 25 preparation of Compound 25
Compound 25 (i.e., compound 25) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000242
intermediate 23-1 was prepared by substituting bromoethanol for 4-bromobutanol and p-nitrobenzyl bromide for p-fluorobenzyl bromide with reference to the procedure of example 1 (yield 39%); intermediate 25-2 was prepared (yield 53%) by substituting methyl 4-bromobutyrate with methyl bromoacetate, benzyl bromide with p-fluorobenzyl bromide and benzyl bromide with p-chlorobenzyl bromide according to the procedure of example 1.
Equimolar (1mmol) of the intermediates 23-1 and 25-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to give 0.26 g of white powder, compound 25. ESI, M2+：322.1。
EXAMPLE 26 preparation of Compound 26
Compound 26 (i.e., compound 26) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000251
intermediate 26-1 was prepared by substituting bromoethanol for 3-bromopropanol and p-nitrobenzyl bromide for 4-ethoxycarbonylbenzyl bromide, according to the procedure of example 1 (yield 51%); intermediate 7-2 was prepared by substituting methyl 4-bromobutyrate for methyl 3-bromopropionate according to the procedure of example 1 (yield 43%).
Equimolar (1mmol) of the intermediates 26-1 and 7-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to give 0.26 g of white powder, compound 25. ESI, M2+：345.6。
EXAMPLE 27 preparation of Compound 27
Compound 27 (i.e., compound 27) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000252
intermediate 27-1 was prepared by substituting bromoethanol for 3-bromopropanol and p-nitrobenzyl bromide for 3, 4-dimethylbenzyl bromide, according to the procedure of example 1 (yield 64%); intermediate 7-2 was prepared by substituting methyl 4-bromobutyrate for methyl 3-bromopropionate according to the procedure of example 1 (yield 40%).
Equimolar (1mmol) of intermediates 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 white powder, compound 27. ESI, M2+：323.6。
EXAMPLE 28 preparation of Compound 28
Compound 28 (i.e., compound 28) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000253
intermediate 28-1 was prepared by substituting bromoethanol for 4-bromobutanol and piperidine for 4-methylpiperidine according to the procedure of example 1 (yield 44%); referring to the procedure of example 1, intermediate 6-2 was prepared by substituting methyl bromoacetate with methyl 4-bromobutyrate (yield 50%).
Equimolar (1mmol) of intermediates 28-1 and 6-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to give 0.25 g of white powder, compound 28. ESI, M2+：339.1。
EXAMPLE 29 preparation of Compound 29
Compound 29 (i.e., compound 29) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000261
intermediate 29-1 was prepared (34% yield) by substituting bromoethanol for 3-bromopropanol, p-nitrobenzyl bromide for p-fluorobenzyl bromide, and piperidine for 4, 4-difluoropiperidine according to the procedure of example 1; intermediate 29-2 was prepared by substituting methyl 4-bromobutyrate for methyl 3-bromopropionate, benzyl bromide for p-fluorobenzyl bromide and p-nitrobenzyl bromide for p-fluorobenzyl bromide according to the procedure of example 1 (yield 42%).
Equimolar (1mmol) amounts of intermediates 29-1 and 29-2 were dissolved in 10 ml of acetonitrile and stirred at 50 ℃After 12 hours, the solvent was evaporated under reduced pressure and the residue was subjected to reverse phase preparative chromatography to give 0.28 g of a white powder, compound 29. ESI, M2+：332.1。
EXAMPLE 30 preparation of Compound 30
Compound 30 (i.e., compound 30) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000262
intermediate 30-1 was prepared by substituting bromoethanol for 4-bromobutanol, p-nitrobenzyl bromide for p-fluorobenzyl chloride and piperidine for 4, 4-difluoropiperidine according to the procedure of example 1 (yield 29%); intermediate 30-2 was prepared by substituting methyl 4-bromobutyrate for methyl 3-bromopropionate, benzyl bromide for p-fluorobenzyl chloride and p-nitrobenzyl bromide for p-chlorobenzyl chloride according to the procedure of example 1 (yield 39%).
Equimolar (1mmol) of the intermediates 30-2 and 30-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.33 g of white powder, namely the compound 30. ESI, M2+：347.1。
EXAMPLE 31 preparation of Compound 31
Compound 31 (i.e., compound 31) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000271
intermediate 31-1 was prepared by substituting p-nitrobenzyl bromide for p-cyanobenzyl chloride according to the procedure of example 1 (yield 59%); intermediate 31-2 was prepared by substituting benzyl bromide for para-cyanobenzyl chloride and para-nitrobenzyl bromide for para-cyanobenzyl chloride according to the procedure of example 1 (yield 49%).
