WO2020156359A1 - 一种季铵盐类化合物及其制备方法与用途 - Google Patents

一种季铵盐类化合物及其制备方法与用途 Download PDF

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WO2020156359A1
WO2020156359A1 PCT/CN2020/073387 CN2020073387W WO2020156359A1 WO 2020156359 A1 WO2020156359 A1 WO 2020156359A1 CN 2020073387 W CN2020073387 W CN 2020073387W WO 2020156359 A1 WO2020156359 A1 WO 2020156359A1
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unsubstituted
alkyl
substituted
group
compound
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PCT/CN2020/073387
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French (fr)
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柯博文
刘进
张文胜
杨俊�
唐磊
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四川大学华西医院
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Priority to US17/427,521 priority Critical patent/US20220135526A1/en
Priority to EP20748885.9A priority patent/EP3919476A4/en
Priority to JP2021544526A priority patent/JP2022518599A/ja
Publication of WO2020156359A1 publication Critical patent/WO2020156359A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of chemical medicine, and specifically relates to a quaternary ammonium salt compound and a preparation method and application thereof.
  • Local anesthetics are a class of drugs that can reversibly block the occurrence and transmission of sensory nerve impulses during local administration, referred to as "local anesthetics".
  • local anesthetics When animals or humans are conscious, these drugs can locally reversibly block sensory nerve impulse generation and signal conduction, causing temporary sensory loss in the innervated parts of the nerves, thereby reversibly causing loss of local tissue pain.
  • the effect of local anesthetics is limited to the administration site and disappears rapidly as the drug diffuses from the administration site.
  • Local anesthetics block the generation of action potentials and the conduction of nerve impulses by directly inhibiting the related ion channels on nerve cells and fiber membranes, thereby producing local anesthesia.
  • the currently recognized mechanism of action of local anesthetics is to block voltage-gated Na + channels on nerve cell membranes, block nerve impulses, and produce local anesthesia.
  • the local anesthetics currently used in clinical practice are all hydrophobic compounds with no charge. Such local anesthetics can easily enter nerve cells through cell membranes through diffusion and permeation to reach the blocking site of sodium channels, and block the nerves by blocking sodium channels. Yuan excitement.
  • these local anesthetic molecules are easy to diffuse into nerve cells to exert their effects, they are also easy to diffuse rapidly from the drug delivery site through diffusion, freeing nerve cells, and the local anesthetic effect cannot be sustained for a long time. Even if the dosage is increased, the local anesthesia time can only be prolonged to a certain extent, and these local anesthetics cannot obtain the ideal long-term local anesthesia effect.
  • Traditional local anesthetics generally contain at least one non-amide tertiary N atom in their chemical structure. When the N atom is substituted, the corresponding quaternary ammonium compound will be obtained. The molecular structure of the quaternary ammonium compound has a positive charge, and its ability to penetrate the cell membrane is significantly reduced. For example: Ethyl substitution of the tertiary amine N atom of lidocaine will result in a quaternary ammonium compound called QX-314. Similar to QX-314, QX-222 is another quaternary ammonium salt with similar structure. Because QX-314 and QX-222 have positive charges in their structure, they cannot pass through cell membranes under normal circumstances, and therefore cannot quickly produce local anesthesia.
  • the present invention provides a new class of quaternary ammonium salt compounds, which have both long-acting local anesthesia and selective local anesthesia (sensory nerve block time is greater than motor nerve block time), which is different from the existing ones.
  • QX314 and QX314 compositions have the advantages of quick onset, long local anesthetic action time, good local anesthetic selectivity, less nerve damage, and high safety.
  • the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt, or stereoisomer, or solvate, or prodrug, or metabolite thereof:
  • X and Y are each independently selected from O or NR 10 , wherein R 10 is selected from H, deuterium or C 1 -C 4 alkyl;
  • Z - is a pharmaceutically acceptable anion
  • R 1 is selected from n 1 aryl groups substituted by R 11 ;
  • R 2 is selected from n 1 'aryl groups substituted by R 11 ';
  • n 1 and n 1 ' are each independently selected from an integer of 0 to 5
  • R 11 and R 11 ' are each independently selected from deuterium, C 1 to C 4 alkyl, and C 1 to C 4 alkoxy , Halogen, nitro, cyano, hydroxyl, carboxy, amino;
  • R 3 is selected from substituted C 1 ⁇ C 10 alkyl or unsubstituted C 5 ⁇ C 10 alkyl
  • R 4 is independently selected from substituted or Unsubstituted C 1 ⁇ C 10 alkyl
  • the substituent is deuterium, substituted or unsubstituted C 1 ⁇ C 4 alkoxy, halogen, nitro, cyano, hydroxyl, carboxy, amino, ester, C 1 to C 6 alkylthio, mercapto;
  • the substituent of the alkoxy is hydroxyl;
  • R 3 and R 4 are independently selected from substituted or unsubstituted C 1 ⁇ C 4 alkylene groups, and the substituents are C 1 ⁇ C 3 Alkyl; wherein, the main chain of the alkylene group contains 0 to 4 heteroatoms, the heteroatoms are selected from O, S, NR 12 , wherein the R 12 is selected from hydrogen, deuterium, C 1 ⁇ C 4 alkyl;
  • L 1 is selected from substituted or unsubstituted C 1 to C 14 alkylene groups; wherein the main chain of the alkylene group contains 0 to 4 heteroatoms, and the heteroatoms are selected from O, S, NR 12 , wherein the R 12 is selected from hydrogen, deuterium, C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 alkoxy; the substituent is deuterium, C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 alkoxy, halogen;
  • the dotted line of L 2 is a bond, and L 2 is selected from substituted or unsubstituted C 1 to C 8 alkylene groups, and the substituents are deuterium, C 1 to C 4 alkyl groups, and C 1 to C 4 ⁇ alkoxy, halogen.
  • X and Y are each independently selected from NH or NCH 3 ;
  • Z - is bromide, chloride, sulfonate
  • R 1 is selected from n 1 aryl groups substituted by R 11 ;
  • R 2 is selected from n 1 'aryl groups substituted by R 11 ';
  • n 1 and n 1 ' are each independently selected from an integer of 0 to 5
  • R 11 and R 11 ' are each independently selected from deuterium, C 1 to C 4 alkyl, and C 1 to C 4 alkoxy , Halogen, nitro, cyano, hydroxyl;
  • R 3 is selected from substituted C 1 ⁇ C 10 alkyl or unsubstituted C 5 ⁇ C 10 alkyl
  • R 4 is independently selected from substituted or An unsubstituted C 1 ⁇ C 10 alkyl group, the substituent being deuterium, a substituted or unsubstituted C 1 ⁇ C 4 alkoxy group, a hydroxyl group, a carboxyl group, a C 2 ⁇ C 5 alkylthio group, or a mercapto group;
  • the substituent of the oxy group is a hydroxyl group;
  • R 3 and R 4 are independently selected from C 1 to C 4 alkylene groups, wherein the main chain of the alkylene group contains 0 to 2 heteroatoms, the heteroatoms are selected from O;
  • L 1 is selected from C 3 to C 14 alkylene groups; wherein, the substituent is an alkyl group, the main chain of the alkylene group contains 0 to 2 heteroatoms, and the heteroatoms are selected from O, S;
  • the dotted line of L 2 is a bond, and L 2 is selected from a C 1 to C 6 alkylene group.
  • X and Y are each independently selected from NH or NCH 3 ;
  • Z - is bromide, chloride, sulfonate
  • R 1 is selected from n 1 aryl groups substituted by R 11 ;
  • R 2 is selected from n 1 'aryl groups substituted by R 11 ';
  • n 1 and n 1 ' are each independently selected from an integer of 2 to 3, and R 11 and R 11 ' are methyl, propyl, methoxy, hydroxy, nitro, cyano, halogen;
  • R 3 is selected from substituted C 1 ⁇ C 8 alkyl or unsubstituted C 5 ⁇ C 10 alkyl
  • R 4 is independently selected from substituted or An unsubstituted C 1 ⁇ C 10 alkyl group, the substituent being deuterium, a substituted or unsubstituted C 1 ⁇ C 3 alkoxy group, a hydroxyl group, a carboxyl group, a C 2 ⁇ C 3 alkylthio group, or a mercapto group
  • the substituent of the oxy group is a hydroxyl group;
  • R 3 and R 4 are independently selected from substituted or unsubstituted C 2 ⁇ C 3 alkylene groups, wherein the substituent is C 1 alkane
  • the main chain of the alkylene group contains 0 to 1 heteroatoms, and the heteroatoms are selected from O;
  • L 1 is selected from unsubstituted C 3 to C 14 alkylene groups; wherein the main chain of the alkylene group contains 0 to 2 heteroatoms, and the heteroatoms are selected from O and S;
  • the dotted line of L 2 is a bond, and L 2 is selected from unsubstituted C 1 to C 6 alkylene groups.
  • X and Y are each independently selected from NH;
  • R 1 is selected from n 1 aryl groups substituted by R 11 ;
  • R 2 is selected from n 1 'aryl groups substituted by R 11 ';
  • n 1 and n 1 ' are each independently selected from an integer of 2 to 3, and R 11 and R 11 ' are methyl groups;
  • R 3 is selected from substituted C 1 ⁇ C 8 alkyl or unsubstituted C 5 ⁇ C 10 alkyl
  • R 4 is independently selected from substituted or Unsubstituted C 1 ⁇ C 10 alkyl
  • the substituent of the alkyl is deuterium, substituted or unsubstituted C 1 ⁇ C 3 alkoxy, hydroxyl, carboxyl, C 2 ⁇ C 3 alkylthio, or mercapto
  • the substituent of the alkoxy group is a hydroxyl group
  • R 3 and R 4 are independently selected from unsubstituted C 2 ⁇ C 3 alkylene groups; wherein, the main chain of the alkylene group is Contains 1 heteroatom, and the heteroatom is selected from O;
  • L 1 is selected from an unsubstituted C 3 to C 14 alkylene group; wherein, the main chain of the alkylene group contains one heteroatom, and the heteroatom is selected from O, S;
  • the dotted line of L 2 is a bond, and L 2 is selected from unsubstituted C 2 -C 6 alkylene groups.
  • X and Y are each independently selected from NH or NCH 3 ;
  • n 1 and n 1 ' are each independently selected from an integer of 2 to 3, and R 11 and R 11 ' are methyl, propyl, methoxy, hydroxy, nitro, cyano, or halogen;
  • R 3 is selected from substituted C 1 ⁇ C 8 alkyl or unsubstituted C 5 ⁇ C 10 alkyl
  • R 4 is independently selected from substituted or unsubstituted C 1 ⁇ C 10 alkyl
  • substitution of the alkyl The group is deuterium, a substituted or unsubstituted C 1 -C 3 alkoxy group, a hydroxyl group, a carboxyl group, a C 2 -C 3 alkylthio group, or a mercapto group; the substituent of the alkoxy group is a hydroxyl group;
  • L 1 is selected from unsubstituted C 3 to C 14 alkylene groups; wherein the main chain of the alkylene group contains 0, 1 or 2 heteroatoms, and the heteroatoms are selected from O, S;
  • L 2 is selected from unsubstituted C 2 to C 6 alkylene groups.