Dissolving equimolar (1mmol) intermediate 31-1 and 31-2 in 10 ml acetonitrile, stirring at 50 deg.C for 12 hr, evaporating solvent under reduced pressure, and separating residue by reversed phase preparative chromatography to obtain white powder 0.31 g, i.e. compound31。ESI，M2+：324.6。
EXAMPLE 32 preparation of Compound 32
Compound 32 (i.e., compound 32) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000272
intermediate 32-1 was prepared (59% yield) by substituting bromoethanol for 4-bromo-2-ene-butanol and p-nitrobenzyl bromide for p-fluorobenzyl chloride with reference to the procedure of example 1; intermediate 30-2 was prepared (43% yield) by substituting methyl 4-bromobutyrate for methyl 3-bromopropionate, benzyl bromide for p-fluorobenzyl chloride and p-nitrobenzyl bromide for p-chlorobenzyl chloride according to the procedure of example 1.
Equimolar (1mmol) of the intermediates 32-1 and 30-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to obtain 0.32 g of white powder, i.e. the compound 32. ESI, M2+：328.1。
EXAMPLE 33 preparation of Compound 33
Compound 33 (i.e., compound 33) of the present invention was prepared according to the following synthetic route:
Figure BDA0002292072840000273
intermediate 31-1 was prepared by substituting p-nitrobenzyl bromide for p-cyanobenzyl chloride according to the procedure of example 1 (yield 41%); intermediate 33-2 was prepared by substituting p-nitrobenzyl bromide for p-cyanobenzyl chloride according to the procedure of example 1 (yield 38%).
Equimolar (1mmol) of the intermediates 31-1 and 33-2 are dissolved in 10 ml of acetonitrile, stirred at 50 ℃ for 12 hours, the solvent is evaporated under reduced pressure, and the residue is separated by reverse phase preparative chromatography to give 0.22 g of white powder, compound 33. ESI, M2+：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, the mixture was stirred for 30 minutes, the precipitate was removed by filtration, and the filtrate was lyophilized to give compound 2 as p-toluenesulfonate, Compound 34.
Figure BDA0002292072840000281
EXAMPLE 35 preparation of Compounds 35-50
Referring to the method of example 1, the corresponding new intermediate 1 (yield 25-68%) and intermediate 2 (yield 21-71%) were prepared by replacing the starting reagents used with the starting reagents containing the target molecular fragment as in examples 2-33, then equimolar (1mmol) amounts 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 separated by reverse phase preparative chromatography to give the target compound in 11-32% yield.
If it is desired to shift the anion in the target compound, this can be achieved using the usual means of ion exchange. The structures of compounds 35-50 and their mass spectral data are shown in table 1:
TABLE 1 Mass Spectrometry data for Compounds 35-50
Figure BDA0002292072840000282
Figure BDA0002292072840000291
Figure BDA0002292072840000301
Figure BDA0002292072840000311
The beneficial effects of the invention are demonstrated by the following experimental examples.
Experimental example 1 muscle relaxation experiment of the Compound of the present invention
1. Experimental methods
Adult male white rabbits with the weight of 2-3 kg are anesthetized and induced by using the diprenia intravenously at the dose of 5mg/kg, trachea intubation is carried out, oxygen is supplied by a breathing machine, and the diprenia maintains anesthesia at the intravenous infusion speed of 0.6 mg/kg/min. Subsequently, a physiological saline solution containing a dose of the compound of the present invention was administered in groups intravenously, changes in muscle strength were detected using a TOF muscle relaxation monitor, and the time required for onset (T1 ≦ 5%) and complete recovery of muscle Tone (TOF) were recorded>90%) required time, 6 animals per group. The compound of the invention and the control drugs of succincholine and cisatracurium use two times of ED respectively95As the dose administered (see table 2 for specific doses).