  • R 3 is selected from substituted C 1 ⁇ C 5 alkyl
  • R 4 is independently selected from substituted or unsubstituted C 1 ⁇ C 5 alkyl; the substituent of the alkyl is hydroxy;
  • L 1 is selected from unsubstituted C 3 to C 6 alkylene groups
  • L 2 is selected from unsubstituted C 4 alkylene.
  • X and Y are each independently selected from NH;
  • n 1 and n 1 ' are each independently selected from an integer of 2 to 3, and R 11 and R 11 ' are methyl groups;
  • R 3 and R 4 are independently selected from substituted or unsubstituted C 2 ⁇ C 3 alkylene groups; wherein, the substituent is a C 1 alkyl group, and the main chain of the alkylene group contains a heteroatom , The heteroatom is selected from O;
  • L 1 is selected from an unsubstituted C 3 to C 14 alkylene group; wherein, the main chain of the alkylene group contains 0 or 1 heteroatom, and the heteroatom is selected from O, S;
  • L 2 is selected from unsubstituted C 2 to C 6 alkylene groups.
  • the structure of the compound is one of the following compounds:
  • the present invention also provides the aforementioned compound, or a pharmaceutically acceptable salt, or a stereoisomer, or a solvate, or a prodrug, or a metabolite thereof, formed with a pharmaceutically acceptable carrier
  • a pharmaceutically acceptable carrier The use of preparations in the preparation of local anesthetic drugs.
  • the local anesthetic drug makes the sensory nerve block time longer than the motor nerve block time
  • the local anesthesia is a long-acting local anesthesia
  • the anesthesia time of the local anesthesia exceeds 24 hours.
  • the present invention also provides a drug, which is based on the aforementioned compound, or a pharmaceutically acceptable salt, or a stereoisomer, or a solvate, or a prodrug, or a metabolite thereof, and A preparation prepared with pharmaceutically acceptable excipients.
  • the compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming system.
  • substitution refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Alkyl is a hydrocarbon group formed by missing one hydrogen atom in an alkane molecule, such as methyl -CH 3 , ethyl -CH 3 CH 2 and so on.
  • the C 1 to C 4 alkyl group refers to a straight or branched hydrocarbon chain containing one to four carbon atoms.
  • Alkylene refers to a hydrocarbon group formed by omitting two hydrogen atoms in an alkane molecule, such as methylene -CH 2 -, ethylene -CH 2 CH 2 -, etc.
  • the "C 1 -C 4 alkylene group” refers to a straight or branched hydrocarbon chain containing one to four carbon atoms.
  • the "substituted or unsubstituted C 1 to C 12 alkyl group” means that the C 1 to C 12 alkyl group may be substituted or unsubstituted.
  • L 1 is selected from substituted or unsubstituted C 1-12 alkylene groups; wherein the main chain of the alkylene group contains 0-4 heteroatoms" means a straight chain containing one to twelve carbon atoms Or branched hydrocarbon chain; the hydrocarbon chain can be substituted or unsubstituted; the hydrocarbon chain containing heteroatoms in the main chain means that the carbon atoms on the main chain are replaced with heteroatoms, and the heteroatoms are O, S or substituted N.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) groups having a conjugated ⁇ -electron system, such as phenyl and naphthyl.
  • the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be in a conjugated ⁇ -electron system On the carbon atom on the ring.
  • the aryl group can be substituted or unsubstituted, that is, it can be substituted by 0 to 4 deuterium, C 1 to C 4 alkyl, C 1 to C 4 alkoxy, C 1 to C 4 alkylthio, halogen , Nitro, cyano, hydroxyl, carboxyl, amino and other substituents.
  • pharmaceutically acceptable salt refers to the salt formed by the compound of the present invention and pharmaceutically acceptable inorganic acid and organic acid, which is suitable for contact with the tissue of a subject (for example, human) without causing uncomfortable side effects salt.
  • preferred inorganic acids include (but are not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid;
  • preferred organic acids include (but are not limited to): formic acid, acetic acid, propionic acid, succinic acid, naphthalene Disulfonic acid (1,5), aceous acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethyl acetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid Acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascor
  • solvate refers to a solvate formed by the compound of the present invention and a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes but is not limited to water, ethanol, methanol, isopropanol, propylene glycol, and tetrahydrofuran , Dichloromethane.
  • stereoisomer means that the chiral carbon atom involved in the compound of the present invention can be in the R configuration or S configuration, or a combination thereof.
  • the present invention provides a quaternary ammonium compound with a novel structure and a preparation method and application thereof.
  • the compound has a fast onset of action and has a long-term local anesthesia after a single administration (more than 24 hours, and the local anesthesia time for most compounds) More than 40 hours), with selective nerve block (sensory nerve block time is greater than motor nerve block time, and the difference time is greater than or equal to 5 hours, and the difference time of most compounds is greater than 10 hours), both with long-term effects Local anesthesia and selective local anesthesia significantly reduce the side effects of QX314, QX314 composition and quaternary ammonium compounds with surfactant structure characteristics, and have better safety, that is, the compound of the present invention and its pharmaceutically acceptable
  • the salt can be used to prepare safe drugs with long-term local anesthesia and selective local anesthesia. It has the advantages of long local anesthesia effect, good local anesthetic nerve selectivity, less nerve damage, and high safety.
  • the raw materials and equipment used in the specific embodiments of the present invention are all known products, which are obtained by purchasing commercially available products.
  • the intermediates 8b (1.5g, 2.24mmol) and 8c (0.61g, 2.47mmol) prepared above were dissolved in a mixed solvent of 30ml of ethanol and 5ml of methanol, and DIPEA (0.58g, 0.74ml, 4.48mmol) was added and reacted at 30°C. 12 days.
  • silica gel column chromatography is used for purification.
  • the yield is 32.1%.
  • Example 5 Refer to the method of Example 5 to obtain a white solid powder with a yield of 28.5%.
  • the compound 1-76, lidocaine (positive control group), and levobupivacaine (positive control group) prepared in the examples were selected to be given to SD rats of 250 to 300 grams (half male and female) that were fully adapted to the experimental environment. , 8 rats in each group.
  • Lidocaine is formulated with distilled water to a concentration of 2% (74mmol/L) in the lidocaine group, and levobupivacaine is formulated with distilled water to a concentration of 0.75% (22mmol/L).
  • /L solution the compound of the present invention is formulated with distilled water into a solution with a concentration of 20 mmol/L.
  • each rat is 0.5ml, which is guided by a nerve locator and injected near the sciatic nerve of the rat.
  • the rats were stimulated to inject drugs into the soles of their feet to observe the effect of local anesthesia.
  • postural Extensor Thrust PET was used to evaluate the motor function of rats: the rat was lifted vertically and the injection side hindlimb was pedaled on the electronic platform. At this time, the rat's hindlimb muscle strength was pedaled by the limbs on the balance. And the displayed value indicates.
  • the reading is the limb's own weight, about 20g. The measured value exceeds half of the difference between the baseline and the limb weight as motor function recovery, and less than or equal to this value is regarded as motor function loss.
  • Example 13 Product 4min 55h 14h Example 14 Product 5min 41h 13h Example 15 Product 5min 44h 16h Example 16 product 5min 60h 17h Example 17 product 5min 37h 18h Example 18 product 2min 38h 16h Example 19 Product 5min 39h 10h Example 20 product 5min 54h 14h Example 21 Product 5min 47h 13h Example 22 product 3min 47h 15h Example 23 product 5min 54h 14h Example 24 product 4min 54h 11h Example 25 product 5min 44h 12h Example 26 product 5min 45h 16h Example 27 product 3min 37h 15h Example 28 product 2min 39h 14h Example 29 product 5min 50h 15h Example 31 product 5min 45h 19h Example 32 product 2min 46h 17h Example 33 product 5min 49h 16h Example 34 product 5min 45h 9h Example 35 product 2min 54h 13h Example 36 product 5min 52h 21h Example 37 Product 1min 45h 17h Example 38 product 1min 43h 19h Example 39 product 3min 61h 19h Example 40 product 2min 53h 13h Example 41 product 2min 46h 11h Example
  • Example 48 product 5min 57h 15h Example 49 product 4min 45h 20h Example 50 product 5min 56h 13h Example 51 Product 5min 44h 19h Example 52 product 2min 56h 15h Example 53 product 5min 59h 16h Example 54 product 5min 66h 15h Example 55 Product 1min 55h 16h Example 56 product 1min 54h 18h Example 57 product 5min 69h 13h Example 58 Product 3min 57h 16h Example 59 Product 1min 54h 15h Example 60 product 1min 54h 20h Example 61 Product 3min 6 1h 11h Example 62 product 5min 51h 21h Example 62 product 5min 51h 21h Example 62 product 5min 51h 21h Example 62 product 5min 51h 21h Example 62 product 5min 51h 21h Example 62 product 5min 51h 21h Example 62 product 5min 51h 21h Example 62 product 5min 51h 21h Example 62 product 5min 51h 21h Example 62 product 5min 51h 21h Example 62 product 5min 51h 21h Example 62 product 5min 51h
  • the experimental results show that the compound of the present invention can produce local anesthesia for more than 24 hours, meanwhile the sensory nerve block time is significantly shorter than the motor nerve block time, and the difference time is greater than or equal to 5 hours, and most of the compounds are greater than or equal to 10 hour.
  • Test Example 2 Local anesthetic effect of subcutaneous infiltration of the compound of the present invention
  • the compound 1-76 prepared in the example was selected, and the lidocaine positive control group and the levobupivacaine positive control group were respectively given 250-300 grams of SD rats (male and female) that were fully adapted to the experimental environment. , 8 in each group.
  • Lidocaine is formulated with distilled water to a concentration of 2% (74mmol/L) in the lidocaine group, and levobupivacaine is formulated with distilled water to a concentration of 0.75% (22mmol/L).
  • /L solution the compound of the present invention is formulated with distilled water into a solution with a concentration of 20 mmol/L.
  • each rat is 0.5ml, which is injected near the sciatic nerve of the rat.
  • the experimental rats were euthanized by injecting bupivacaine into the heart under isoflurane anesthesia. Take the sciatic nerve about 1.5 cm from the injection site, store it in 10% formaldehyde solution for 48 hours, HE stain and cut into 5 ⁇ m thick sections.
  • the dosage is as follows: the lidocaine group is made up of lidocaine with distilled water to a concentration of 2% (74mmol/L), and the levobupivacaine group is made up of levobupivacaine with distilled water to a concentration of 0.75% ( 22mmol/L), the compound of the present invention is prepared with distilled water to make a solution with a concentration of 6mmol/L.