2. Results of the experiment
TABLE 1 relaxation of rabbit muscle caused by each drug
Figure BDA0002292072840000312
Figure BDA0002292072840000321
The above experimental results show that the compound of the present invention has a small dosage and a fast onset of action, and can rapidly produce muscle relaxation (<1min) in animals, and the time required for complete recovery of muscle tone (TOF > 90%) is much shorter than that of the control drug cisatracurium, and is also significantly shorter than that of the depolarizing muscle relaxant succinylcholine. The compounds of the invention, especially compounds 1, 2, 3, 5, 13 and 22, are shown to have significantly better rapid onset and rapid recovery effects at the same time under the condition of using dosage equivalent to or lower than that of the control muscle relaxant cisatracurium and succinylcholine.
In addition, after the compound disclosed by the invention is administered, the ratio of T1-4 is gradually reduced when the compound is taken as an effect of a test animal, the ratio is not reduced in an equal ratio, the ratio of T1-4 is gradually restored when the compound is restored, and the change characteristic of TOF belongs to the characteristic of a non-depolarizing muscle relaxant drug. Therefore, the experiments prove that the compound disclosed by the patent has the activity of a non-depolarizing muscle relaxant with quick response and ultra-short effect, and belongs to a typical non-depolarizing muscle relaxant.
In conclusion, the invention provides the quaternary bis-ammonium compound shown in the formula (I), the quaternary bis-ammonium compound has small single-dose administration dosage and quick response, can provide a thorough muscle relaxation effect within 2-10 minutes, can realize an ultra-short-acting non-depolarizing muscle relaxation effect only by depending on the metabolism of an organism, and still shows the quick regression of the muscle relaxation effect after large-dose and continuous administration. Compared with contrast muscle relaxants such as cisatracurium and succincholine, the compound disclosed by the invention is smaller in dosage, faster in effect, shorter in time required for complete recovery of muscle tension (TOF is more than 90%), and has a very good application prospect in preparation of skeletal muscle relaxants which are fast in effect, fast in recovery and small in toxic and side effects.

Claims (10)

1. A dicationic quaternary ammonium salt compound, or a stereoisomer, or a solvate, or a salt, or a crystal form, or an isotopic label thereof, characterized in that: the structure of the dicationic quaternary ammonium salt compound is shown as the formula (I):
Figure FDA0002292072830000011
wherein:
R1，R2，R3，R4each independently selected from substituted or unsubstituted, saturated or unsaturated C1～20A hydrocarbon radical, or C1～20A group in which a skeleton atom in the hydrocarbon group is replaced with a hetero atom; said C is1～20The substituents on the hydrocarbon radical are selected from the group consisting of nitro, cyano, hydroxy, halogenated or non-halogenated alkyl, halogenated or non-halogenated alkoxy, halogen, aryl, heteroaryl, -OCOR9、-COR9、-COOR9，R9Is selected from C1～8An alkyl group;
R5selected from H, C1～6Alkyl, hydroxy, halogen, cycloalkyl;
m1selected from substituted or unsubstituted C1～8Alkylene, or C1～81 to 3-CH in the alkylene skeleton of (A)2-substituted by heteroatoms, vinyl or cycloalkyl; said C is1～8The substituents on the alkylene group of (a) are selected from C1～6Alkyl radical, C1～6Alkoxy, cycloalkyl, hydroxy, halogen;
m2selected from substituted or unsubstituted C1～8Alkylene, or C1～81 to 3-CH in the alkylene skeleton of (A)2-substituted by heteroatoms, vinyl or cycloalkyl; said C is1～8The substituents on the alkylene group of (a) are selected from C1～6Alkyl radical, C1～6Alkoxy, cycloalkyl, hydroxy, halogen;
e is O, S or CR7R8，R7、R8Each independently selected from H, halogen, C1～6An alkyl group;
n is 1 or 2;
g is selected from O or NR6Wherein R is6Is H, C1～6Alkyl, cycloalkyl;
a is O or S; b is O or S;
p is 0 or 1; q is 0 or 1; h is 0 or 1;
Z1、Z2each independently selected from anions.