  • each rat is 0.5ml, which is injected into the back of the rat subcutaneously.
  • the experimental rats were euthanized by injecting bupivacaine into the heart under isoflurane anesthesia.
  • the skin tissue at the injection site was taken, stored in 10% formaldehyde solution for 48 hours, stained with HE and cut into sections with a thickness of 5 ⁇ m.
  • the neuropathological damage evaluation showed that the compound of the example had no nerve damage, vascular proliferation, degree of demyelination, muscle inflammation, and degree of connective tissue inflammation compared with the lidocaine positive control group and the levobupivacaine positive control group. Significant difference, with good safety.
  • the present invention provides a quaternary ammonium salt compound with a novel structure and a preparation method and application thereof.
  • the compound has a fast onset of action and has a long-term local anesthesia after a single administration (more than 24 hours, and most compounds The effect of local anesthesia for more than 40 hours), with selective nerve block (sensory nerve block time is greater than motor nerve block time, and the difference time is greater than or equal to 5 hours, and the difference time of most compounds is greater than 10 hours), and It has long-acting local anesthesia and selective local anesthesia, and significantly reduces the side effects of QX314, QX314 compositions and quaternary ammonium salt compounds with surfactant structure characteristics, and has better safety, that is, the compound of the present invention and its pharmacy
  • the above-acceptable salt can be used to prepare safe drugs with long-term local anesthesia and selective local anesthesia. It has the advantages of long local anesthetic effect, good local anesthetic nerve selectivity, less nerve damage, and high safety. .

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  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明公开了一种季铵盐类化合物及其制备方法与用途，属于化学医药领域。本发明提供了一种式Ⅰ所示的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物。该化合物具有起效快，单次给药后具有长时间局部麻醉的效果，感觉神经阻滞时间大于运动神经阻滞时间，兼具长效局部麻醉作用和选择性局部麻醉作用，同时显著降低了具有表面活性剂结构特征的季铵盐化合物的副作用，具有良好的安全性，即本发明式Ⅰ化合物及其药学上可接受的盐，可用于制备安全的、具有长时间局部麻醉和选择性局部麻醉作用的药物，具有局部麻醉作用时间长、局部麻醉选择性好、安全性高的优点。

Description

一种季铵盐类化合物及其制备方法与用途 技术领域
本发明属于化学医药领域，具体涉及一种季铵盐类化合物及其制备方法与用途。
背景技术
局部麻醉药(Local anesthetics)是一类能在用药局部可逆性的阻断感觉神经冲动发生与传递的药物，简称“局麻药”。该类药物在动物或人意识清醒的情况下，局部可逆的阻断感觉神经冲动产生与信号传导，使有关神经支配的部位出现暂时性感觉丧失，从而可逆的引起局部组织痛觉消失。一般的，局麻药的作用局限于给药部位，并随药物从给药部位扩散而迅速消失。局部麻醉药通过直接抑制神经细胞和纤维膜上的相关离子通道，阻滞动作电位的产生和神经冲动的传导，从而产生局部麻醉作用。目前公认的局麻药作用机制是阻断神经细胞膜上的电压门控性Na +通道，使神经冲动传导阻滞，从而产生局部麻醉作用。
临床目前所使用的局麻药均为不具备电荷的疏水性化合物，该类局麻药容易通过扩散和渗透方式通过细胞膜进入神经细胞达到钠通道的阻断位点，通过阻断钠通道从而阻断神经元的兴奋性。实际上，这些局部麻醉药分子虽然容易通过扩散进入神经细胞内发挥作用，但同时也容易通过扩散作用从给药部位迅速扩散，游离出神经细胞，导致局部麻醉作用无法长时间持续。即使加大使用剂量也只能在一定程度内延长局部麻醉时间，这些局部麻醉药物无法获得理想的长时间局部麻醉作用。目前临床常用的局部麻醉药物作用时间大多不超过4小时。由于传统局部麻醉药的作用维持时间较短，不得不使用镇痛泵来维持神经阻滞，采取椎管内、神经根、皮下等部位的置管，大大增加了医疗成本和感染的发生率。
另一方面，传统局部麻醉药物对神经的阻滞并不具有特异的选择性，在使用过程中广泛地阻滞多种神经纤维，影响感觉、痛觉、运动以及交感神经等多种神经功能，这一药理特点极大的限制了局部麻醉药在临床中的广泛应用。例如膝关节置换术后患者早期的功能锻炼康复尤为重要，但是目前使用的局麻药中并无选择性阻滞痛觉的药物，大部分手术患者由于使用局部麻醉药，导致患者的运动神经被阻滞，无法恢复运动功能从而使得术后康复受限。局部麻醉药研究急需引入新的研究思路，开发具有选择性阻滞感觉功能而不影响运动功能的长效局部麻醉药物以满足临床需求。
传统局部麻醉药物化学结构中一般都含有至少一个及以上非酰胺叔N原子。当该N原子被取代时，将获得相应的季铵盐化合物。季铵盐化合物的分子结构由于具有一个正电荷，穿透细胞膜能力显著降低。例如：对利多卡因的叔胺N原子进行乙基取代后将得到被称为QX-314的季铵盐化合物。与QX-314相似，QX-222也是另外一种结构类似的季铵盐。由于QX-314和QX-222结构中带有正电荷，正常情况下无法穿过细胞膜，因而无法快速地产生局部麻醉作用。但其一旦穿过细胞膜，就能在神经细胞内对钠离子通道进行显著的抑制，从而产生持久的局部麻醉作用(Courtney KR.J Pharmacol Exp Ther.1975,195:225–236)。目前的研究发现，QX-314能在辣椒素(瞬时受体电位通道香草酸亚型1激动剂，即TRPV1 Agonist)的协助下，通过TRPV1通道的激活，顺利进入神经细胞内，从而产生长时间神经阻滞(Craig R.Ries.Anesthesiology.2009；111:122–126)。但辣椒素的强烈刺激性使其难以具有应用前景。
Figure PCTCN2020073387-appb-000001
还有研究表明，QX314与临床上使用的如布比卡因、利多卡因等局部麻醉药物合用能够迅速产生的麻醉作用，可避免辣椒素的刺激性，但以上药物的协同使用依然无法达到理想的局部麻醉效果。在外加表面活性剂条件下，亦可帮助QX314进入细胞膜，引起超过8小时的局麻作用(Daniel S.Kohane，PNAS.2010；107:3745-3750)。但目前研究发现，QX314存在一些安全问题，QX314的安全性问题主要表现为局部神经损伤，鞘内注射时会引起实验动物死亡等。在QX-314的基础上，发展了一系列具有表面活性剂结构的长链化合物。该类化合物虽然可以在一定程度上获得较长的局部麻醉效果，但由于该类化合物具有类似表面活性剂的结构，虽然能够一定程度获得长效作用，但也会造成局部注射部位严重的肌肉和神经损伤，安全性差。同时，目前已报道的类似化合物也不具有选择性局部麻醉作用，无法满足临床的需求。因此，无论是QX314单独使用、QX314与其它活性药物联合使用，还是具有表面活性剂结构特征的QX314长链化合物都存在安全性差、局部麻醉选择性差的缺陷。
因此，研究一种麻醉起效快、时间长，使用安全性好，且具有特异选择性的局部麻醉药物具有重要意义。
发明内容
针对上述问题，本发明提供了一类新的季铵盐化合物，该化合物兼具长 效局部麻醉作用和选择性局部麻醉作用(感觉神经阻滞时间大于运动神经阻滞时间)，与现有的QX314、QX314组合物以及具有表面活性剂结构特征的长链化合物相比，具有起效快、局部麻醉作用时间长、局部麻醉选择性好、神经损伤更小、安全性高的优点。
本发明提供了式I所示的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物：
Figure PCTCN2020073387-appb-000002
式中，
X、Y各自独立地选自O或NR 10，其中R 10选自H、氘或C 1～C 4烷基；
Z -为药学上可接受的阴离子；
R 1选自n 1个R 11取代的芳基；
R 2选自n 1’个R 11’取代的芳基；
其中，n 1、n 1’各自独立地选自0～5的整数，R 11、R 11’各自独立地选自氘、C 1～C 4的烷基、C 1～C 4的烷氧基、卤素、硝基、氰基、羟基、羧基、氨基；
当式Ⅰ中R 3、R 4之间的虚线为无时，R 3选自取代的C 1～C 10烷基或未取代的C 5～C 10烷基，R 4独立的选自取代或未取代的C 1～C 10烷基，所述取代基为氘、取代或未取代的C 1～C 4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、酯基、C 1～C 6烷硫基、巯基；所述烷氧基的取代基为羟基；
当式Ⅰ中R 3、R 4之间的虚线为键时，R 3、R 4独立的选自取代或未取代的C 1～C 4亚烷基，所述取代基为C 1～C 3烷基；其中，所述亚烷基的主链上中含有0～4个杂原子，所述杂原子选自O、S、NR 12，其中所述R 12选自氢、氘、C 1～C 4的烷基；
L 1选自取代或未取代的C 1～C 14的亚烷基；其中，所述亚烷基的主链上中含有0～4个杂原子，所述杂原子选自O、S、NR 12，其中所述R 12选自氢、氘、C 1～C 4的烷基、C 1～C 4的烷氧基；所述取代基为氘、C 1～C 4的烷基、C 1～C 4的烷氧基、卤素；
式Ⅰ中L 2的虚线为键，L 2选自取代或未取代的C 1～C 8的亚烷基，所述取代基为氘、C 1～C 4的烷基、C 1～C 4的烷氧基、卤素。
进一步地，
X、Y各自独立地选自NH或NCH 3；
Z -为溴离子、氯离子、磺酸根；
R 1选自n 1个R 11取代的芳基；