2. The biscationic quaternary ammonium salt compound of claim 1, or a stereoisomer thereof, or a solvate thereof, or a salt thereof, or a crystalline form thereof, or an isotopic label thereof, wherein:
R1，R2，R3，R4each independently selected from C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, alkynyl,
Figure FDA0002292072830000021
Wherein a is an integer of 0-2, R10Selected from the following substituted or unsubstituted groups: aryl, heteroaryl, benzoheterocyclyl, saturated cycloalkyl, saturated heterocyclyl, said R10OnThe substituent group is selected from nitro, cyano, hydroxy, halogenated or non-halogenated C1-4Alkyl, halogenated or non-halogenated C1-4Alkoxy, halogen, -OCOR9、-COR9、-COOR9，R9Is selected from C1～4An alkyl group;
R5selected from H, C1～4Alkyl, hydroxy, halogen, cycloalkyl;
m1selected from substituted or unsubstituted C1～6Alkylene, or C1～61 to 2-CH in the alkylene skeleton of (A)2-substituted by heteroatoms, vinyl or cycloalkyl; said C is1～6The substituents on the alkylene group of (a) are selected from C1～4Alkyl radical, C1～4Alkoxy, cycloalkyl, hydroxy, halogen;
m2selected from substituted or unsubstituted C1～6Alkylene, or C1～61 to 2-CH in the alkylene skeleton of (A)2-substituted by heteroatoms, vinyl or cycloalkyl; said C is1～6The substituents on the alkylene group of (a) are selected from C1～4Alkyl radical, C1～4Alkoxy, cycloalkyl, hydroxy, halogen;
e is O, S or CR7R8，R7、R8Each independently selected from H, halogen, C1～4An alkyl group;
n is 1 or 2;
g is selected from O or NR6Wherein R is6Is H or C1～4An alkyl group;
a is O; b is O;
p is 0 or 1; q is 0 or 1; h is 0 or 1;
Z1、Z2each independently selected from anions.
3. The biscationic quaternary ammonium salt compound of claim 2, or a stereoisomer thereof, or a solvate thereof, or a salt thereof, or a crystalline form thereof, or an isotopic label thereof, wherein: the structure of the dicationic quaternary ammonium salt compound is shown as the formula (II):
Figure FDA0002292072830000022
wherein R is1Is selected from C1-4Alkyl radical, C2-4An alkenyl group,
Figure FDA0002292072830000023
R10，R11Each independently selected from phenyl, heteroaryl, benzoheterocyclyl substituted with 0-3 substituents; each of said substituents being independently selected from nitro, cyano, hydroxy, halogenated or non-halogenated C1-3Alkyl, halogenated or non-halogenated C1-3Alkoxy, halogen, -OCOR9、-COR9、-COOR9，R9Is C1～3An alkyl group;
preferably, the heteroaryl is
Figure FDA0002292072830000031
Said benzoheterocyclyl is
Figure FDA0002292072830000032
b is an integer of 0 to 3, R12Selected from nitro, cyano, hydroxy, halogenated or non-halogenated C1-3Alkyl, halogenated or non-halogenated C1-3Alkoxy, halogen, -OCOR9、-COR9、-COOR9，R9Is C1～3An alkyl group;
R5selected from H, C1～4Alkyl, hydroxy, halogen;
m1selected from substituted or unsubstituted C1～6Alkylene, or C1～61 to 2-CH in the alkylene skeleton of (A)2-substituted by a heteroatom selected from O or S, vinyl or cycloalkyl, said cycloalkyl being a 3-membered cycloalkyl; said C is1～6The substituents on the alkylene group of (a) are selected from C1～3Alkyl, hydroxy, halogen;
m2is selected fromSubstituted or unsubstituted C1～6Alkylene, or C1～61 to 2-CH in the alkylene skeleton of (A)2-a group substituted by a heteroatom selected from O or S; said C is1～6The substituents on the alkylene group of (a) are selected from C1～3Alkyl, hydroxy, halogen;
e is O, S or CR7R8，R7、R8Each independently selected from H, halogen, C1～3An alkyl group;
n is 1 or 2;
g is selected from O or NR6Wherein R is6Is H or C1～3An alkyl group;
p is 0 or 1; q is 0 or 1; h is 0 or 1;
Z1、Z2each independently selected from anions.
4. The biscationic quaternary ammonium salt compound of claim 3, or a stereoisomer thereof, or a solvate thereof, or a salt thereof, or a crystalline form thereof, or an isotopic label thereof, wherein: the structure of the dicationic quaternary ammonium salt compound is shown as the formula (III):
Figure FDA0002292072830000041
wherein R is1Is selected from C1-4Alkyl radical, C2-4An alkenyl group,
Figure FDA0002292072830000042
b. c and d are each independently an integer of 0 to 2, R12、R13、R14Each independently selected from nitro, cyano, hydroxy, halogenated or non-halogenated C1-3Alkyl, halogenated or non-halogenated C1-3Alkoxy, halogen, -OCOR9、-COR9、-COOR9，R9Is C1～3An alkyl group;
R5selected from H, C1～4Alkyl, hydroxy, halogen;
m1selected from substituted or unsubstituted C1～5Alkylene radical of the formula C1～5The substituents on the alkylene group of (a) are selected from C1～3Alkyl, hydroxy, halogen;
m2selected from substituted or unsubstituted C1～5Alkylene, or C1～51 to 2-CH in the alkylene skeleton of (A)2-a group substituted by a heteroatom selected from O or S; said C is1～5The substituents on the alkylene group of (a) are selected from C1～3Alkyl, hydroxy, halogen;
e is CR7R8，R7、R8Each independently selected from H, halogen, C1～3An alkyl group;
n is 1 or 2;
Z1、Z2each independently selected from pharmaceutically acceptable anions.