R 2选自n 1’个R 11’取代的芳基；
其中，n 1、n 1’各自独立地选自0～5的整数，R 11、R 11’各自独立地选自氘、C 1～C 4的烷基、C 1～C 4的烷氧基、卤素、硝基、氰基、羟基；
当式Ⅰ中R 3、R 4之间的虚线为无时，R 3选自取代的C 1～C 10烷基或未取代的C 5～C 10烷基，R 4独立的选自取代或未取代的C 1～C 10烷基，所述取代基为氘、取代或未取代的C 1～C 4烷氧基、羟基、羧基、C 2～C 5烷硫基、巯基；所述烷氧基的取代基为羟基；
当式Ⅰ中R 3、R 4之间的虚线为键时，R 3、R 4独立的选自C 1～C 4亚烷基，其中，所述亚烷基的主链上中含有0～2个杂原子，所述杂原子选自O；
L 1选自C 3～C 14的亚烷基；其中，所述取代基为烷基，所述亚烷基的主链上中含有0～2个杂原子，所述杂原子选自O、S；
式Ⅰ中L 2的虚线为键，L 2选自C 1～C 6的亚烷基。
进一步地，
X、Y各自独立地选自NH或NCH 3；
Z -为溴离子、氯离子、磺酸根；
R 1选自n 1个R 11取代的芳基；
R 2选自n 1’个R 11’取代的芳基；
其中，n 1、n 1’各自独立地选自2～3的整数，R 11、R 11’为甲基、丙基、甲氧基、羟基、硝基、氰基、卤素；
当式Ⅰ中R 3、R 4之间的虚线为无时，R 3选自取代的C 1～C 8烷基或未取代的C 5～C 10烷基，R 4独立的选自取代或未取代的C 1～C 10烷基，所述取代基为氘、取代或未取代的C 1～C 3烷氧基、羟基、羧基、C 2～C 3烷硫基、巯基；所述烷氧基的取代基为羟基；
当式Ⅰ中R 3、R 4之间的虚线为键时，R 3、R 4独立的选自取代或未取代的C 2～C 3亚烷基，其中，所述取代基为C 1烷基，所述亚烷基的主链上中含有0～1个杂原子，所述杂原子选自O；
L 1选自未取代的C 3～C 14的亚烷基；其中，所述亚烷基的主链上中含有0～2个杂原子，所述杂原子选自O、S；
式Ⅰ中L 2的虚线为键，L 2选自未取代的C 1～C 6的亚烷基。
进一步地，
X、Y各自独立地选自NH；
Z -为溴离子；
R 1选自n 1个R 11取代的芳基；
R 2选自n 1’个R 11’取代的芳基；
其中，n 1、n 1’各自独立地选自2～3的整数，R 11、R 11’为甲基；
当式Ⅰ中R 3、R 4之间的虚线为无时，R 3选自取代的C 1～C 8烷基或未取代的C 5～C 10烷基，R 4独立的选自取代或未取代的C 1～C 10烷基；所述烷基的取代基为氘、取代或未取代的C 1～C 3烷氧基、羟基、羧基、C 2～C 3烷硫基、巯基；所述烷氧基的取代基为羟基；
当式Ⅰ中R 3、R 4之间的虚线为键时，R 3、R 4独立的选自未取代的C 2～C 3亚烷基；其中，所述亚烷基的主链上中含有1个杂原子，所述杂原子选自O；
L 1选自未取代的C 3～C 14的亚烷基；其中，所述亚烷基的主链上中含有1个杂原子，所述杂原子选自O、S；
式Ⅰ中L 2的虚线为键，L 2选自未取代的C 2～C 6的亚烷基。
进一步地，所述化合物如式II所示：
Figure PCTCN2020073387-appb-000003
式中，
X、Y各自独立地选自NH或NCH 3；
n 1、n 1’各自独立地选自2～3的整数，R 11、R 11’为甲基、丙基、甲氧基、羟基、硝基、氰基、卤素；
R 3选自取代的C 1～C 8烷基或未取代的C 5～C 10烷基，R 4独立的选自取代或未取代的C 1～C 10烷基；所述烷基的取代基为氘、取代或未取代的C 1～C 3烷氧基、羟基、羧基、C 2～C 3烷硫基、巯基；所述烷氧基的取代基为羟基；
L 1选自未取代的C 3～C 14的亚烷基；其中，所述亚烷基的主链上中含有0、1或2个杂原子，所述杂原子选自O、S；
L 2选自未取代的C 2～C 6的亚烷基。
进一步地，所述化合物如式III所示：
Figure PCTCN2020073387-appb-000004
式中，
R 3选自取代的C 1～C 5烷基，R 4独立的选自取代或未取代的C 1～C 5烷基；所述烷基的取代基为羟基；
L 1选自未取代的C 3～C 6的亚烷基；
L 2选自未取代的C 4的亚烷基。
进一步地，所述化合物如式IV所示：
Figure PCTCN2020073387-appb-000005
式中，
X、Y各自独立地选自NH；
n 1、n 1’各自独立地选自2～3的整数，R 11、R 11’为甲基；
R 3、R 4独立的选自取代或未取代的C 2～C 3亚烷基；其中，所述取代基为C 1烷基，所述亚烷基的主链上中含有1个杂原子，所述杂原子选自O；
L 1选自未取代的C 3～C 14的亚烷基；其中，所述亚烷基的主链上中含有0或1个杂原子，所述杂原子选自O、S；
L 2选自未取代的C 2～C 6的亚烷基。
进一步地，化合物的结构为如下化合物之一：
Figure PCTCN2020073387-appb-000006
Figure PCTCN2020073387-appb-000007
Figure PCTCN2020073387-appb-000008
本发明还提供了前述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，与药学上可接受的载体形成的制剂，在制备局部麻醉的药物中的用途。
进一步地，所述局部麻醉的药物使得感觉神经阻滞时间长于运动神经阻滞时间；
和/或，所述局部麻醉为长效局部麻醉；
优选地，所述局部麻醉的麻醉时间超过24小时。
本发明还提供了一种药物，它是以前述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，加上药学上可接受的辅料制备而成的制剂。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学 联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
卤素为氟、氯、溴或碘。
“烷基”是烷烃分子中少掉一个氢原子而成的烃基，例如甲基-CH 3、乙基-CH 3CH 2等。C 1～C 4烷基是指含有一个至四个碳原子的直链或支链的烃链。
“亚烷基”是指烷烃分子中少掉两个氢原子而成的烃基，例如亚甲基-CH 2-、亚乙基-CH 2CH 2-等。“C 1～C 4亚烷基”是指含有一个至四个碳原子的直链或支链的烃链。
“取代或未取代的C 1～C 12烷基”是指C 1～C 12烷基可以是被取代的，也可以没有被取代基的。
“L 1选自取代或未取代的C 1～12的亚烷基；其中，亚烷基的主链上中含有0～4个杂原子”是指含有一个至十二个碳原子的直链或支链的烃链；该烃链可以是取代的，也可以是未取代的；该烃链的主链上含有杂原子是指主链上的碳原子替换为杂原子，杂原子为O、S或取代的N。
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环)，但不能含有杂原子如氮，氧，或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的，即可以被0～4个氘、C 1～C 4的烷基、C 1～C 4的烷氧基、C 1～C 4的烷硫基、卤素、硝基、氰基、羟基、羧基、氨基等取代基取代。
术语“药学上可接受的盐”指本发明化合物与药学上可接受的无机酸和有机酸所形成的盐，适合与对象(例如，人)的组织接触，而不会产生不适度的副作用的盐。其中，优选的无机酸包括(但并不限于)：盐酸、氢溴酸、磷酸、硝酸、硫酸；优选的有机酸包括(但并不限于)：甲酸、乙酸、丙酸、丁二酸、萘二磺酸(1,5)、亚细亚酸、草酸、酒石酸、乳酸、水杨酸、苯甲酸、戊酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、庚二酸、己二酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、对甲苯磺酸、柠檬酸，以及氨基酸。
术语“溶剂合物”指本发明化合物与药学上可接受的溶剂形成溶剂合物，其中，所述药学上可接受的溶剂包括但并不限于水、乙醇、甲醇、异丙醇、丙二醇、四氢呋喃、二氯甲烷。
术语“立体异构体”指本发明化合物所涉及手性碳原子可以为R构型，也可以为S构型，或其组合。
本发明提供了一种结构新颖的季铵盐类化合物及其制备方法与用途，该化合物具有起效快，单次给药后具有长时间局部麻醉(大于24小时，且大多数化合物局部麻醉时间超过40小时)的效果，具有神经阻滞选择性(感觉神经阻滞时间大于运动神经阻滞时间，且相差时间大于或等于5小时，且大多数化合物相差时间大于10小时)，兼具长效局部麻醉作用和选择性局部麻醉作用，显著降低了QX314、QX314组合物以及具有表面活性剂结构特征季铵盐类化合物的副作用，具有更好的安全性，即本发明化合物及其药学上可接受的盐，可用于制备安全的、具有长时间局部麻醉和选择性局部麻醉作用的药物，具有局部麻醉作用时间长、局部麻醉神经选择性好、神经损伤更小、安全性高的优点。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1、本发明化合物的制备
Figure PCTCN2020073387-appb-000009
化合物1a(5.0g,45.39mmol)溶于15mL的1,3-二溴丙烷，加热至75℃反应40h，TLC监测(DCM:MeOH＝10:1，R f＝0.3)。加入适量的乙酸乙酯，生成粘稠的糖浆状物质，倾出上层清液，剩余粗产品6g，使用30mL甲醇溶解后与硅胶进行拌样，干法上样后硅胶柱柱层析纯化。洗脱剂为CH 2Cl 2:MeOH＝10:1，收集洗脱液，浓缩得粗产品3g。乙酸乙酯和二氯甲烷重结晶，制备得到2.5g类白色固体粉末(1b)，产率：31.6％，用于下一步反应。
将上述制备得到的中间体1b(2.00g,3.66mmol)、N-(2,6-二甲基苯基) -2-哌啶甲酰胺(0.934g,4.03mmol，CAS:15883-20-2)溶于20mL的乙醇中，加入DIPEA(0.94g,1.21mL,7.32mmol)，升温至80℃，加热40小时，蒸干溶剂，粗产品硅胶柱柱层析纯化，洗脱剂为CH 2Cl 2:MeOH＝10:1，收集洗脱液，浓缩得1.2g白色固体(1)。产率：48.9％。 1H NMR(300MHz,CDCl 3)δ(ppm):10.35(s,1H),7.84(s,1H),7.11–7.01(m,6H),4.89(s,2H),3.80–3.45(m,7H),2.71-2.57(m,4H),2.28-2.17(m,12H),1.90-1.63(m,8H),1.60-1.27(m,12H),1.02-0.87(m,6H).HRMS:[C 37H 59N 4O 2] +,591.9048.
实施例2、本发明化合物的制备
Figure PCTCN2020073387-appb-000010
化合物2a(2.0g,40.32mmol)溶于5mL的双(2-溴乙基)醚中，加热至75℃反应24h，TLC监测(DCM：MeOH＝10：1，R f＝0.3)。加入适量的乙酸乙酯，反应液固化有白色固体产生，滤出粗产品3g白色固体，硅胶柱层析纯化。洗脱剂为CH 2Cl 2:MeOH＝20:1，收集洗脱液，浓缩得到5.9g白色固体(2b)，产率：31.5％，用于下一步反应。
上述制备得到的中间体2b(1.0g，2.16mmol)、N-(2,6-二甲基苯基)-2-哌啶甲酰胺(0.55g，2.37mmol，CAS:15883-20-2)溶于15mL的乙醇，加入DIPEA(0.53g，0.68ml，4.12mol)，30℃反应10天，蒸干溶剂，粗产品硅胶柱层析纯化，洗脱剂为CH 2Cl 2:MeOH＝10:1，收集洗脱液，浓缩得995mg白色粉末状固体(2)。产率：75.1％。 1H NMR(300MHz,CDCl 3)δ(ppm):9.79(s,1H),7.60(s,1H),7.02-6.90(m,6H),4.33(s,2H),3.63-3.41(m,3H),3.25-3.01(m,6H),2.87-2.68(m,6H),2.08(s,6H),2.07(s,6H),1.89-1.74(m,6H),1.60-1.40(m,4H),1.40-1.20(m,28H),1.05-0.88(m,6H).HRMS:[C 48H 81N 4O 3] +,763.2013.
实施例3、本发明化合物的制备
Figure PCTCN2020073387-appb-000011
化合物3a(500mg，1.2mmol)，1,14-二溴十四烷(2g,6.0mmol)溶于5mL乙腈中，加热至70℃反应24h，TLC监测(DCM：MeOH＝20:1，R f＝0.3)。加入适量的乙酸乙酯，反应液固化有白色固体产生，滤出粗产品0.9g白色固体，硅胶柱层析纯化。洗脱剂为CH 2Cl 2:MeOH＝20:1，收集洗脱液，浓缩 得到500mg白色粉末状固体(3b)，产率：54.1％，用于下一步反应。
上述制备得到的中间体3b(500mg，0.65mmol)、3c(0.18g，0.71mmol)溶于30ml的乙醇和5ml甲醇混合溶剂，加入DIPEA(0.17g，0.21mL，1.3mmol)，30℃反应10天。待反应完全后硅胶柱层析纯化。洗脱剂为CH 2Cl 2:MeOH＝10:1，收集洗脱液，浓缩得到白色粉末状固体产品(3)400mg，产率：39.6％。 1H NMR(300MHz,CDCl 3)δ(ppm):10.24(s,1H),8.39(s,1H),7.05-6.87(m,5H),4.38(s,2H),3.60-3.50(m,4H),3.30-3.05(m,3H),2.45-2.32(m,4H),2.26(s,3H),2.17-2.14(m,12H),2.05-1.83(m,8H),1.55-1.23(m,48H),1.02-0.83(m,6H).HRMS:[C 56H 97N 4O 2] +,858.4177.
实施例4、本发明化合物的制备
Figure PCTCN2020073387-appb-000012
化合物4a(1g,2.7mmol)溶于3mL的溴代-三聚乙二醇，加热至75℃反应40h，TLC监测(DCM：MeOH＝10：1)。加入适量的乙酸乙酯，生成粘稠的糖浆状物质，倾出上层清液，剩余固体溶解拌样，硅胶柱层析纯化。洗脱剂为CH 2Cl 2:MeOH＝10:1,收集洗脱液，浓缩得粗产品1.6g。乙酸乙酯和二氯甲烷重结晶，制备得到1.2g类白色固体粉末(4b)，直接用于下一步反应。
将上述制备得到的中间体4b(1.00g,1.54mmol)、4c(420mg,1.7mmol)溶于10mL的乙醇，加入DIPEA(0.88mL,5.3mmol)，升温至80℃，加热40小时。蒸干溶剂，粗产品硅胶柱层析纯化，洗脱剂为CH 2Cl 2:MeOH＝10:1，收集洗脱液，浓缩得500mg白色固体(4)。收率：39.7％。 1H NMR(300MHz,CDCl 3)δ(ppm):10.50(s,1H),9.19(s,1H),8.13(s,1H),7.11–7.01(m,4H),4.73(s,2H),3.81-3.73(m,6H),3.56-3.23(s,13H),2.53-2.40(m,3H),2.27(s,6H),2.23(s,6H),2.95-1.78(m,8H),1.42-1.29(s,14H),0.99-0.88(m,6H).HRMS:[C 43H 71N 4O 6] +,740.0623.
实施例5、本发明化合物的制备
Figure PCTCN2020073387-appb-000013
化合物5a(5.0g,13.7mmol)溶于10mL的1,8-二溴辛烷中，加热至70℃反应，TLC监测反应(DCM：MeOH＝10：1)。待反应完全后，蒸干溶剂，粗产品硅胶柱层析纯化。洗脱剂为CH 2Cl 2:MeOH＝20:1，收集洗脱液，浓缩 得黑褐色化合物5g(5b)，产率：57.5％，进行下一步反应。
将上述制备得到的中间体5b(1g，1.58mmol)、5c(0.40g，1.74mmol)溶于15mL的乙醇，加入DIPEA(0.52ml，3.15mmol)，30℃反应13天，TLC监测反应(DCM:MeOH＝10:1)。待反应完全后，蒸干溶剂，粗产品硅胶柱层析纯化，洗脱剂为CH 2Cl 2:MeOH＝10:1，收集洗脱液，浓缩得600mg白色固体(5)。产率：48.8％。 1H NMR(300MHz,CDCl 3)δ(ppm):9.81(s,1H),8.69(s,1H),7.06–6.90(m,5H),4.64(s,2H),3.81-3.76(m,4H),3.41-3.22(m,11H),3.07-2.95(m,1H),2.65-2.42(m,4H),2.15-1.95(m,12H),1.80-1.60(m,10H),1.60-1.12(m,14H),1.01-0.88(m,6H).HRMS:[C 43H 71N 4O 4] +,708.0641.
实施例6、本发明化合物的制备
Figure PCTCN2020073387-appb-000014
化合物6a(2.0g,5.28mmol)溶于8mL的1,6-二溴己烷，加热至75℃反应30h，TLC监测(DCM:MeOH＝10:1，R f＝0.3)。加入适量的乙酸乙酯，生成粘稠的糖浆状物质，倾出上层清液，剩余粗产品3g，使用30mL甲醇溶解后与硅胶进行拌样，干法上样后硅胶柱柱层析纯化。洗脱剂为CH 2Cl 2:MeOH＝10:1，收集洗脱液，浓缩得粗产品1.5g。乙酸乙酯和二氯甲烷重结晶，制备得到1.2g类白色固体粉末(6b)，产率：36.6％，用于下一步反应。
将上述制备得到的中间体6b(1.00g,1.61mmol)、6c(0.44g,1.77mmol)溶于10mL的乙醇中，加入DIPEA(0.42g,0.53mL,3.22mmol)，升温至80℃，加热50小时。蒸干溶剂，粗产品硅胶柱柱层析纯化，洗脱剂为CH 2Cl 2:MeOH＝10:1，收集洗脱液，浓缩得400mg白色固体(6)。产率：31.6％。 1H NMR(300MHz,CDCl 3)δ(ppm):10.35(s,1H),9.89(s,1H),7.84(m,3H),7.11-7.01(m,2H),4.77(s,2H),3.51-3.45(m,3H),3.28-3.19(m,6H),2.71-2.57(m,4H),2.28-2.07(m,15H),2.02(m,1H),1.90-1.63(m,12H),1.60-1.27(m,13H),0.95-0.88(m,3H).HRMS:[C 41H 66N 5O 5] +,709.0084.
实施例7、本发明化合物的制备
Figure PCTCN2020073387-appb-000015
化合物7a(2.0g,5.11mmol)溶于10mL的1,5-二溴戊烷，加热至75℃反应50h，TLC监测(DCM：MeOH＝10：1)。加入适量的乙酸乙酯，生成粘稠的糖浆状物质，倾出上层清液，剩余固体溶解拌样，硅胶柱层析纯化。洗脱剂为CH 2Cl 2:MeOH＝10:1，收集洗脱液，浓缩得粗产品2.0g。乙酸乙酯和二氯甲烷重结晶，制备得到1.4g类白色固体粉末(7b)，直接用于下一步反应。
将上述制备得到的中间体7b(1.00g,1.58mmol)、7c(431mg,1.74mmol)溶于10mL的乙醇，加入DIPEA(0.52mL,3.16mmol)，升温至80℃，加热40小时。蒸干溶剂，粗产品硅胶柱层析纯化，洗脱剂为CH 2Cl 2:MeOH＝10:1，收集洗脱液，浓缩得450mg白色固体(7)。收率：37.0％。 1H NMR(300MHz,CDCl 3)δ(ppm):9.58(s,1H),8.13(s,1H),7.11-7.01(m,4H),4.85(s,2H),3.77(s,3H),3.65-3.42(s,5H),3.31-3.24(m,4H),2.86-2.79(m,2H),2.43-2.18(m,9H),2.15-2.08(m,9H),2.17-1.96(m,4H),1.76(s,8H),1.60-1.42(m,12H).HRMS:[C 41H 64N 5O 4S] +,723.0535.
实施例8、本发明化合物的制备
Figure PCTCN2020073387-appb-000016
化合物8a(2.0g，4.85mmol)溶于4mL的1,7-二溴庚烷，加热至70℃反应48h，TLC监测(DCM：MeOH＝20:1，R f＝0.3)。加入适量的乙酸乙酯，反应液固化有白色固体产生，滤出粗产品3.0g白色固体，硅胶柱层析纯化。洗脱剂为CH 2Cl 2:MeOH＝20:1，收集洗脱液，浓缩得到1.6g白色粉末状固体(8b)，产率：49.3％，用于下一步反应。
上述制备得到的中间体8b(1.5g，2.24mmol)、8c(0.61g，2.47mmol)溶于30ml的乙醇和5ml甲醇混合溶剂，加入DIPEA(0.58g，0.74ml，4.48mmol)，30℃反应12天。待反应完全后硅胶柱层析纯化。洗脱剂为CH 2Cl 2:MeOH＝10:1，收集洗脱液，浓缩得到白色粉末状固体产品600mg，产率：32.1％。 1H NMR(300MHz,CDCl 3)δ(ppm):10.02(s,1H),9.89(s,1H),7.23-6.87(m,5H),4.48(s,2H),3.60-3.50(m,3H),3.45-3.33(m,6H),2.63-2.40(m,6H),2.17-2.14(m,12H),1.93-1.75(m,11H),1.49-1.31(m,22H),0.92-0.83(m,3H).HRMS:[C 44H 72ClN 4O 2S] +,756.5955.
实施例9、本发明化合物的制备
Figure PCTCN2020073387-appb-000017
化合物9a(3.0g,6.2mmol)、9b(8g,31mmol)，加热至75℃反应40h，TLC监测(DCM:MeOH＝10:1，R f＝0.3)。加入适量的乙酸乙酯，生成粘稠的糖浆状物质，倾出上层清液，剩余粗产品4.5g，使用30mL甲醇溶解后与硅胶进行拌样，干法上样后硅胶柱柱层析纯化。洗脱剂为CH 2Cl 2:MeOH＝10:1，收集洗脱液，浓缩得粗产品2.5g。乙酸乙酯和二氯甲烷重结晶，制备得到2.0g类白色固体粉末(9c)，产率：43.4％,用于下一步反应。-
将上述制备得到的中间体9c(1.00g,1.35mmol)、9d(0.344g,1.48mmol)溶于10mL的乙醇中，加入DIPEA(0.35g,0.45mL,2.70mmol)，升温至80℃，加热40小时。蒸干溶剂，粗产品硅胶柱柱层析纯化，洗脱剂为CH 2Cl 2:MeOH＝10:1，收集洗脱液，浓缩得400mg白色固体(9)。产率：33.2％。 1H NMR(300MHz,CDCl 3)δ(ppm):10.05(s,1H),7.84(s,1H),7.11–7.01(m,5H),4.15(s,2H),3.60-3.35(m,7H),3.25-3.18(s,8H),2.45-2.21(m,8H),2.14-2.03(m,12H),1.91-1.56(m,12H),1.46-1.23(m,14H).HRMS:[C 44H 70BrN 4O 6] +,830.9697.