5. The biscationic quaternary ammonium salt compound of claim 4, or a stereoisomer thereof, or a solvate thereof, or a salt thereof, or a crystalline form thereof, or an isotopic label thereof, wherein: the structure of the dicationic quaternary ammonium salt compound is shown as a formula (IV):
Figure FDA0002292072830000051
wherein R is1Is selected from C1-4Alkyl radical, C2-4An alkenyl group,
Figure FDA0002292072830000052
R12、R13、R14Each independently selected from nitro, cyano, hydroxy, halogenated or non-halogenated C1-3Alkyl, halogenated or non-halogenated C1-3Alkoxy, halogen, -OCOR9、-COR9、-COOR9，R9Is C1～3An alkyl group;
R5selected from H, C1～4Alkyl, hydroxy, halogen;
m1selected from substituted or unsubstituted C1～5Alkylene radical of the formula C1～5The substituents on the alkylene group of (a) are selected from C1～3Alkyl, hydroxy, halogen;
m2selected from substituted or unsubstituted C1～5Alkylene, or C1～51 to 2-CH in the alkylene skeleton of (A)2-a group substituted by a heteroatom selected from O or S; said C is1～5The substituents on the alkylene group of (a) are selected from C1～3Alkyl, hydroxy, halogen;
e is CR7R8，R7、R8Each independently selected from H, halogen, C1～3An alkyl group;
Z1、Z2each independently selected from bromide, chloride, acetate, sulfate, citrate, sulfonate.
6. The biscationic quaternary ammonium salt compound of claim 5, or a stereoisomer thereof, or a solvate thereof, or a salt thereof, or a crystalline form thereof, or an isotopic label thereof, wherein:
R1is methyl;
R12、R13、R14each independently selected from nitro, methyl, halogen, halomethyl;
R5selected from H or methyl;
m1selected from substituted or unsubstituted C1～5Alkylene radical of the formula C1～5The substituents on the alkylene group of (a) are selected from methyl, halogen;
m2selected from substituted or unsubstituted C1～5Alkylene, or C1～51 to 2-CH in the alkylene skeleton of (A)2-a group substituted by a heteroatom selected from O or S; said C is1～5The substituents on the alkylene group of (a) are selected from methyl, halogen;
e is CR7R8，R7、R8Each independently of the otherIs selected from H, halogen, C1～2An alkyl group.
7. The biscationic quaternary ammonium salt compound of claim 6, or a stereoisomer thereof, or a solvate thereof, or a salt thereof, or a crystalline form thereof, or an isotopic label thereof, wherein:
the halogen is selected from F, Cl or Br; the halomethyl group is selected from CF3。
8. The biscationic quaternary ammonium salt compound according to any one of claims 1-7, or a stereoisomer thereof, or a solvate thereof, or a salt thereof, or a crystalline form thereof, or an isotopic label thereof, wherein: the dicationic quaternary ammonium salt compound has a structure selected from one of the following structures:
Figure FDA0002292072830000061
Figure FDA0002292072830000071
Figure FDA0002292072830000081
Figure FDA0002292072830000091
Figure FDA0002292072830000101
Figure FDA0002292072830000111
9. use of the dicationic quaternary ammonium salt compound of any one of claims 1-8, or a stereoisomer thereof, or a solvate thereof, or a salt thereof, or a crystal form thereof, or an isotopic label thereof, in the preparation of a skeletal muscle relaxation drug.
10. A pharmaceutical composition characterized by: the pharmaceutical composition is prepared by taking the dicationic quaternary ammonium salt compound, or the stereoisomer, or the solvate, or the salt, or the crystal form, or the isotope marker thereof of any one of claims 1 to 8 as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
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