实施例10、本发明化合物的制备
Figure PCTCN2020073387-appb-000018
将实施例1产物200mg溶解于二氯甲烷10mL，冰浴下滴加等物质的量浓度的0.1mol/L的盐酸-甲醇溶液，减压浓缩至干。真空干燥，得到淡黄色固体(10)。产率97.5％。 1H NMR(300MHz,CDCl 3)δ(ppm):10.33(s,1H),8.68(s,1H),7.19-7.11(m,6H),4.93(s,2H),3.76-3.38(m,7H),2.70-2.59(m,4H),2.27-2.18(m,12H),1.91-1.61(m,8H),1.64-1.27(m,12H),1.10-0.88(m,6H).HRMS:[C 37H 59N 4O 2] +,591.9047.
实施例11、本发明化合物的制备
Figure PCTCN2020073387-appb-000019
将实施例9产物200mg溶解于二氯甲烷10mL，加入1eq的对甲苯磺酸，减压浓缩至干。真空干燥，得到淡黄色固体(11)。产率92.5％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.03(s,1H),8.92(s,1H),7.13–7.02(m,5H),4.19(s,2H),3.62-3.37(m,7H),3.27-3.19(s,8H),2.48-2.23(m,8H),2.17-2.06(m,12H),1.94-1.58(m,12H),1.46-1.24(m,14H).HRMS:[C 44H 70BrN 4O 6] +,830.9699.
实施例12、本发明化合物的制备
Figure PCTCN2020073387-appb-000020
参照实施例6方法，得到类白色固体粉末，产率：35.2％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.30(s,1H),9.89(s,1H),7.33(m,6H),4.72(s,1H),4.25(s,2H),3.67(t,2H),3.45(t,1H),3.26-3.18(m,6H),2.51-2.37(m,4H),2.13(s,12H),2.02(m,2H),1.90-1.63(m,6H),1.60-1.27(m,18H),0.95-0.88(m,3H).HRMS:[C 40H 65N 4O 3] +,649.9843.
实施例13、本发明化合物的制备
Figure PCTCN2020073387-appb-000021
参照实施例6方法，得到类白色固体粉末，产率：37.0％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.28(s,1H),9.99(s,1H),7.30(m,6H),4.31(s,1H),4.24(s,2H),3.95(m,2H),3.40-3.46(m,3H),3.24-3.16(m,4H),2.47-2.41(m,4H),2.12(s,12H),1.90-1.63(m,6H),1.57-1.28(m,14H),0.88(t,3H).HRMS:[C 37H 59N 4O 3] +,607.9031.
实施例14、本发明化合物的制备
Figure PCTCN2020073387-appb-000022
参照实施例6方法，得到类白色固体粉末，产率：38.9％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.07(s,1H),9.73(s,1H),7.11(m,6H),4.38(s,1H),4.18(s,2H),3.42-3.52(m,3H),3.26-3.14(m,6H),2.47-2.41(m,4H),2.15(s,12H),1.93-1.68(m,8H),1.55-1.27(m,14H),0.86(t,3H).HRMS:[C 38H 61N 4O 3] +,621.9341.
实施例15、本发明化合物的制备
Figure PCTCN2020073387-appb-000023
参照实施例6方法，得到类白色固体粉末，产率：33.2％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.28(s,1H),9.98(s,1H),7.32(m,6H),5.47(s,2H),4.23(s,2H),4.12(s,1H),3.40-3.44(t,1H),3.24-3.17(m,4H),2.43-2.38(m,4H),2.12(s,12H),1.90-1.63(m,6H),1.57-1.28(m,14H),0.88(t,3H).HRMS:[C 36H 57N 4O 3] +,593.8762.
实施例16、本发明化合物的制备
Figure PCTCN2020073387-appb-000024
参照实施例6方法，得到类白色固体粉末，产率：40.2％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.08(s,1H),9.89(s,1H),7.06(m,6H),4.18(s,2H),4.12(s,1H),3.52-3.45(m,3H),3.26-3.18(m,6H),2.53-2.39(m,4H),2.16(s,12H),2.05(m,2H),1.90-1.72(m,6H),1.61-1.28(m,16H),0.92-0.87(m,3H).HRMS:[C 39H 63N 4O 3] +,635.9577.
实施例17、本发明化合物的制备
Figure PCTCN2020073387-appb-000025
参照实施例6方法，得到类白色固体粉末，产率：36.1％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.11(s,1H),9.88(s,1H),7.05(m,6H),4.28(s,2H),4.15(s,2H),3.97-3.84(m,4H),3.51-3.42(m,5H),3.26-3.11(m,2H),2.47-2.32(m,4H),2.16(s,12H),1.92-1.72(m,4H),1.63-1.28(m,10H).HRMS:[C 34H 53N 4O 4] +,581.8216.
实施例18、本发明化合物的制备
Figure PCTCN2020073387-appb-000026
参照实施例6方法，得到类白色固体粉末，产率：36.1％。
1H NMR(300MHz,CDCl 3)δ(ppm):9.96(s,1H),9.72(s,1H),7.02(m,6H),4.28(s,1H),4.18(m,2H),4.14(s,1H),3.51-3.42(m,5H),3.21-3.11(m,6H),2.47-2.30(m,4H),2.15(s,12H),1.97-1.71(m,8H),1.66-1.26(m,12H).HRMS:[C 37H 59N 4O 4] +,623.9029.
实施例19、本发明化合物的制备
Figure PCTCN2020073387-appb-000027
参照实施例6方法，得到类白色固体粉末，产率：42.2％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.02(s,1H),9.87(s,1H),7.03(m,6H),5.48(s,2H),4.18(s,2H),4.15(s,2H),3.52-3.45(m,3H),3.26-3.18(m,4H),2.47-2.39(m,4H),2.16(s,12H),1.92-1.73(m,6H),1.57-1.28(m,12H).HRMS:[C 35H 55N 4O 4] +,675.7533.
实施例20、本发明化合物的制备
Figure PCTCN2020073387-appb-000028
参照实施例5方法，得到类白色固体粉末，产率：33.6％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.01(s,1H),9.88(s,1H),7.08-6.98(m,6H),4.25(s,2H),3.81(t,2H),3.51-3.28(m,5H),3.21-2.99(m,4H),2.52-2.41(m,4H),2.13-1.98(m,12H),1.85-1.65(m,6H),1.53-1.14(m,14H),1.04(t,3H),0.87(t,3H).HRMS:[C 39H 63N 4O 3] +,635.9579.
实施例21、本发明化合物的制备
Figure PCTCN2020073387-appb-000029
参照实施例5方法，得到白色固体粉末，产率：28.5％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.08(s,1H),9.75(s,1H),7.06-6.93(m,6H),4.53(s,2H),3.84-3.78(m,4H),3.42-3.28(m,5H),3.05-2.96(m,8H),2.72-2.49(m,4H),2.16-1.90(m,12H),1.80-1.63(m,4H),1.53-1.12(m,10H).HRMS:[C 36H 57N 4O 4] +,689.7804.
实施例22、本发明化合物的制备
Figure PCTCN2020073387-appb-000030
参照实施例5方法，得到白色固体粉末，产率：30.2％。
1H NMR(300MHz,CDCl 3)δ(ppm):9.92(s,1H),8.76(s,1H),7.06-6.90(m,6H),4.53(s,2H),3.41-3.22(m,9H),3.07-2.95(m,6H),2.66-2.42(m,4H),2.16-1.92(m,12H),1.80-1.63(m,8H),1.53-1.12(m,10H),1.05-0.89(m,6H).HRMS:[C 40H 65N 4O 4] +,665.9831.
实施例23、本发明化合物的制备
Figure PCTCN2020073387-appb-000031
参照实施例5方法，得到类白色固体粉末，产率：35.2％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.02(s,1H),9.65(s,1H),7.08-6.98(m,6H),4.25(s,2H),3.50-3.33(m,3H),3.26–3,08(m,9H),2.48-2.36(m,4H),2.16–2.05(m,12H),1.85-1.65(m,8H),1.52-1.17(m,14H),0.88(t,3H).HRMS:[C 39H 63N 4O 3] +,635.9571.
实施例24、本发明化合物的制备
Figure PCTCN2020073387-appb-000032
参照实施例3方法，得到白色固体粉末，产率：43.2％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.04(s,1H),9.39(s,1H),7.05-6.88(m,5H),4.38(s,2H),3.65-3.54(m,4H),3.33-3.09(m,3H),2.45-2.32(m,4H),2.29(s,3H),2.18-2.15(m,12H),2.05-1.83(m,8H),1.48-1.20(m,44H),1.01-0.83(m,6H).HRMS:[C 54H 93N 4O 2] +,830.3031.
实施例25、本发明化合物的制备
Figure PCTCN2020073387-appb-000033
参照实施例5方法，得到类白色固体粉末，产率：30.1％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.01(s,1H),9.88(s,1H),7.08-6.98(m,6H),4.25(s,2H),3.81(t,2H),3.65(t,1H),3.51-3.42(m,4H),3.31–3.13(m,4H),2.52-2.21(m,4H),2.14-2.02(m,12H),1.85-1.49(m,6H),1.43-1.14(m,22H),1.05(t,3H),0.88(t,3H).HRMS:[C 43H 71N 4O 3] +,692.0656.
实施例26、本发明化合物的制备
Figure PCTCN2020073387-appb-000034
参照实施例6方法，得到类白色固体粉末，产率：38.2％。
1H NMR(300MHz,CDCl 3)δ(ppm):9.75(s,1H),7.98(s,1H),7.05(m,6H),4.21(s,2H),4.12(s,1H),3.63(t,1H),3.52-3.45(m,2H),3.26-3.18(m,6H),2.53-2.39(m,4H),2.16(s,12H),1.90-1.72(m,10H),1.61-1.28(m,18H),0.92-0.87(m,3H).HRMS:[C 41H 67N 4O 3] +,664.0112.
实施例27、本发明化合物的制备
Figure PCTCN2020073387-appb-000035
参照实施例7方法，得到类白色固体粉末，产率：35.8％。
1H NMR(300MHz,CDCl 3)δ(ppm):9.76(s,1H),8.29(s,1H),7.18-7.01(m,6H),4.85(s,2H),3.61(t,2H),3.45(t,1H),3.31-3.24(m,4H),2.86(t,2H),2.43-2.18(m,6H),2.15-2.10(m,12H),2.05-1.76(m,8H),1.60-1.22(m,10H),1.15(t,3H),0.86(t,3H).HRMS:[C 38H 61N 4O 2S] +,637.9918.
实施例28、本发明化合物的制备
Figure PCTCN2020073387-appb-000036
参照实施例8方法，得到类白色固体粉末，产率：35.8％。
产率：32.1％。 1H NMR(300MHz,CDCl 3)δ(ppm):10.02(s,1H),9.89(s,1H),7.23-6.87(m,6H),4.33-4.14(m,4H),3.60-3.49(m,4H),3.33-3.28(m,6H),2.63-2.39(m,6H),2.15-2.11(m,12H),1.93-1.75(m,6H),1.49- 1.31(m,4H),1.30-1.15(m,7H).HRMS:[C 36H 57ClN 4O 3S] +,625.9327.
实施例29、本发明化合物的制备
Figure PCTCN2020073387-appb-000037
参照实施例2方法，得到类白色固体粉末，产率：35.8％。
1H NMR(300MHz,CDCl 3)δ(ppm):11.88(s,1H),9.79(s,1H),8.78(s,1H),7.09-6.98(m,6H),4.25(s,2H),3.52-3.40(m,5H),3.27-3.21(m,4H),2.54-2.36(m,8H),2.22-2.07(s,16H),1.89-1.74(m,6H),1.60-1.40(m,10H),1.40-1.20(m,6H),0.98(t,3H).HRMS:[C 43H 69N 4O 5] +,754.1078.
实施例30、本发明化合物的制备
Figure PCTCN2020073387-appb-000038
参照实施例1方法，得到类白色固体粉末，产率：36.3％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.35(s,1H),9.70(s,1H),7.11-7.02(m,6H),4.26(s,2H),3.88-3.67(m,4H),3.68-3.45(m,5H),2.71-2.57(m,6H),2.28-2.17(m,12H),1.90-1.63(m,4H),1.60-1.27(m,6H).HRMS:[C 32H 47N 4O 3] +,535.7521.
实施例31、本发明化合物的制备
Figure PCTCN2020073387-appb-000039
参照实施例1方法，得到类白色固体粉末，产率：34.2％。
1H NMR(300MHz,CDCl 3)δ(ppm):9.72(s,1H),8.60(s,1H),7.07-7.02(m,6H),4.18(s,2H),4.02(m,2H),3.54-3.33(m,7H),2.52-2.38(m,4H),2.18-2.06(m,12H),1.90-1.63(m,4H),1.60-1.27(m,18H),1.12-1.03(m,6H).HRMS:[C 40H 63N 4O 3] +,647.9683.
实施例32、本发明化合物的制备
Figure PCTCN2020073387-appb-000040
参照实施例2方法，得到类白色固体粉末，产率：28.5％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.02(s,1H),9.35(s,1H),7.11-7.01(m,6H),4.20(s,2H),4.03(m,2H),3.51-3.35(m,11H),2.45-2.39(m,4H),2.15-2.11(m,12H),1.99-1.72(m,4H),1.57-1.41(m,6H),1.18-1.13(m,6H).HRMS:[C 36H 55N 4O 4] +,607.8599.
实施例33、本发明化合物的制备
Figure PCTCN2020073387-appb-000041
参照实施例3方法，得到类白色固体粉末，产率：39.1％。
1H NMR(300MHz,CDCl 3)δ(ppm):11.87(s,1H),10.02(s,1H),9.69(s,1H),7.04(s,3H),6.91-6.85(m,2H),4.27(s,2H),3.51-3.29(m,7H),2.66–2.45(m,6H),2.31-2.18(m,2H),2.12(d,12H),1.98-1.63(m,12H),1.60-1.27(m,21H).HRMS:[C 44H 70FN 4O 4S] +,770.1255.
实施例34、本发明化合物的制备
Figure PCTCN2020073387-appb-000042
参照实施例5方法，得到类白色固体粉末，产率：33.4％。
1H NMR(300MHz,CDCl 3)δ(ppm):10.06(s,1H),9.77(s,1H),7.18-7.01(m,3H),6.85-6.74(m,2H),4.24(s,1H),3.97(t,2H),3.81(t,2H),3.58-3.16(m,11H),2.43-2.18(m,4H),2.15-2.10(m,12H),2.05-1.76(m,4H),1.61-1.29(m,10H),1.05(t,3H).HRMS:[C 37H 56F 3N 4O 4] +,677.8732.
按照上述实施例的制备方法，还制备得到以下化合物35～76(对应实施例35～实施例76)：
Figure PCTCN2020073387-appb-000043
Figure PCTCN2020073387-appb-000044
Figure PCTCN2020073387-appb-000045
Figure PCTCN2020073387-appb-000046
Figure PCTCN2020073387-appb-000047
以下通过具体的试验例证明本发明化合物的有益效果。
试验例1、本发明化合物的局部麻醉效果
选取实施例制备的化合物1-76、利多卡因(阳性对照组)、左布比卡因(阳性对照组)分别给予完全适应实验环境的250～300克体重的SD大鼠(雌雄各半)，每组大鼠8只。
给药剂量：利多卡因组将利多卡因用蒸馏水配制成浓度为2％(74mmol/L)的溶液，左布比卡因组将左布比卡因用蒸馏水配制成浓度为0.75％(22mmol/L)的溶液，本发明化合物用蒸馏水配制成浓度为20mmol/L的溶液。
每只大鼠给药注射的体积为0.5ml，通过神经定位器导向定位，注射于大鼠坐骨神经附近。通过von Frey刺激仪，刺激大鼠注射药物体侧足底，观测局部麻醉效果。同时，由后肢蹬踏试验(Postural Extensor Thrust,PET)评价大鼠运动功能情况：垂直提起大鼠并使注射侧后肢蹬在电子天平台面上，此时大鼠后肢肌力由肢体蹬踏天平而显示出的数值表示。肢体完全麻痹时，读数为肢体自身重量，约20g。测量值超过基线与肢体重量差值的一半视为运动功能恢复，小于或等于该值视为运动功能消失。
表1.本发明化合物的局部麻醉效果
待测药物 局麻起效时间 感觉阻滞持续时间 运动阻滞持续时间
实施例1产物 3min 32h 21h
实施例2产物 4min 44h 33h
实施例3产物 4min 35h 24h
实施例4产物 7min 23h 13h
实施例5产物 4min 26h 15h
实施例6产物 1min 34h 29h
实施例7产物 5min 26h 16h
实施例8产物 4min 43h 18h
实施例9产物 4min 34h 15h
实施例10产物 3min 25h 19h
实施例11产物 5min 34h 16h
实施例12产物 5min 42h 11h
实施例13产物 4min 55h 14h
实施例14产物 5min 41h 13h
实施例15产物 5min 44h 16h
实施例16产物 5min 60h 17h
实施例17产物 5min 37h 18h
实施例18产物 2min 38h 16h
实施例19产物 5min 39h 10h
实施例20产物 5min 54h 14h
实施例21产物 5min 47h 13h
实施例22产物 3min 47h 15h
实施例23产物 5min 54h 14h
实施例24产物 4min 54h 11h
实施例25产物 5min 44h 12h
实施例26产物 5min 45h 16h
实施例27产物 3min 37h 15h
实施例28产物 2min 39h 14h
实施例29产物 5min 50h 15h
实施例31产物 5min 45h 19h
实施例32产物 2min 46h 17h
实施例33产物 5min 49h 16h
实施例34产物 5min 45h 9h
实施例35产物 2min 54h 13h
实施例36产物 5min 52h 21h
实施例37产物 1min 45h 17h
实施例38产物 1min 43h 19h
实施例39产物 3min 61h 19h
实施例40产物 2min 53h 13h
实施例41产物 2min 46h 11h
实施例42产物 5min 56h 11h
实施例43产物 5min 59h 12h
实施例44产物 5min 69h 16h
实施例45产物 3min 58h 20h
实施例46产物 5min 49h 14h
实施例47产物 3min 65h 17h
实施例48产物 5min 57h 15h
实施例49产物 4min 45h 20h
实施例50产物 5min 56h 13h
实施例51产物 5min 44h 19h
实施例52产物 2min 56h 15h
实施例53产物 5min 59h 16h
实施例54产物 5min 66h 15h
实施例55产物 1min 55h 16h
实施例56产物 1min 54h 18h
实施例57产物 5min 69h 13h
实施例58产物 3min 57h 16h
实施例59产物 1min 54h 15h
实施例60产物 1min 54h 20h
实施例61产物 3min 6 1h 11h
实施例62产物 5min 51h 21h
实施例63产物 3min 64h 14h
实施例64产物 3min 67h 13h
实施例65产物 5min 59h 19h
实施例66产物 1min 60h 10h
实施例67产物 1min 67h 14h
实施例68产物 1min 79h 21h
实施例69产物 1min 62h 10h
实施例70产物 2min 53h 17h
实施例71产物 1min 60h 19h
实施例72产物 1min 65h 10h
实施例73产物 3min 51h 20h
实施例74产物 1min 72h 17h
实施例75产物 1min 61h 14h
实施例76产物 3min 59h 14h
0.75％盐酸左布比卡因 1min 2.5h 2.5h
2％盐酸利多卡因 1min 1h 1h
实验结果表明，本发明化合物能够产生大于24小时的局部麻醉作用，同时感觉神经阻滞时间显著小于运动神经阻滞时间，且相差时间大于或等于5小时，其中大多数化合物相差时间大于或等于10小时。
试验例2、本发明化合物的皮下浸润局部麻醉效果
250～300克体重的SD大鼠(雌雄各半)背部剃毛消毒后，在裸露的背部一侧画出直径约1.5厘米圆形，并将圆形进行6等分。在中心的皮肤处皮下注射含有药物的溶液0.5mL：以生理盐水为溶剂，0.75％盐酸布比卡因(22mmol/L)，2％盐酸利多卡因(74mmol/L)，本发明化合物1-76浓度为6mmol/L，每组10只大鼠。将Von Frey纤维丝中100克力度的纤维丝与针头绑定进行皮肤局部刺激。药物注射1min后，使用上述方法在6个划分范围内进行刺激，若在同一等分范围内的连续3次刺激均未出现背部皮肤收缩行为，视为药效效应阳性，若出现背部皮肤收缩则视为局部麻醉效应消失。6个等分范围中有4个或4个以上区域显示局部麻醉阳性，则视为药物的局部麻醉有效，6个等分范围中少于4个区域显示阳性，视为局部麻醉失效。每种化合物使用10只大鼠进行实验。
表2.本发明化合物的皮下浸润局部麻醉效果
Figure PCTCN2020073387-appb-000048
Figure PCTCN2020073387-appb-000049
Figure PCTCN2020073387-appb-000050
实验结果表明，该类药物在大鼠皮下浸润模型中能够产生大于24小时的局部麻醉作用，其中大部分化合物能产生大于40小时的局部麻醉作用。
试验例3、本发明化合物神经病理损伤评估
选取实施例制备的化合物1-76，利多卡因阳性对照组、左布比卡因阳性对照组分别给予完全适应实验环境的250～300克体重的SD大鼠(雌雄各半)受试大鼠，每组8只。
给药剂量：利多卡因组将利多卡因用蒸馏水配制成浓度为2％(74mmol/L)的溶液，左布比卡因组将左布比卡因用蒸馏水配制成浓度为0.75％(22mmol/L)的溶液，本发明化合物用蒸馏水配制成浓度为20mmol/L的溶液。
每只大鼠给药注射的体积为0.5ml，注射于大鼠坐骨神经附近。在坐骨神经注射后第7天和第14天，将实验大鼠异氟醚麻醉下心脏注射布比卡因安乐死。取注射部位坐骨神经约1.5cm，保存于10％甲醛溶液中48h，HE染色并切成5μm厚度的切片。
给药剂量为：利多卡因组将利多卡因用蒸馏水配制成浓度为2％(74mmol/L)的溶液，左布比卡因组将左布比卡因用蒸馏水配制成浓度为0.75％(22mmol/L)的溶液，本发明化合物用蒸馏水配制成浓度为6mmol/L的溶液。
每只大鼠给药注射的注射体积为0.5ml，注射于大鼠背部皮下。在皮下注射后第7天和第14天，将实验大鼠异氟醚麻醉下心脏注射布比卡因安乐死。取注射部位皮肤组织，保存于10％甲醛溶液中48h，HE染色并切成5μm厚度的切片。
神经病理损伤评估显示：实施例化合物与利多卡因阳性对照组、左布比卡因阳性对照组相比，在神经损伤、血管增生、脱髓鞘程度、肌肉炎症、结缔组织炎症程度方面都没有显著差异，具有良好的安全性。
综上，本发明提供了一种结构新颖的季铵盐类化合物及其制备方法与用途，该化合物具有起效快，单次给药后具有长时间局部麻醉(大于24小时，且大多数化合物局部麻醉时间超过40小时)的效果，具有神经阻滞选择性(感觉神经阻滞时间大于运动神经阻滞时间，且相差时间大于或等于5小时，且大多数化合物相差时间大于10小时)，兼具长效局部麻醉作用和选择性局部麻醉作用，显著降低了QX314、QX314组合物以及具有表面活性剂结构特征季铵盐类化合物的副作用，具有更好的安全性，即本发明化合物及其药学上可接受的盐，可用于制备安全的、具有长时间局部麻醉和选择性局部麻醉作用的药物，具有局部麻醉作用时间长、局部麻醉神经选择性好、神经损伤更小、安全性高的优点。

Claims (11)

  1. 式I所示的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物：
    Figure PCTCN2020073387-appb-100001
    式中，
    X、Y各自独立地选自O或NR 10，其中R 10选自H、氘或C 1～C 4烷基；
    Z -为药学上可接受的阴离子；
    R 1选自n 1个R 11取代的芳基；
    R 2选自n 1’个R 11’取代的芳基；
    其中，n 1、n 1’各自独立地选自0～5的整数，R 11、R 11’各自独立地选自氘、C 1～C 4的烷基、C 1～C 4的烷氧基、卤素、硝基、氰基、羟基、羧基、氨基；
    当式Ⅰ中R 3、R 4之间的虚线为无时，R 3选自取代的C 1～C 10烷基或未取代的C 5～C 10烷基，R 4独立的选自取代或未取代的C 1～C 10烷基，所述取代基为氘、取代或未取代的C 1～C 4烷氧基、卤素、硝基、氰基、羟基、羧基、氨基、酯基、C 1～C 6烷硫基、巯基；所述烷氧基的取代基为羟基；
    当式Ⅰ中R 3、R 4之间的虚线为键时，R 3、R 4独立的选自取代或未取代的C 1～C 4亚烷基，所述取代基为C 1～C 3烷基；其中，所述亚烷基的主链上中含有0～4个杂原子，所述杂原子选自O、S、NR 12，其中所述R 12选自氢、氘、C 1～C 4的烷基；
    L 1选自取代或未取代的C 1～C 14的亚烷基；其中，所述亚烷基的主链上中含有0～4个杂原子，所述杂原子选自O、S、NR 12，其中所述R 12选自氢、氘、C 1～C 4的烷基、C 1～C 4的烷氧基；所述取代基为氘、C 1～C 4的烷基、C 1～C 4的烷氧基、卤素；
    式Ⅰ中L 2的虚线为键，L 2选自取代或未取代的C 1～C 8的亚烷基，所述取代基为氘、C 1～C 4的烷基、C 1～C 4的烷氧基、卤素。
  2. 根据权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    X、Y各自独立地选自NH或NCH 3；
    Z -为溴离子、氯离子、磺酸根；
    R 1选自n 1个R 11取代的芳基；
    R 2选自n 1’个R 11’取代的芳基；
    其中，n 1、n 1’各自独立地选自0～5的整数，R 11、R 11’各自独立地选自氘、C 1～C 4的烷基、C 1～C 4的烷氧基、卤素、硝基、氰基、羟基；
    当式Ⅰ中R 3、R 4之间的虚线为无时，R 3选自取代的C 1～C 10烷基或未取代的C 5～C 10烷基，R 4独立的选自取代或未取代的C 1～C 10烷基，所述取代基为氘、取代或未取代的C 1～C 4烷氧基、羟基、羧基、C 2～C 5烷硫基、巯基；所述烷氧基的取代基为羟基；
    当式Ⅰ中R 3、R 4之间的虚线为键时，R 3、R 4独立的选自C 1～C 4亚烷基，其中，所述亚烷基的主链上中含有0～2个杂原子，所述杂原子选自O；
    L 1选自C 3～C 14的亚烷基；其中，所述取代基为烷基，所述亚烷基的主链上中含有0～2个杂原子，所述杂原子选自O、S；
    式Ⅰ中L 2的虚线为键，L 2选自C 1～C 6的亚烷基。
  3. 根据权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    X、Y各自独立地选自NH或NCH 3；
    Z -为溴离子、氯离子、磺酸根；
    R 1选自n 1个R 11取代的芳基；
    R 2选自n 1’个R 11’取代的芳基；
    其中，n 1、n 1’各自独立地选自2～3的整数，R 11、R 11’为甲基、丙基、甲氧基、羟基、硝基、氰基、卤素；
    当式Ⅰ中R 3、R 4之间的虚线为无时，R 3选自取代的C 1～C 8烷基或未取代的C 5～C 10烷基，R 4独立的选自取代或未取代的C 1～C 10烷基，所述取代基为氘、取代或未取代的C 1～C 3烷氧基、羟基、羧基、C 2～C 3烷硫基、巯基；所述烷氧基的取代基为羟基；
    当式Ⅰ中R 3、R 4之间的虚线为键时，R 3、R 4独立的选自取代或未取代的C 2～C 3亚烷基，其中，所述取代基为C 1烷基，所述亚烷基的主链上中含有0～1个杂原子，所述杂原子选自O；
    L 1选自未取代的C 3～C 14的亚烷基；其中，所述亚烷基的主链上中含有0～2个杂原子，所述杂原子选自O、S；
    式Ⅰ中L 2的虚线为键，L 2选自未取代的C 1～C 6的亚烷基。
  4. 根据权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    X、Y各自独立地选自NH；
    Z -为溴离子；
    R 1选自n 1个R 11取代的芳基；
    R 2选自n 1’个R 11’取代的芳基；
    其中，n 1、n 1’各自独立地选自2～3的整数，R 11、R 11’为甲基；
    当式Ⅰ中R 3、R 4之间的虚线为无时，R 3选自取代的C 1～C 8烷基或未取代的C 5～C 10烷基，R 4独立的选自取代或未取代的C 1～C 10烷基；所述烷基的取代基为氘、取代或未取代的C 1～C 3烷氧基、羟基、羧基、C 2～C 3烷硫基、巯基；所述烷氧基的取代基为羟基；
    当式Ⅰ中R 3、R 4之间的虚线为键时，R 3、R 4独立的选自未取代的C 2～C 3亚烷基；其中，所述亚烷基的主链上中含有1个杂原子，所述杂原子选自O；
    L 1选自未取代的C 3～C 14的亚烷基；其中，所述亚烷基的主链上中含有1个杂原子，所述杂原子选自O、S；
    式Ⅰ中L 2的虚线为键，L 2选自未取代的C 2～C 6的亚烷基。
  5. 根据权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物如式II所示：
    Figure PCTCN2020073387-appb-100002
    式中，
    X、Y各自独立地选自NH或NCH 3；
    n 1、n 1’各自独立地选自2～3的整数，R 11、R 11’为甲基、丙基、甲氧基、羟基、硝基、氰基、卤素；
    R 3选自取代的C 1～C 8烷基或未取代的C 5～C 10烷基，R 4独立的选自取代或未取代的C 1～C 10烷基；所述烷基的取代基为氘、取代或未取代的C 1～C 3烷氧基、羟基、羧基、C 2～C 3烷硫基、巯基；所述烷氧基的取代基为羟基；
    L 1选自未取代的C 3～C 14的亚烷基；其中，所述亚烷基的主链上中含有0、1或2个杂原子，所述杂原子选自O、S；
    L 2选自未取代的C 2～C 6的亚烷基。
  6. 根据权利要求5所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物如式III所示：
    Figure PCTCN2020073387-appb-100003
    式中，
    R 3选自取代的C 1～C 5烷基，R 4独立的选自取代或未取代的C 1～C 5烷基；所述烷基的取代基为羟基；
    L 1选自未取代的C 3～C 6的亚烷基；
    L 2选自未取代的C 4的亚烷基。
  7. 根据权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物如式IV所示：
    Figure PCTCN2020073387-appb-100004
    式中，
    X、Y各自独立地选自NH；
    n 1、n 1’各自独立地选自2～3的整数，R 11、R 11’为甲基；
    R 3、R 4独立的选自取代或未取代的C 2～C 3亚烷基；其中，所述取代基为C 1烷基，所述亚烷基的主链上中含有1个杂原子，所述杂原子选自O；
    L 1选自未取代的C 3～C 14的亚烷基；其中，所述亚烷基的主链上中含有0或1个杂原子，所述杂原子选自O、S；
    L 2选自未取代的C 2～C 6的亚烷基。
  8. 根据权利要求1～7任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：化合物的结构为如下化合物之一：
    Figure PCTCN2020073387-appb-100005
    Figure PCTCN2020073387-appb-100006
    Figure PCTCN2020073387-appb-100007
  9. 权利要求1～8任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，与药学上可接受的载体形成的制剂，在制备局部麻醉的药物中的用途。
  10. 根据权利要求9所述的用途，其特征在于：所述局部麻醉的药物使得感觉神经阻滞时间长于运动神经阻滞时间；
    和/或，所述局部麻醉为长效局部麻醉；
    优选地，所述局部麻醉的麻醉时间超过24小时。
  11. 一种药物，其特征在于：它是以权利要求1～8任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物，加上药学上可接受的辅料制备而成的制剂。
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